bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–07–19
eighty papers selected by
Luca Bolliger, lxBio
  1. Engineering CAR-Tregs with Phage-Selected scFv Enables a New Paradigm for Immune Regulation.
  2. Emerging target antigen landscape for CAR T-cell therapy in solid tumors: current advances and future directions.
  3. From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.
  4. Statistical analysis plan considerations for autologous cell and cell-based gene therapy clinical trials.
  5. Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
  6. 3D bioluminescence imaging assays for measuring in vitro CAR T cell cytotoxicity.
  7. Overcoming challenges in the implementation of chimeric antigen receptor (CAR) T-cell therapy in resource-constrained settings: Lessons from Brazil and India.
  8. Designs of the clinical trials aiming at evaluating cell and gene therapy products: A critical appraisal from a literature review.
  9. Engineered Extracellular Vesicles as Programmable Immune Interfaces: Surface and Cargo Engineering for Cancer Immunotherapy and Tolerance.
  10. Breaking the resistance barrier: synergistic evolution of CAR-T cells and bispecific antibodies in the era of precision immuno-oncology.
  11. Patient-operated imaging for clinical assessment: regulatory and reimbursement challenges in European health systems.
  12. Clinical outcomes of Epstein-Barr virus infection/reactivation following CAR-T cell therapy: A systematic review.
  13. Modulating CAR-T cell exhaustion and fitness in acute myeloid leukemia: mechanistic metabolic and microenvironmental strategies.
  14. South America and Mexico's cell and gene therapy landscape: accelerating growth and persistent challenges.
  15. Lessons Learned: Operationalizing Chimeric Antigen Receptor T-Cell Therapy in the Community Oncology Private Practice Healthcare Setting.
  16. Oncology Nurses' Role in Cell and Gene Therapy: Future Expansions and Evolving Foundations.
  17. Integrated Engineering of CAR-T Cells for Solid Tumours.
  18. Feasibility and outcomes of decentralized point-of-care CD19 CAR T cell for relapsed large B cell lymphoma in resource-limited settings.
  19. Nursing Considerations for CAR T-Cell Therapy: Management of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome.
  20. Domains in Health Technology Assessment of Digital Health Technologies: A Mapping Review.
  21. Evidence mapping of concepts, methods, and outcomes in the evaluation of diagnostic and therapeutic technologies for ultra-rare diseases: a systematic scoping review.
  22. Regulatory T-cells technology and vascularized composite allotransplantation: A scoping review.
  23. Low-dose docetaxel reprograms CAR T cells for enhanced solid tumor immunity.
  24. Navigating Acute and Late-Onset Toxicities After Chimeric Antigen Receptor T-Cell Therapy: A Patient-Centered Nursing Approach.
  25. Clinical Impact of a Germline CD19 Variant on Treatment Outcome After CAR-T Cell Therapy in Relapsed/Refractory Mantle Cell Lymphoma.
  26. Cellular Therapy Nurse Experts as a Conduit Between Hospital Clinical, Business Operations, and Revenue Cycle Teams.
  27. Engineering a juxtamembrane-targeting CAR T-cell against mesothelin: a novel binder resilient to shed antigen for enhanced efficacy against ovarian and pancreatic cancer.
  28. Gene expression profiling of recipient immune cells induced by 7 × 19 CAR-T cell dosing in a syngeneic mouse model.
  29. Quality control of biological raw materials to ensure the viral safety of cell and gene therapy products.
  30. Injectable bioinstructive microfoam for rapid bedside/in vivo programming of CAR-T cells.
  31. Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment.
  32. Real-World Dermatologic Adverse Events of CAR T-Cell Therapy: A Decade-Wide Disproportionality Analysis of the FDA Adverse Event Reporting System.
  33. Interleukin-18 armours antitumour immune effectors.
  34. mRNA CAR T cells promote tolerable, tunable therapy in preclinical high grade glioma models.
  35. Nanomaterials Drive In Vivo CAR Immune Cells Engineering.
  36. CAR-based cellular therapy for refractory systemic lupus erythematosus: an overlap-controlled systematic review.
  37. Potential of new BCMA-targeting therapies in overcoming resistance in multiple myeloma.
  38. EF-1α-driven nanobody-based CD19-redirected CAR-T cells retain the antitumor efficacy, antigen-driven expansion, and cytokine secretion of CMV-driven counterparts.
  39. The impact of radiotherapy on the therapeutic response of patients treated with CAR T-cell therapy for high-grade lymphoma: a systematic review.
  40. The development of novel chimeric antigen receptor gamma-delta T cells against multiple myeloma and single-cell RNA sequencing analysis.
  41. Re-Arming the Immunological Radar: The Translational Landscape of Dendritic Cell-Centric Nanotherapeutics and Microenvironment Remodeling for Osteosarcoma.
  42. Recent applications of artificial intelligence in cancer radiotherapy and immunotherapy: current status and future directions.
  43. Reversible control of CAR T cells through PROTAC compound targeting bromodomain mutant.
  44. Adaptive spline-based weighting functions for blended survival curve extrapolation.
  45. Coordinated expansion of CD163⁺ monocytes and immature CD177⁺ neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy.
  46. Overview of dose-finding designs and trials in cell and gene therapies.
  47. The role of radiotherapy in bridging to CAR T-cell therapy for high-grade B-cell lymphoma.
  48. Protecting Informational Self-Determination in AI-driven Precision Oncology: Privacy, Ethics, and Governance Challenges.
  49. A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host Disease.
  50. Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.
  51. A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.
  52. From barriers to cloud-based regulatory collaboration: An industry perspective on accelerating innovation in pharmaceutical manufacturing.
  53. Chimeric Antigen Receptor-Immune Cell-Based Therapies for Clear Cell Renal Cell Carcinoma: Latest Advancements and Directions.
  54. The Rise of AI Companions: From Prediction to Surgery in the Digital Twin Era.
  55. Digital and AI-enabled models in pharmaceutical development and manufacturing: a regulatory-focused industry survey.
  56. Blockchain technology for secure and efficient nephrology data management.
  57. Steroid-resistant bilateral facial nerve palsies, ophthalmoparesis, and multilevel thoracic radiculopathy as immune effector cell-associated late-onset neurotoxicity after cilta-cel CAR-T therapy: a case report and review of similar cases.
  58. A Simulation and Case Study to Evaluate the Extrapolation Performance of Flexible Bayesian Survival Models when Incorporating Real-World Data.
  59. Advances in ex vivo mRNA-based gene transfer for cell-based cancer immunotherapy.
  60. Cultivating Functional Natural Killer Cells from Mobilized Hematopoietic Stem Cells in Heavily Pretreated Hematologic Malignancies.
  61. Development of a 3-day manufacturing method to generate CD19-CD20-CD22 trispecific CAR T-cells from whole blood.
  62. A new paradigm for medical data circulation: research on medical data sharing based on evolutionary game theory.
  63. Immunomodulatory effects of nematode-microbiota interactions in cancer therapy.
  64. Beyond innovation: why rare disease gene therapy needs a reset.
  65. GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma.
  66. Embracing Digital as a Paradigm Shift in Medical Affairs.
  67. A Regulatory-Ready Bayesian Evidence Framework across Clinical Development and Pharmacovigilance: Practical Expectations from FDA, EMA, and ICH Guidance.
  68. Life-saving therapies to patients in hours - the new algorithmic digital regulatory exchange model.
  69. R WE ready for reimbursement? A round-up of developments in real-world evidence relating to health technology assessment: part 27.
  70. Approval and delay status of United States -approved new drugs (2010-2023) in European Union, Japan, and China.
  71. Economic Evidence on Biliary Tract Cancer: A Systematic Review.
  72. Decision-grade digital twins for in situ bioremediation of contaminated soil and groundwater: a critical review.
  73. Pharmaceutical Engineering of Lipid-Based Nanocarriers for Cancer Nanomedicines: From Doxorubicin to mRNA Platforms.
  74. Hydrogels in Autoimmune Disease: A Comprehensive Review of Current Research and Clinical Potentials.
  75. Rational Immune Checkpoint Inhibitor-Based Combination Immunotherapy in Cancer: Mechanistic Design, Biomarker Selection, and Implications for Oncology Pharmacy.
  76. Therapeutic platforms for cancer management centered on blocking the PD-L1/PD-1 interaction through the use of aptamers: A review.
  77. Ethical and Governance Challenges of AI in Medical Imaging and Diagnostics: A Systematic Survey and Policy Framework Recommendations.
  78. Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.
  79. A Comprehensive HLA-DR4 MHC Class II Tetramer Platform for the Detection and Functional Validation of Post-Translational Modification Neoantigens.
  80. Digital infrastructures and data interoperability in radiology for prevention: from digital health to AI-enabled, quantitative imaging workflows.
  1. Bioessays. 2026 Jul;48(7): e70164
    Engineering CAR-Tregs with Phage-Selected scFv Enables a New Paradigm for Immune Regulation.
    Fatih Noyan, Matthias Hardtke-Wolenski.
      Regulatory T cells (Tregs) are central to immune tolerance, yet antigen-specific cell therapies lag behind cytotoxic CAR-T approaches. Most CAR-Treg programs still use single-chain variable fragments (scFvs) derived from monoclonal antibodies optimized for effector function, a bias that may promote CAR clustering, tonic signaling, and lineage instability. Here, we propose a phage-first binder discovery framework for CAR-Tregs and state testable hypotheses linking phage-display selection pressures to scFv biophysical properties and Treg fate. We hypothesize that multi-parameter selection and counter-selection can enrich scFvs with moderate affinity, low polyspecificity, and improved framework stability, thereby lowering tonic signaling in defined backbone architectures and preserving FOXP3/TSDR stability under inflammatory stress. We outline a falsifiable two-phase roadmap-bench triage followed by mechanistic and preclinical validation to determine how scFv properties, expression level, and intracellular signaling domains define an optimal tonic window for durable immune regulation.
    Keywords:  FOXP3; Treg cell; cell biology; chimeric antigen receptor; immune system; immune tolerance; monoclonal antibody; scfv antibodies
    DOI:  https://doi.org/10.1002/bies.70164
  2. Immunol Res. 2026 Jul 14. pii: 70. [Epub ahead of print]74(1):
    Emerging target antigen landscape for CAR T-cell therapy in solid tumors: current advances and future directions.
    Debolina Chakraborty, Subhadip Kundu, Sudhir Kumar Rawal, Samson Mani.
      Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable clinical success in hematologic malignancies but remains largely ineffective in solid tumors due to antigen heterogeneity, immune evasion, and dose-limiting toxicities. A central challenge is the identification of optimal target antigens that balance tumor specificity with therapeutic efficacy. In this review, we define the emerging antigenic landscape for CAR T-cell therapy in solid tumors through integrative curation and systems-level analysis. We reviewed 58 candidate targets spanning tumor-associated surface molecules, stromal and angiogenic components, immune checkpoints, and regulatory signaling nodes. Pathway enrichment reveals convergence on key oncogenic and immune regulatory circuits, including cell adhesion, receptor tyrosine kinase signaling, and PD-1/PD-L1 mediated immune suppression, underscoring their roles in tumor progression and immune escape. Notably, most prioritized targets localize to the plasma membrane and cell-cell interfaces, reinforcing their accessibility for CAR-based interventions. We further highlight advances in multi-antigen targeting, logic-gated CAR designs, and engineered resistance to immunosuppressive cues that collectively address tumor heterogeneity and functional exhaustion. By integrating antigen biology with emerging engineering strategies, this review provides a conceptual framework for rational target selection and combinatorial design. These insights advance the development of next-generation CAR T-cell therapies with improved precision and durability against solid tumors.
    Keywords:  CAR T-cell therapy; Gene ontology; Pathway analysis; Solid tumor; Target antigen
    DOI:  https://doi.org/10.1007/s12026-026-09806-x
  3. Mol Biol Rep. 2026 Jul 15. pii: 1163. [Epub ahead of print]53(1):
    From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.
    Parisa Pedram Rad, Ali Reyhani, Mohammadreza Dashti.
      CAR-T cell therapy has revolutionized the treatment of hematologic malignancies, yet its translation to solid tumors remains a formidable challenge. A central determinant of this limitation is the hypoxic tumor microenvironment, which imposes profound immunosuppressive pressure on infiltrating CAR-T cells, impairing their persistence, effector function, and metabolic fitness. Rather than viewing hypoxia purely as an obstacle, emerging engineering paradigms are reframing it as a tumor-selective switch one that can be harnessed to spatially confine CAR-T cell activation, enhance metabolic fitness, and reduce off-tumor toxicity. This review critically examines how hypoxia subverts CAR-T cell immunity, and how next-generation hypoxia-responsive constructs, metabolic reprogramming strategies, and armored cytokine-secreting designs are beginning to turn this hostile microenvironment into a therapeutic advantage. We further discuss unresolved clinical challenges and the translational outlook for hypoxia-adapted CAR-T cells in solid tumor immunotherapy.
    Keywords:  CAR-T cell therapy; HIF-1α; Hypoxia; Immunotherapy; Metabolic reprogramming; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s11033-026-12321-9
  4. J Biopharm Stat. 2026 Jul 16. 1-17
    Statistical analysis plan considerations for autologous cell and cell-based gene therapy clinical trials.
    Patricia Anderson, Revathi Ananthakrishnan, Zhenzhen Xu, Khadija Rerhou Rantell, Susan Bell, Daniel Li, Allen Xue, Alan Y Chiang.
      By early 2023, there were over 100 gene, cell and RNA products approved globally (Chancellor et al. 2023). The way in which autologous cell and cell-based gene therapy products are administered can include multiple treatment stages, at times including leukapheresis, optional bridging therapy during manufacturing, conditioning regimen, and one or more doses of product. This brings important considerations in the development of the statistical analysis plan for clinical trials of autologous cell and cell-based gene therapies, including application of the estimand framework for key facets. In this article, we review all of the FDA currently approved autologous cell and cell-based gene therapy products as examples as they apply to general considerations for the statistical analysis plan as well as more in-depth discussion of treatment exposure, safety and efficacy analyses, and other aspects.
    Keywords:  Autologous cell therapy; CAR T-cell; cell therapy; cell-based gene therapy; statistical analysis plan
    DOI:  https://doi.org/10.1080/10543406.2026.2685280
  5. Anticancer Agents Med Chem. 2026 Jul 10.
    Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.
    Qasim Javed, Shoaib Majeed, Adnan Shahid, Naheed Bano, Bushra Munir, Mohanad W Mahdi Alzubadiy, Esha Mustafa, Sara Siddique, Magda H Abdellattif, Alaa Abu Alnjaa, Ajmal Khan, Ahmed Al-Harrasi.
      Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.
    Keywords:  CAR-T cells; checkpoint inhibitors; chronic lymphocytic leukemia; combination therapies; hematological malignancies; solid tumors
    DOI:  https://doi.org/10.2174/0118715206422827251203222619
  6. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00127-5. [Epub ahead of print]209 123-139
    3D bioluminescence imaging assays for measuring in vitro CAR T cell cytotoxicity.
    Eugenia Cambiaso, Benjamin Motais, Ralph Geoffrey Tieland, Corine Pleijte, Marta Cuenca, Victor Peperzak.
      For the past decades, many advances were made in the field of immunotherapies, most notably the development of chimeric antigen receptor (CAR) T cells, that allowed development of potent and targeted treatment options against cancers and other diseases. To determine the preclinical cytotoxic efficacy of T cell therapies, such as CAR T cell therapy, bioluminescence-based assays have emerged as a common technique, thanks to their high sensitivity, reproducibility and ease of use. Because the extracellular matrix (ECM) plays a key role in tumor development, numerous 3D cancer models have been generated to reduce the use of animals while simultaneously reproducing the tumor microenvironment during the testing of novel cell therapies. In this chapter, we describe a simple and reliable method to determine CAR T cell cytotoxicity in 3D matrices using bioluminescence detection, eliminating the need to harvest cells from the matrix.
    Keywords:  3D culture models; Bioluminescence imaging; CAR T cells; Cytotoxicity assays
    DOI:  https://doi.org/10.1016/bs.mcb.2026.04.006
  7. Cytotherapy. 2026 Mar 11. pii: S1465-3249(26)00741-3. [Epub ahead of print]28(9): 102780
    Overcoming challenges in the implementation of chimeric antigen receptor (CAR) T-cell therapy in resource-constrained settings: Lessons from Brazil and India.
    Flavia Gava, Alka Dwivedi, Hasmukh Jain, Kirk R Schultz, Diego V Clé, Nirali N Shah.
      Advances in immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, have achieved remarkable outcomes in treating relapse/refractory hematologic malignancies. However, despite the broad adoption of cellular immunotherapy in resource-rich countries such as the United States, Europe, and China, access remains limited in countries with fewer resources. The high cost and many requirements to implement CAR T-cell therapy further exacerbate pre-existing disparities in access to costly therapies. In this review, we discuss specific barriers limiting the widespread adoption of CAR T-cell therapy in resource-constrained settings, with a focus on emerging economies such as Brazil and India, including regulatory and implementation aspects, health care infrastructure, government investment, and geographic and social disparities. We also address unique limitations to implementing CAR T-cell therapy in the pediatric setting. Lastly, we highlight alternative solutions to overcome challenges and report the initiatives adopted by Brazil and India that aim to make CAR T-cells more accessible. These efforts, supported by partnerships with academic institutions, international collaborations, and biotechnology companies, focus on expanding access and developing a cost-effective product.
    Keywords:  Brazil; CAR T-cell therapy; India; access to health care; hematologic malignancies; leukemia; lymphoma; social disparities
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102780
  8. Mol Ther Adv. 2026 Mar 12. 34(1): 201651
    Designs of the clinical trials aiming at evaluating cell and gene therapy products: A critical appraisal from a literature review.
    JOIN4ATMP consortium
      There is growing interest in advanced therapy medicinal products (ATMPs). However, there is debate about how they should be clinically evaluated. We aimed to assess the heterogeneity of trial designs used for ATMPs, based on a review of the most recently published ATMP trials from 2022 to 2024, and then make recommendations to improve the level of evidence. The 276 selected trials concerned CAR-T cells (28%), other gene therapies (22%), and somatic cell therapy (50%) and targeted different underlying diseases, hematological malignancies for CAR-T cells, genetic or congenital diseases for gene therapy, and other diseases for somatic cells (p < 0.0001). The most common designs were single-center (48%), early-phase (63%), single-dose (74%) designs; randomization was used in close to one-third of trials, more common in somatic cells (43%). The median sample size was the highest for CAR-T cells therapy trials (26 vs. 15 and 20 for other gene and somatic cells therapy, respectively), and the median follow-up was the highest for other gene therapy (23.5 vs. 15.4 for CAR-T cells and 12.2 months for somatic cells therapy). These results highlight the relatively short-term nature of evaluation of these innovative products.
    Keywords:  advanced therapy medicinal products; cell therapy; clinical trials; gene therapy; trial design
    DOI:  https://doi.org/10.1016/j.omta.2025.201651
  9. Cells. 2026 Jul 03. pii: 1213. [Epub ahead of print]15(13):
    Engineered Extracellular Vesicles as Programmable Immune Interfaces: Surface and Cargo Engineering for Cancer Immunotherapy and Tolerance.
    Tomoyoshi Yamano, Rikinari Hanayama.
      Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication in the immune system by transferring proteins, nucleic acids, and lipids. Their biocompatibility, nanoscale size, and capacity for cell-type-selective delivery have stimulated growing interest in engineering EVs as therapeutic platforms. In this review, we discuss recent advances in EV engineering for immune regulation, focusing on surface display, cellular targeting, and cargo loading strategies. A central concept is that engineered EVs should not be viewed simply as delivery vehicles, but as programmable immune interfaces. EVs can integrate antigen specificity, target-cell recognition, therapeutic cargo delivery, and defined immunostimulatory or tolerogenic signals within a single nanoscale particle. By combining these modular elements, engineered EVs can be designed to direct immune responses in a context-dependent manner. We examine how this principle is being applied to cancer immunotherapy, immune suppression, and antigen-specific tolerance induction, including antigen-presenting EVs, cytotoxic and RNA-loaded EVs, checkpoint-modulatory EVs, MSC-derived EVs, and engineered platforms for autoimmune and inflammatory diseases. We also discuss the clinical translation of engineered EV therapeutics, with emphasis on manufacturing, characterization, potency assays, biodistribution, safety, and regulatory challenges. Together, current advances suggest that programmable EV immune interfaces may provide a versatile foundation for next-generation cancer immunotherapy and antigen-specific immune regulation.
    Keywords:  EV engineering; MSC-EV; cancer immunotherapy; cargo loading; clinical translation; extracellular vesicles; immune regulation; surface display
    DOI:  https://doi.org/10.3390/cells15131213
  10. Front Immunol. 2026 ;17 1859167
    Breaking the resistance barrier: synergistic evolution of CAR-T cells and bispecific antibodies in the era of precision immuno-oncology.
    Xiaoqiang Wang, Yali Liu, Qiang Yang, Hai Zhao.
      The therapeutic landscape of oncology has undergone a profound paradigm shift, transitioning from conventional cytotoxic regimens to a sophisticated era of precision immunotherapy. Despite the remarkable clinical success of immune checkpoint inhibitors, significant challenges such as primary resistance, limited T-cell infiltration in solid tumors, and severe immune-related adverse events persist. As the second volume of "The Role of Immunotherapy in Cancer Therapy and Its Challenges" Community Series, this review systematically evaluates the recent breakthroughs and persistent hurdles in CAR-T cell therapy and bispecific antibodies (BsAbs). We emphasize a critical strategic shift: transitioning these potent modalities from late-stage salvage therapies to earlier treatment lines to preserve the patient's immune repertoire and improve long-term survival. Furthermore, we dissect the molecular engineering of innovative CAR-T and BsAb constructs-such as armored CARs and multi-specific engagers-specifically designed to antagonize the immunosuppressive tumor microenvironment (TME) in solid cancers. A central focus is placed on the optimization of combination strategies, including the synergistic integration of cellular therapies with hematopoietic stem cell transplantation (HSCT) and targeted agents to eradicate minimal residual disease (MRD). By synthesizing the latest clinical data on overall survival (OS) and progression-free survival (PFS), we propose an evidence-based framework for sequential therapy and toxicity management. Ultimately, this review aims to provide a roadmap for the next generation of personalized immuno-oncology, addressing how innovative molecular design and strategic timing can overcome current resistance barriers and redefine the standard of care for refractory malignancies.
    Keywords:  BsAbs; cancer immunotherapy; combination strategies; next-generation CAR-T cells; solid tumors; treatment sequencing
    DOI:  https://doi.org/10.3389/fimmu.2026.1859167
  11. Front Digit Health. 2026 ;8 1854287
    Patient-operated imaging for clinical assessment: regulatory and reimbursement challenges in European health systems.
    Chifra Fenton, Charles Tibi, Jacob Glazer, Nadia Prisant.
       Background: Patient-operated medical technologies are increasingly integrated into European care. Under EU regulation, CE marking confirms safety and performance for each specific intended use, while reimbursement requires separate demonstration of clinical and economic value. Imaging has historically differed because acquisition and interpretation are typically coupled within the same clinical encounter.
    Objective: To examine patient-operated imaging for clinical assessment (POICA) as a regulatory and reimbursement boundary case under the EU Medical Device Regulation (MDR), and to analyse how redistribution of image acquisition to patients, while preserving clinician-led interpretation, challenges regulatory classification, liability allocation, and reimbursement models historically built around a unified professional imaging act.
    Methods: We conducted a structured policy and regulatory analysis examining how patient-operated imaging interacts with existing European regulatory and reimbursement frameworks. Sources were selected based on their relevance to decentralized acquisition, clinical reliability, workflow organization, and reimbursement integration. The analysis integrates MDR and Medical Device Coordination Group (MDCG) guidance documents, usability and risk-management standards), liability principles for home-use medical devices, and the structure of European health technology assessment (HTA) and reimbursement systems. Patient-operated imaging was evaluated against precedents in which elements of technical execution moved outside institutional settings (e.g., self-testing in vitro diagnostics, home-based therapies, and remote monitoring models) to identify where existing frameworks accommodate decentralized image acquisition and where structural tensions arise.
    Results: Imaging, even in structured monitoring contexts such as fertility care, requires each acquisition to meet clinical adequacy thresholds at the time of interpretation. This creates acquisition-dependent risk that cannot be mitigated through repetition alone. Under the MDR, adequacy criteria and the mechanisms ensuring them must be explicit; usability validation must demonstrate interpretative reliability rather than procedural completion. Responsibility becomes hybrid, with patients performing acquisition while clinicians retain interpretive and clinical decision-making authority. Economically, this redistribution disrupts reimbursement models built around a single bundled professional imaging act.
    Conclusions: The central challenge is not regulatory authorization but maintaining clinical reliability when acquisition is decentralized. Integration into European health systems will depend on demonstrable reliability of patient-acquired images, clear allocation of responsibility, and reimbursement mechanisms capable of recognizing distributed clinical workflows, while maintaining alignment between physician incentives and high-quality care.
    Keywords:  fertility monitoring; health technology assessment (HTA); medical device regulation (MDR); patient-operated imaging; point of care ultrasound (POCUS); reimbursement policy; telemedicine
    DOI:  https://doi.org/10.3389/fdgth.2026.1854287
  12. Transpl Immunol. 2026 Jul 13. pii: S0966-3274(26)00077-8. [Epub ahead of print]98 102419
    Clinical outcomes of Epstein-Barr virus infection/reactivation following CAR-T cell therapy: A systematic review.
    Pramod Singh, Ali Shan Hafeez, Asad Zaman, Abdul Rafae Faisal, Muhammad Faizan, Ahmar Jan Qureshi, Hareem Saleem, Muhammad Atif Khan, Abat Khan.
       BACKGROUND: Epstein-Barr virus (EBV) infection or reactivation is an emerging but underrecognized complication following chimeric antigen receptor T-cell (CAR-T) therapy and is likely associated with treatment-induced immune dysregulation. Data regarding its clinical impact remain limited.
    OBJECTIVE: To evaluate the reported occurrence, clinical manifestations, and outcomes of EBV infection or reactivation in adults undergoing CAR-T therapy.
    METHODS: A systematic review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Embase, and Cochrane CENTRAL were searched from inception to March 2025 for studies reporting EBV infection or reactivation after CAR-T therapy in adults. Due to limited and heterogeneous data, results were synthesized descriptively.
    RESULTS: Five studies comprising 80 patients were included (median age, 55 years; 52.6% male among patients with reported sex data [10/19]). Across the included studies, 11 EBV infection/reactivation events were identified among 80 described CAR-T recipients, representing 13.8% of the reported sample rather than a true incidence estimate. Among events with usable individualized timing data, the median interval from CAR-T infusion to EBV detection/reactivation was 9.8 months (approximate range, 1-44 months). Because EBV surveillance strategies and definitions were inconsistently reported across studies, this proportion should not be interpreted as a true incidence estimate. Four patients (36.4%) developed EBV-associated disease, including three cases of EBV-related lymphoproliferative disorder and one case of EBV-associated diffuse large B-cell lymphoma. Among seven patients with reported post-CAR-T treatment response, four achieved Complete Remission/ Continuous Complete Remission; treatment response should be interpreted separately from final survival status. Confirmed EBV-related mortality occurred in 2/11 patients with reported EBV infection/reactivation and in 2/4 patients with EBV-associated disease; all-cause mortality could not be reliably estimated because patient-level vital status could not be fully attributed to the EBV-reactivated subgroup. Reported toxicities predominantly consisted of low-grade cytokine-release syndrome; however, toxicity data were limited.
    CONCLUSION: Although infrequently reported, EBV infection or reactivation after CAR-T therapy may be associated with substantial morbidity and mortality among affected patients. However, the available evidence is limited by the small sample size, heterogeneous study designs, and inconsistent EBV surveillance practices.
    Keywords:  CAR-T therapy; DLBCL; EBV; Epstein-Barr virus; Immunotherapy; Lymphoproliferative disease; Reactivation
    DOI:  https://doi.org/10.1016/j.trim.2026.102419
  13. Front Immunol. 2026 ;17 1863485
    Modulating CAR-T cell exhaustion and fitness in acute myeloid leukemia: mechanistic metabolic and microenvironmental strategies.
    Erden Atilla.
      Chimeric antigen receptor (CAR) T-cell therapy has achieved transformative outcomes in B-cell malignancies but remains limited in acute myeloid leukemia (AML), where antigenic heterogeneity, a suppressive myeloid-driven microenvironment, and a metabolically restrictive bone marrow niche collectively impair efficacy. In AML, CAR T-cell failure is driven not only by antigen escape but by a coordinated program of exhaustion encompassing transcriptional, epigenetic, metabolic, and functional dysfunction. The AML bone marrow niche further enforces dysfunction through suppressive immune populations, inhibitory cytokines, checkpoint signaling, metabolic competition, and impaired trafficking. This review outlines a "fitness-first" framework consolidating intrinsic and extrinsic determinants of CAR T-cell performance. Optimized manufacturing, cellular programming, and microenvironmental modulation provide a unified strategy to enhance CAR T-cell fitness and enable durable therapeutic responses in AML.
    Keywords:  AML; CAR T-cell engineering; CAR T-cell exhaustion; epigenetic regulation; metabolic fitness; microenvironment; mitochondrial function
    DOI:  https://doi.org/10.3389/fimmu.2026.1863485
  14. Cytotherapy. 2026 Mar 07. pii: S1465-3249(26)00103-9. [Epub ahead of print]28(9): 102142
    South America and Mexico's cell and gene therapy landscape: accelerating growth and persistent challenges.
    Heloisa Brand, Beatriz Brunini, Tatiana Maron-Gutierrez, Samuel C F Couto, Péricles N da Costa, Rafaela Rossetti, Maroun Khoury, Hector Mayani, Andres Caicedo, Martín Hernán Bonamino, Virginia Picanço-Castro.
      Cell and gene therapies (CGTs) are expanding globally, and South America and Mexico are gaining tangible momentum. This review maps the region's CGT landscape across four axes that together highlight regional progress: (i) patent activity as a signal of innovation and market pull; (ii) clinical trial activity and sponsorship patterns; (iii) manufacturing capabilities, including GMP (good manufacturing pratices) sites, platform maturity, vector/plasmid access, and QC/QA (quality control/quality assurance) readiness; and (iv) regulatory evolution. Although Central America was included in the search strategy, measurable CGT activity is currently concentrated in South America and Mexico. The emerging picture is of a region moving from isolated initiatives toward an integrated, capability-based ecosystem. We observe steady growth in early-phase trials across modalities, thereby establishing a robust translational pipeline. Brazil leads in volume and scope, while Argentina, Chile, and Mexico contribute specific programs, highlighting the existence of distributed centers of specialization. Industry-driven sponsorship indicates rising market confidence, and temporal trends in patent filings by public institutions and multinational assignees align with the recent acceleration in activity. On the policy front, regulatory frameworks are evolving and moving closer to international benchmarks, creating better conditions for multicenter studies. Based on these advances, a practical plan can transform momentum into lasting capacity and access: maintaining consistent public-private investment to expand GMP-compliant manufacturing capacity; aligning local standards with international ones (FDA/EMA/FACT) and improving consistency of requirements across countries; and structuring regional collaboration to share experiences, coordinate early-stage clinical trials, and establish reference laboratories and training centers. Together, these measures can reduce cell collection time, lower costs, and convert pilot programs into reliable clinical supply, positioning South America and Mexico as growing contributors to global innovation in gene and cell therapy and to equitable access.
    Keywords:  GMP manufacturing; South and Central America; cell and gene therapy; clinical trials; regulatory frameworks and access
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102142
  15. Clin J Oncol Nurs. 2026 Jul 08. 30 E73-E79
    Lessons Learned: Operationalizing Chimeric Antigen Receptor T-Cell Therapy in the Community Oncology Private Practice Healthcare Setting.
    Martie M Steinfeld, Xiaoxiao Zhang, Ashley Todd, Kathleen L Murphy.
       BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is an established therapy for relapsed or refractory hematologic malignancies. Traditionally, it has been administered in outpatient or inpatient settings at urban academic medical centers that are affiliated with established stem cell transplantation programs. Tennessee Oncology has successfully treated more than 30 patients with CAR T-cell therapy since August 2024 in the community oncology outpatient setting.
    OBJECTIVES: This article reviews key discoveries and lessons learned in creating a cellular therapy program in a nontraditional setting. Tennessee Oncology approached this endeavor with confidence, not fully understanding the complexity of transitioning from concept to care for the first patient.
    METHODS: Oncology nurses across several roles collaborated, planned, developed, implemented, and educated staff about CAR T-cell therapy across 24 months. The first 12 months were spent without a patient in the program, to assist other facilities in operationalizing their first CAR T-cell therapy program.
    FINDINGS: Building an institutional CAR T-cell therapy program from inception is a resource-intensive and iterative process; however, successful execution can be achieved through unwavering stakeholder investment and a highly skilled specialized nursing workforce.
    Keywords:  CAR T-cell therapy; education; outpatient; remote monitoring
    DOI:  https://doi.org/10.1188/26.CJON.S2.E73-E79
  16. Clin J Oncol Nurs. 2026 Jul 08. 30 E38-E39
    Oncology Nurses' Role in Cell and Gene Therapy: Future Expansions and Evolving Foundations.
    Kristin Marie Ferguson, Joaquin Buitrago.
      During the past decade, cell and gene therapies have moved from experimental interventions to integral components of contemporary oncology nursing practice. In response to the continuously changing landscape and the widening.
    Keywords:  CAR T-cell therapy; cell and gene therapy; oncology nursing; tumor-infiltrating lymphocyte therapy
    DOI:  https://doi.org/10.1188/26.CJON.S2.E38-E39
  17. Cell Prolif. 2026 Jul 14. e70263
    Integrated Engineering of CAR-T Cells for Solid Tumours.
    Chao Yang, Tan Li, Ping He, Zhijie Zhao, Shenglong Li, Liming Wang.
      Chimeric antigen receptor (CAR) T-cell therapy has achieved durable efficacy in hematologic malignancies but encounters persistent obstacles in solid tumours, including antigen heterogeneity, a suppressive tumour microenvironment (TME), and intrinsic T-cell dysfunction. This review examines the transition from single-axis engineering to an integrated framework that addresses these hurdles in sequence. We delineate how next-generation CAR-T cells are designed for precise spatiotemporal activation through logic-gated and pharmacologically regulatable receptors, while being reinforced by metabolic and epigenetic reprogramming to resist TME-driven exhaustion. We also assess strategies that actively reshape the immunosuppressive TME, including depletion of regulatory cell populations, blockade of 'don't eat me' signals, and the use of biomaterial scaffolds for locoregional delivery. The synthesis of controllable activation, intrinsic resilience, and extrinsic TME modulation is defining a class of adaptive therapeutic systems. Clinical implementation of this approach requires careful management of toxicities, notably cytokine release syndrome (CRS), and support from advanced monitoring technologies. Progress will depend on rational combinations that move beyond isolated optimisations, enabling cellular therapies to dynamically respond to evolving tumour ecosystems and narrowing the efficacy gap between hematologic and solid cancers.
    Keywords:  CAR‐T cell; metabolic reprogramming; regional delivery; solid tumours; tumour microenvironment (TME)
    DOI:  https://doi.org/10.1111/cpr.70263
  18. Mol Ther Oncol. 2026 Sep 17. 34(3): 201278
    Feasibility and outcomes of decentralized point-of-care CD19 CAR T cell for relapsed large B cell lymphoma in resource-limited settings.
    Koramit Suppipat, Supannikar Tawinwung, Ornnicha Sathitakorn, Chantiya Chanswangphuwana, Kanhatai Chiengthong, Mutita Surakijboworn, Thiti Asawapanumas, Phandee Watanaboonyongcharoen, Palada Pitakkitnukun, Manaschanok Tippawan, Supanat Kumjan, Udomsak Bunworasate, Nattiya Hirankarn, Kitsada Wudhikarn.
      CD19 chimeric antigen receptor (CAR) T cell therapy has transformed outcomes for patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL), yet access to commercial products remains severely limited in low- and middle-income countries due to high cost, infrastructure requirements, and centralized manufacturing. Herein, we developed and implemented a decentralized point-of-care (POC) CAR T cell platform in Thailand using an automated closed system (CliniMACS Prodigy), integrating local manufacturing with clinical delivery. Between 2020 and 2025, 12 patients with R/R LBCL (median age 45.8 years) were treated, with a median vein-to-vein time of 12 days. Manufacturing was successful in 11 patients, while one received an out-of-specification dose. Final products demonstrated a balanced CD4:CD8 ratio and were enriched for memory T cell subsets. Cytokine release syndrome occurred in 5 patients (grade 3 in 1), and neurotoxicity in 1 patient (grade 1). At 3 months, the overall response rate was 58.3%, including 33.3% complete responses. One-year event-free and overall survival were 58.3% and 90%. The median total cost was USD 111,231. These findings demonstrate that decentralized POC CAR T cell therapy is feasible, effective, and more affordable, supporting scalable implementation in resource-limited settings.
    Keywords:  CD19 CAR T cell; academic; care access; decentralized; feasibility; large B cell lymphoma; point-of-care; resource-limited
    DOI:  https://doi.org/10.1016/j.omton.2026.201278
  19. Clin J Oncol Nurs. 2026 Jul 08. 30 E67-E72
    Nursing Considerations for CAR T-Cell Therapy: Management of Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome.
    Demi M Miller.
       BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for certain hematologic malignancies, but many nurses are not trained in caring for two common side effects, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).
    OBJECTIVES: This article provides foundational knowledge of CRS and ICANS, including the oncology nurse's role in toxicity monitoring, care coordination, and patient education.
    METHODS: To support safe, evidence-based CAR T-cell therapy administration, this article discusses grading guidelines, nursing assessments, interventions, and education strategies for CRS and ICANS.
    FINDINGS: Nurses serve a key role in mitigating CRS and ICANS through early recognition, continuous monitoring, therapeutic intervention, and patient and caregiver education. Using standardized protocols, frequently monitoring vital signs, and performing neurologic assessments optimize patient safety and outcomes.
    Keywords:  CAR T-cell therapy; ICANS; cytokine release syndrome; neurotoxicity
    DOI:  https://doi.org/10.1188/26.CJON.S2.E67-E72
  20. Value Health. 2026 Jul 14. pii: S1098-3015(26)02537-4. [Epub ahead of print]
    Domains in Health Technology Assessment of Digital Health Technologies: A Mapping Review.
    Jeremy Dietz, Zoe Garrett, Lynda Ayiku, Livio Battaglia, Iga Lipska, Wija Oortwijn, Dario Sacchini, Joan Segur Ferrer, Emmanouil Tsiasiotis, Dalia Dawoud.
       BACKGROUND: Health Technology Assessment (HTA) plays an important role in evaluating digital health technologies (DHTs) to inform decision-making. Commonly used HTA frameworks have been criticised as inadequate for assessing DHTs leading to the development of many DHT-specific HTA frameworks. The proliferation of frameworks creates a lack of clarity around evidence expectations for DHT HTA and perceptions of divergence in approach to HTA.
    OBJECTIVES: The study, which was completed for the European Digital Health Technology Assessment (EDiHTA) project, reviews the domains used for DHT HTA.
    METHODS: The study had 3 parts: (1) scoping review (2) targeted search of HTA agency websites and hospitals for DHT methods documents (3) review of European DHT HTA reports. Data were extracted into a common template and analysed descriptively to identify the domains and topics included in the documents.
    RESULTS: A total of 44 documents were included: 1) 11 published studies 2) 13 HTA agencies' methods documents 3) a sample of 20 DHT HTA reports. From these documents, 13 domains were identified. Topics relating to HTA domains health condition, technology use, clinical safety, clinical effectiveness, economic aspects, organisational aspects appeared consistently in retrieved documents. Topics relating to environmental, technical, legal and regulatory, and some ethical and human aspects were not consistently included or reported in the documents.
    CONCLUSION: This study identifies commonalities in DHT HTA across established areas of HTA and areas of DHT HTA where there remains inconsistency in reporting of information and where efforts towards further alignment and refinement are still needed.
    Keywords:  artificial intelligence; digital health; eHealth; health technology assessment; mHealth; mapping review; methodological framework; mobile health; telehealth
    DOI:  https://doi.org/10.1016/j.jval.2026.06.017
  21. Value Health. 2026 Jul 14. pii: S1098-3015(26)02535-0. [Epub ahead of print]
    Evidence mapping of concepts, methods, and outcomes in the evaluation of diagnostic and therapeutic technologies for ultra-rare diseases: a systematic scoping review.
    Raul Edison Luna Lazo, Daniela Gorski, Fernanda Coelho Vilela, Júlia Barbosa Domingues da Silva, Laura Helena Schroeder Borges, Pharm Stefany Scalco, Irene Tomoko Nakano, Fernando Fernandez-Llimos, Roberto Pontarolo, Inajara Rotta.
       OBJECTIVES: This systematic scoping review provides an overview of the concepts, methodological approaches, and outcome measures used to evaluate diagnostic and therapeutic technologies for URDs.
    METHODS: Searches covered countries where English, Portuguese or Spanish are official languages and were expanded to INAHTA and ICMRA countries using additional Roman-character languages. A search was conducted for official documents, reports, recommendations, and legal frameworks from health technology assessment (HTA) agencies and regulatory authorities in these countries. Data were extracted on URD definitions, primary sources, methodological approaches, and outcome measures used in HTA.
    RESULTS: A total of 55 publications were included. The definitions of URDs varied, with most countries adopting a prevalence threshold of ≤ 1 in 50,000 people, while others applied stricter criteria (≤ 1 in 100,000). Conventional methods, such as randomized controlled trials, were seldom feasible, with evidence often derived from observational studies, historical cohorts, or real-world data. Innovative approaches, including matching-adjusted indirect comparisons (MAIC), simulated treatment comparisons (STC), and multicriteria decision analysis (MCDA), were increasingly employed. Outcome measures prioritized overall survival, quality of life, functional independence, and caregiver burden, with jurisdiction allowing more flexible cost-effectiveness thresholds or exceptional coverage criteria.
    CONCLUSIONS: Despite heterogeneity, there is growing convergence on prevalence-based criteria and adaptive strategies for URDs, highlighting the need for robust patient registries, international data sharing, and HTA frameworks that incorporate severity, equity, and social value.
    Keywords:  health technology assessment; methodological approaches; outcome measures; prevalence; ultra-rare diseases
    DOI:  https://doi.org/10.1016/j.jval.2026.06.015
  22. Transpl Immunol. 2026 Jul 16. pii: S0966-3274(26)00075-4. [Epub ahead of print] 102417
    Regulatory T-cells technology and vascularized composite allotransplantation: A scoping review.
    Amina Oyuntogos, Pharel Njessi, Olivier Camuzard, Marion Cremoni, Antoine Sicard, Elise Lupon.
       BACKGROUND: Vascularized composite allotransplantation (VCA) offers life changing reconstructive options for patients with traumatic injuries or congenital defects, restoring function and appearance. Its success is limited by strong immune responses, and long-term immunosuppression carries significant risks. Emerging cellular therapies, particularly regulatory T cells (Tregs) offer promising strategies to mitigate rejection and reduce immunosuppression dependence. Preclinical studies in animal models suggest that Treg-based approaches may improve graft survival and potentially reduce the need for conventional immunosuppression in VCA.
    METHODS: An all-time literature search of Regulatory T cell therapy in Vascularized Composite Allotransplantation in animal models was performed on the following electronic databases: PubMed, EMBASE, Cochrane Library, Scopus, Web of Science, and TRIP Database until August 2025. Data was analyzed for graft survival, regulatory T cell activity, chimerism, and tolerance mechanisms.
    RESULTS: A total of 2182 studies were screened across six databases, of which 13 met eligibility criteria and 5 were selected focusing on Treg therapy in VCA animal models. Treg therapy consistently prolonged graft survival (>200 days), promoted chimerism, reduced inflammation, and induced donor specific tolerance. CAR-Tregs demonstrated antigen-specific tolerance, while mesenchymal stem cells (MSCs) enhanced immunomodulation, particularly under hypoxic preconditioning. Other cellular therapies, including hematopoietic stem cells (HSC), also improved graft acceptance, demonstrating their potential as adjuncts or alternatives to long term immunosuppression.
    CONCLUSION: Cellular therapies, especially Treg based approaches such as adoptive transfer and local enrichment or induction of Tregs, consistently promote immune tolerance, suppress graft rejection, and extend allograft survival in VCA animal models. These approaches reduce the need for long term immunosuppression and create a pro-tolerogenic environment, supporting their translational potential. However, further clinical validation is required to optimize dosing, persistence and safety for application in human VCA recipients.
    Keywords:  Cellular therapy; Chimerism; Immune tolerance; Regulatory T cells (Tregs); Vascularized composite allotransplantation
    DOI:  https://doi.org/10.1016/j.trim.2026.102417
  23. J Exp Clin Cancer Res. 2026 Jul 15.
    Low-dose docetaxel reprograms CAR T cells for enhanced solid tumor immunity.
    Songshan Zhu, Jun Yin, Xin Fu, Weiqiang Yang, Yiwei Zeng, Rui Chen, Na Huang, Ling Zhang, Cong Yu, Qianying Huang, Ping Ouyang, Kaisong Huang, Hangjiu Su, Dan Jiang, Guangxian Xu.
       BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy in solid tumors is hampered by dense stromal barriers, rapid functional exhaustion, and limited persistence. Here, we report that low-dose docetaxel acts as an immunomodulatory primer that reprograms CAR T cells to address these barriers. Retrospective analysis of breast cancer patients identifies host lymphocyte reserve as a key determinant of docetaxel treatment benefit, implying an immunological component beyond direct tumor cell killing.
    METHODS: Sub-cytotoxic docetaxel concentrations were evaluated in primary human T cells and CAR T cells using phenotypic, transcriptional, and functional assays. Secretory profiles and extracellular vesicle cargo were characterized, with efficacy assessed in 3D spheroids and xenograft models.
    RESULTS: Docetaxel priming induces a "Metabolic-Cycle Uncoupling" state, constraining proliferation while enhancing cytotoxic effector potency and memory traits. This reprogramming is associated with upregulation of Rab27-dependent exosome biogenesis, accompanied by shedding of exhaustion markers (PD-1, CD57) and enrichment of cytotoxic ligands (FasL, TRAIL), CAR, and homing receptors (CCR5/CCR7). Primed CAR T cells exhibit improved antitumor efficacy with associated stromal remodeling and host T cell activation; secreted exosomes contribute to bystander tumor cell killing.
    CONCLUSIONS: These findings describe a non-genetic pharmacologic priming strategy with potential scalability and compatibility with existing manufacturing processes. This approach demonstrates enhanced CAR T cell performance against solid tumor barriers in preclinical models, highlighting the potential of chemotherapy-immunotherapy synergies.
    Keywords:  CAR T cell; Docetaxel; Exosomes; Immunotherapy; Solid tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-026-03781-9
  24. Clin J Oncol Nurs. 2026 Jul 08. 30 E55-E66
    Navigating Acute and Late-Onset Toxicities After Chimeric Antigen Receptor T-Cell Therapy: A Patient-Centered Nursing Approach.
    Karla V Ow.
       BACKGROUND: Patients with cancer undergoing advanced therapies, such as chimeric antigen receptor (CAR) T-cell therapy, experience complex treatment-related toxicities that require timely recognition and management. Nurses educate, monitor, and intervene to optimize outcomes and support quality survivorship care for patients.
    OBJECTIVES: This article highlights evidence-based interventions for managing treatment-related complications and outlines strategies to support safe, high-quality care throughout CAR T-cell treatment.
    METHODS: The author conducted a literature review using PubMed®, CINAHL®, and key oncology nursing guidelines to examine relevant studies, guidance, and expert consensus statements to synthesize best practices for nursing assessment and management of immune-based therapy complications.
    FINDINGS: Clinicians ensure safe and effective care through early toxicity recognition, standardized assessment protocols, and multidisciplinary coordination. Evidence-based interventions, as well as psychological support, contribute to improved patient outcomes. Ongoing education and professional development remain essential.
    Keywords:  CAR T-cell therapy; oncology nursing; treatment-related adverse events
    DOI:  https://doi.org/10.1188/26.CJON.S2.E55-E66
  25. Cancers (Basel). 2026 Jun 29. pii: 2110. [Epub ahead of print]18(13):
    Clinical Impact of a Germline CD19 Variant on Treatment Outcome After CAR-T Cell Therapy in Relapsed/Refractory Mantle Cell Lymphoma.
    Simona Andrea Ruckstuhl, Katja Seipel, Inna Shaforostova, Martina Bertschinger, Ulrike Bacher, Thomas Pabst.
       BACKGROUND: Brexu-cel is an established CD19-directed CAR-T cell therapy for relapsed or refractory mantle cell lymphoma, but clinical outcomes are heterogeneous, and germline determinants of response are poorly defined.
    METHODS: We investigated the clinical impact of the CD19 single-nucleotide polymorphism rs2904880 on treatment outcome after brexu-cel CAR-T cell therapy by analyzing genotype-outcome associations in a retrospective single-center cohort of patients with relapsed or refractory mantle cell lymphoma treated with this CAR-T cell therapy.
    RESULTS: Overall survival varied according to CD19 polymorphism, with improved survival of patients carrying the V174 homozygous genotype compared with L174V heterozygotes.
    CONCLUSIONS: The germline CD19 polymorphism may have implications for future risk stratification after brexu-cel CAR-T cell therapy in mantle cell lymphoma, but requires validation in larger, multicenter cohorts.
    Keywords:  chimeric antigen receptor (CAR); mantle cell lymphoma (MCL); overall survival (OS); progression-free survival (PFS); single-nucleotide polymorphism (SNP)
    DOI:  https://doi.org/10.3390/cancers18132110
  26. Clin J Oncol Nurs. 2026 Jul 08. 30 E84-E87
    Cellular Therapy Nurse Experts as a Conduit Between Hospital Clinical, Business Operations, and Revenue Cycle Teams.
    Claire White.
       BACKGROUND: Genetically modified cellular therapies (GMCTs) are increasingly used to treat imminently life-threatening illnesses. However, these therapies are associated with substantial costs, require specialized care, and are available at only a limited number of treatment centers, creating significant barriers to patient access and healthcare delivery.
    OBJECTIVES: The aim of this article is to examine the logistic and financial clearance challenges associated with GMCTs and to highlight the role of nurses in facilitating timely patient access and sustainable therapy delivery.
    METHODS: A descriptive overview was conducted of the financial and operational considerations involved in the administration of GMCTs, with a focus on reimbursement processes, access barriers, and nursing contributions to financial clearance workflows.
    FINDINGS: The high cost, specialized care requirements, and limited availability of GMCTs create complex logistic and reimbursement challenges that can delay treatment access and threaten the sustainability of therapy delivery. Nurses play a critical role in supporting financial clearance processes, helping to streamline access pathways and optimal reimbursement outcomes for patients receiving cell and gene therapies.
    Keywords:  GMCT; cell and gene therapies; cost of care; financial clearance; revenue cycle
    DOI:  https://doi.org/10.1188/26.CJON.S2.E84-E87
  27. Front Immunol. 2026 ;17 1805950
    Engineering a juxtamembrane-targeting CAR T-cell against mesothelin: a novel binder resilient to shed antigen for enhanced efficacy against ovarian and pancreatic cancer.
    John Scholler, Ai Song, Mansi Deshmukh, Decheng Song, Khatuna Gabunia, Mei Ji, Shimin Liu, Ting-Jia Fan, Gayathri Gulendran, Carl H June, Don L Siegel.
      Mesothelin is an attractive target for CAR T therapy on a number of cancer types; however, the efficacy of this therapy is diminished because the bulk of the cell surface-expressed mesothelin is shed through naturally occurring proteolysis leaving behind a short juxtamembrane peptide "stump". The two problems this creates are one, the bulk of the target protein is no longer on the tumor cell and two, soluble, shed mesothelin persists in the tumor microenvironment and circulates in blood and other body fluids, where it can bind mesothelin-targeted CAR T cells and act as a decoy that reduces engagement with tumor cell-surface mesothelin. These issues have contributed at least in part to the lack of desired efficacy in human clinical trials utilizing CAR T cells that target membrane distal regions of mesothelin (i.e., the shed domain) such as those utilizing the variable domains of anti-mesothelin monoclonal antibodies SS1 and M5. In addition, there have been safety concerns regarding the targeting of mesothelin on normal tissues. Here we describe CAR T cells that utilize novel phage display-derived antibodies specific for the mesothelin stump domain, thus being unaffected by the natural process of mesothelin shedding. Mesothelin "stump-specific" CAR T cells (CAR 422) had cytotoxicity and in vivo activity that were comparable to previously studied anti-mesothelin CAR T cells. Importantly, CAR 422 T cells were effective against tumor cells that were resistant to conventional anti-mesothelin CAR T cells and showed reduced on-target/off tumor toxicity in a human mesothelin knock-in mouse model. Thus, CAR 422 holds potential as a next-generation therapy for challenging solid tumors.
    Keywords:  adoptive cell therapy; chimeric antigen receptor; efficacy improvement; mesothelin; ovarian and pancreatic cancer; safety enhancement; solid tumors; therapeutic development
    DOI:  https://doi.org/10.3389/fimmu.2026.1805950
  28. PLoS One. 2026 ;21(7): e0352813
    Gene expression profiling of recipient immune cells induced by 7 × 19 CAR-T cell dosing in a syngeneic mouse model.
    Yo Muraki, Yuumi Okuzono, Rina Kurisu, Akiko Abiru, Yukimi Sakoda, Koji Tamada, Chihiro Take.
      Chimeric antigen receptor (CAR)-T cell therapy is effective for hematologic malignancies; however, the response of solid tumors is limited because of the immunosuppressive tumor microenvironment, antigen heterogeneity, and lack of persistence of transferred T cells. To overcome these challenges, CAR-T cells expressing interleukin-7 and CC chemokine ligand 19 (7 × 19 CAR-T) were generated to achieve potent antitumor efficacy through the recruitment and proliferation of CAR-T cells and endogenous immune cells. To elucidate the underlying mechanism of 7 × 19 CAR-T cells against solid tumors, we analyzed the cellular composition and gene expression profiles of host immune cells following CAR-T cell infusion in a murine solid tumor model. Antihuman CD20 7 × 19 CAR-T cells were prepared using Thy 1.1 congenic mice and administered to C57BL/6N mice bearing subcutaneous MC38 tumors expressing human CD20. The tumors were harvested 4 days postinfusion to capture early immune responses before overt tumor regression. CD90.1- recipient immune cells were subjected to flow cytometry analysis, and transcriptomic changes were determined using AmpliSeq and single-cell RNA seq. An increase in recipient CD8 + T cells and macrophages was observed in the tumor of mice treated with 7 × 19 CAR-T cells, but not with conventional CAR-T. The expression of chemokines and genes associated with the inflammatory pathway was upregulated only in recipient immune cells of the 7 × 19 CAR-T-treated mice. Single-cell RNA-seq analysis revealed upregulation of pro-inflammatory genes and chemokines in the dendritic cell and monocyte/macrophage populations. These results indicate that 7 × 19 CAR-T cells initiate the early recruitment and activation of host immune cells, which contributes to their superior antitumor activity compared with conventional CAR-T cells.
    DOI:  https://doi.org/10.1371/journal.pone.0352813
  29. Cytotherapy. 2026 Apr 03. pii: S1465-3249(26)00782-6. [Epub ahead of print]28(9): 102821
    Quality control of biological raw materials to ensure the viral safety of cell and gene therapy products.
    Yusuke Nozaki, Satomi Naito, Ayana Ishii, Kyo Tezuka, Jun Matsumoto, Yoshiaki Maruyama.
      Most cell and gene therapy (CGT) products use human- or animal-derived raw materials during manufacturing. The viral safety of the final products must be ensured from the point of use of the biological raw materials. Cell therapy products, which involve living cells as the final product, are vulnerable to heat and chemicals and cannot be filtered. Therefore, it is not possible to establish a process for removing and inactivating viruses and microorganisms from these products, as is performed for biopharmaceuticals. Ensuring the viral safety of the final product requires rigorous control of the contamination risks posed by biological raw materials, which are considered more critical than those encountered in conventional biopharmaceutical manufacturing. Based on the consultation and review of CGT products by the Pharmaceuticals and Medical Devices Agency, we evaluated frequent issues and described the points to be considered regarding the quality control of biological raw materials used in the manufacturing of CGT products.
    Keywords:  CGT products; PMDA; ancillary material; raw material; standards; viral safety
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102821
  30. Mol Ther. 2026 Jul 17. pii: S1525-0016(26)00605-2. [Epub ahead of print]
    Injectable bioinstructive microfoam for rapid bedside/in vivo programming of CAR-T cells.
    Sirkka B Stephan, Carrie L Cummings, Katelyn Fitzgerald, Hoku West-Foyle, Eric J Cavanaugh, Inci Cevher Zeytin, Stefan Radtke, Hans-Peter Kiem, Andras A Heczey, Matthias T Stephan.
      While chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of hematological malignancies and are being explored for solid tumors, their widespread use remains limited by high costs, complex manufacturing requirements, long wait times, and unequal access. Here, we describe a methylcellulose-based gene therapy microfoam that enables rapid generation of CAR-T cells for subcutaneous administration within hours of blood collection. Specifically, we demonstrate that colocalization of T cells and vector within the foam promotes efficient CAR gene transfer. Following subcutaneous injection, newly programmed CAR-T cells disperse systemically and mediate regression of distal tumors in mouse xenograft models of lymphoma and hepatocellular carcinoma, with anti-tumor activity comparable to conventionally manufactured CAR-T cells. The platform operates as a sterile closed system and does not require prolonged cell culture, centralized manufacturing facilities, or cleanroom-based cell production. These findings establish proof of concept for a simplified CAR-T generation strategy that may reduce manufacturing complexity and infrastructure requirements relative to conventional CAR-T therapy while improving the accessibility of cellular immunotherapies.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.037
  31. bioRxiv. 2026 Jul 03. pii: 2026.07.02.736191. [Epub ahead of print]
    Radioligand therapy in combination with CAR T cells overcomes the heterogeneous immunosuppressive prostate tumor microenvironment.
    Jiangyue Liu, Iveta Fajnorova, Yuwei Ren, Kofi Poku, Shuai Yang, Yu-Hsuan Fu, Cari A Young, Lupita S Lopez, Reginaldo C A Rosa, Handan Hong, Jingting Hao, Deyi Chen, Pauline Jeanjean, Ines Camille Azrour, Ava Fakharpour, Lea Christian, John P Murad, Yukiko Yamaguchi, Laura H Porter, Vikram Adhikarla, Russell Rockne, Stephen J Forman, Yun Rose Li, Tanya B Dorff, Gail R Risbridger, Renea Taylor, Christine E Mona, Saul J Priceman.
      177 Lu-PSMA-617 (Pluvicto TM , Lu-177 RLT) is an FDA-approved targeted radioligand therapy (RLT) for metastatic castration-resistant prostate cancer (mCRPC), but its durability of response to this singular approach poses a challenge to the field. Chimeric antigen receptor (CAR) T cell therapy has revolutionized clinical practice for hematological malignancies, but its clinical development for solid tumors, including mCRPC, has been encumbered by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). Here, we evaluate the therapeutic combination of Lu-177 RLT and PSCA-CAR T cells to overcome these barriers. In human xenograft and mouse syngeneic prostate cancer models with homogeneous or heterogeneous antigen expression, the sequential administration of Lu-177 RLT, cyclophosphamide (Cy), and PSCA-CAR T cells improves tumor control and prolongs survival compared to monotherapies. Mechanistically, Lu-177 RLT alone or with Cy remodels the TME by promoting pro-inflammatory myeloid responses and activating endogenous T cells, while enhancing CAR T cell activation and effector function. We additionally evaluated 225 Ac-PSMA-617 RLT as an emerging approach in combination with CAR T cells and observed anti-tumor responses, supporting its potential as an alternative RLT partner. These findings support RLT as an immune priming strategy to enhance CAR T cell therapy and provide a rationale for clinical translation of this combination in mCRPC.
    One Sentence Summary: Combining 177 Lu-PSMA-617 radioligand therapy with PSCA-CAR T cells improves tumor control and survival in prostate cancer models by overcoming the antigen heterogeneity and reshaping the immunosuppressive tumor microenvironment.
    DOI:  https://doi.org/10.64898/2026.07.02.736191
  32. Cancers (Basel). 2026 Jun 30. pii: 2128. [Epub ahead of print]18(13):
    Real-World Dermatologic Adverse Events of CAR T-Cell Therapy: A Decade-Wide Disproportionality Analysis of the FDA Adverse Event Reporting System.
    Manideepa Maji, Saikat Mandal, Arkadeep Dhali, Ashish Sharma.
      Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed haematological-malignancy care, but its dermatologic safety profile remains incompletely characterised across products and indications. Methods: We analysed 8,431,841 deduplicated FDA Adverse Event Reporting System reports from 2016 Q3 to 2026 Q1. Seven approved CAR T-cell products were identified. The primary outcome was any dermatologic adverse event, defined using the MedDRA Skin and subcutaneous tissue disorders system organ class. Secondary outcomes included broad severe cutaneous adverse reactions, narrow Stevens-Johnson syndrome/toxic epidermal necrolysis, and 14 phenotype-specific categories. Multivariable models adjusted for demographics, polypharmacy, cancer, immune checkpoint inhibitor exposure, lymphodepleting chemotherapy and cytokine release syndrome. Additional sensitivity analyses evaluated HSCT/GVHD co-reporting proxies, infection and cytopenia/bleeding proxies, severe-event clinical characteristics, comparator robustness and multiplicity correction. Results: Dermatologic adverse events were identified in 996,654 reports, including 425 CAR-T-associated cases. CAR T-cell exposure was associated with reduced adjusted reporting odds for the primary outcome (adjusted odds ratio 0.13, 95% confidence interval 0.09-0.20) and broad severe cutaneous adverse reactions (0.35, 0.23-0.52). The primary SKIN_ANY reduced-reporting pattern was consistent across all-FAERS, haematological-malignancy and active haematology-oncology comparators. HSCT/GVHD proxy co-reporting was uncommon and did not materially alter estimates. Severe dermatologic reports frequently co-mentioned CRS and serious outcomes. The tisagenlecleucel vascular cutaneous signal was nominally significant but attenuated after excluding infection-attributable and cytopenia/bleeding-proxy reports. Conclusions: Within spontaneous reporting systems, CAR T-cell therapy showed reduced relative reporting of dermatologic adverse events across broad, phenotype-specific and product-level analyses. These results should be interpreted as differences in reporting behaviour, not as evidence of reduced true clinical incidence or lower patient-level risk. Early severe cutaneous reports frequently overlapped with cytokine release syndrome, while infection, cytopenia/bleeding proxies and supportive-care drugs were important alternative explanations for selected cutaneous signals.
    Keywords:  CAR T-cell therapy; FAERS; cytokine release syndrome; dermatologic adverse events; pharmacovigilance; severe cutaneous adverse reactions
    DOI:  https://doi.org/10.3390/cancers18132128
  33. Nat Rev Immunol. 2026 Jul 16.
    Interleukin-18 armours antitumour immune effectors.
    Akshat Sharma, Gina G Bishara, Scott H Olejniczak, Joyce E Ohm, Renier J Brentjens, Ajay Gupta.
      Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family that has an important role in antitumour and antiviral immunity. Growing interest in its therapeutic potential has led researchers to explore strategies that harness IL-18 to modulate the tumour microenvironment. For example, engineered T cells are being armoured with IL-18 to enhance adoptive cell therapies and strengthen other immunotherapy approaches. As these strategies move towards clinical application, a key translational challenge is identifying the molecular mechanisms that influence treatment response and resistance, crucial for guiding trial design and patient selection across tumour types. This Review revisits the fundamental biology of IL-18, including its origins, cellular sources and regulatory networks, particularly those involving IL-18 binding protein (IL-18BP) and IL-37. We discuss how IL-18 promotes interferon-γ (IFNγ) production within the tumour microenvironment, supporting M1-like macrophage polarization, CD8+ cytotoxic T cell and CD4+ T helper 1 cell responses, natural killer cell activity and durable T cell memory. We also discuss preclinical models of IL-18 delivery, including dendritic cell platforms and cellular therapies, and highlight emerging strategies such as IL-18BP blockade and IL-18-secreting CAR T cells. Finally, we review results from early clinical studies and outline key challenges for translation, including the dual protumour and antitumour roles of IL-18.
    DOI:  https://doi.org/10.1038/s41577-026-01330-1
  34. Mol Ther Oncol. 2026 Sep 17. 34(3): 201273
    mRNA CAR T cells promote tolerable, tunable therapy in preclinical high grade glioma models.
    Monica Pomaville, Jessica B Foster.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201273
  35. Adv Mater. 2026 Jul 15. e74058
    Nanomaterials Drive In Vivo CAR Immune Cells Engineering.
    Meifen Luo, Kai Liao, Jinxi Chang, Junze Xie, Xing-Jie Liang, Qi Lei, Weisheng Guo.
      Chimeric antigen receptor (CAR) immune cell therapy has emerged as a cornerstone of modern cell-based medicine, demonstrating potent clinical efficacy against a range of malignant tumors and autoimmune diseases. Nevertheless, conventional ex vivo CAR immune cell manufacturing is hindered by complexity, high costs, and significant inter-individual variability, which have limited its broad clinical application. These bottlenecks have prompted a paradigm shift toward in vivo CAR engineering, wherein nanocarriers directly deliver genetic material to circulating or tissue-resident immune cells, substantially simplifying the production process. This review first outlines the evolution of CAR immune cell therapy and key limitations of ex vivo approaches and then examines major delivery platforms for in vivo approaches. Comparative analyses are presented across delivery efficiency, cellular tropism, and expression kinetics, with particular emphasis on delineating the mechanistic distinctions and application boundaries between transient and durable expression strategies. We further dissect the critical challenges, including receptor-mediated non-specific immune activation, nanocarrier-associated immunogenicity constraining repeated administration, and delivery barriers imposed by the solid tumor microenvironment. Finally, the intrinsic trade-off between therapeutic durability and biosafety across distinct delivery platforms is discussed, along with the necessity that their clinical translation hinges on systematic optimization of delivery precision, immune compatibility, and expression controllability.
    Keywords:  CAR immune cells; cell therapy; clinical translation; in vivo cell engineering; nanocarriers
    DOI:  https://doi.org/10.1002/adma.74058
  36. Front Immunol. 2026 ;17 1879668
    CAR-based cellular therapy for refractory systemic lupus erythematosus: an overlap-controlled systematic review.
    Sheng-Guang Li, Ruohan Yu, Lina Zhang, Jing Zhang, Yadan Zou, Ji Li, Ting Long, Yanfeng Zhang, Jing Pan.
       Objectives: To define the current evidence for CAR-based cellular therapy in relapsed or refractory systemic lupus erythematosus (SLE) by resolving overlapping reports and synthesising patient-level phenotype, safety and efficacy data. The primary purpose was evidence mapping with duplicate-count control; mechanistic immune-reset interpretation and platform differences were treated as secondary, hypothesis-generating questions rather than formal comparative-effectiveness analyses.
    Methods: PubMed, Embase and Web of Science were searched for reports published from January 2020 to March 2026. Eligible records described CAR-based cellular therapy in relapsed, refractory or organ-threatening SLE. Overlapping publication streams were collapsed into independent study units, and a deduplicated patient-level master dataset was constructed. Outcomes were summarised descriptively using conservative exact patient-level attribution, with endpoint evaluability reported separately from observed outcome proportions.
    Results: Twenty-one independent study units comprising 114 counted patients were included. The cohort was predominantly female (100/114, 87.7%), young (median age 32.0 years) and heavily pretreated, with renal involvement in 89 patients (78.1%). Autologous CD19 CAR-T and BCMA-containing platforms accounted for most treated patients, with additional allogeneic CAR-T and CAR-NK experience. Among exactly evaluable rows, clinical response was documented in 45 of 45 patients, DORIS remission in 13 of 15, SLE Responder Index-4 response in 20 of 20, renal improvement in five of five and drug-free remission in 28 of 58. These proportions should not be read as pooled response rates because exact endpoint denominators were small or incomplete for several outcomes. Cytokine release syndrome was usually low grade, and immune effector cell-associated neurotoxicity syndrome was uncommon. Severe inflammatory toxicities occurred in selected paediatric or highly inflammatory settings. Endpoint evaluability varied substantially across studies.
    Conclusion: CAR-based cellular therapy shows substantial promise as an immune-reset strategy for refractory SLE, particularly in renal-dominant disease. However, current evidence remains early, uncontrolled and incompletely reported. Sparse exactly evaluable denominators, publication bias, selective outcome reporting and short follow-up preclude definitive platform comparisons, supporting standardised prospective studies with harmonised efficacy, immune-reconstitution and toxicity endpoints.
    Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD420261330006.
    Keywords:  CAR-NK; CAR-T; cellular therapy; lupus nephritis; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1879668
  37. Expert Opin Biol Ther. 2026 Jul 13. 1-12
    Potential of new BCMA-targeting therapies in overcoming resistance in multiple myeloma.
    Manraj Singh Sra, Shaji Kumar.
       INTRODUCTION: B-cell maturation antigen is an important therapeutic target in multiple myeloma. Several chimeric antigen receptor T-cell (CAR-T) products, bispecific T-cell engagers, and antibody-drug conjugates targeting BCMA are approved for relapsed/refractory disease.
    AREAS COVERED: This review summarizes the current landscape of BCMA-directed therapies, outlines mechanisms of resistance, and discusses strategies to overcome resistance.
    EXPERT OPINION: Resistance to BCMA-directed therapies is multifactorial and varies by modality. Antigen-related escape, including TNFRSF17 biallelic loss, non-truncating mutations in the BCMA extracellular domain, γ-secretase-mediated shedding, and transcriptional downregulation, is the dominant mechanism after prolonged exposure to bispecifics. T-cell-intrinsic dysfunction, characterized by exhaustion, trogocytosis, and impaired fitness, is a key driver of relapse after CAR-T therapy. Tumor-intrinsic genomic complexity and plasma cell identity escape, a recently described state of highly proliferative, lineage-divergent plasma cells with downregulation of BCMA, predict primary refractoriness across modalities. Development of multi-antigen targeting approaches and combination therapies is a promising strategy to improve outcomes.
    Keywords:  BCMA; Multiple myeloma; ciltacabtagene autoleucel; idecabtagene vicleucel; teclistamab
    DOI:  https://doi.org/10.1080/14712598.2026.2703858
  38. Mol Cell Biochem. 2026 Jul 15.
    EF-1α-driven nanobody-based CD19-redirected CAR-T cells retain the antitumor efficacy, antigen-driven expansion, and cytokine secretion of CMV-driven counterparts.
    Marzieh Mazinani, Pooria Safarzadeh Kozani, Fatemeh Rahbarizadeh.
      Chimeric antigen receptor (CAR) T-cell efficacy requires sustained transgene expression. Cytomegalovirus (CMV) promoters drive strong initial expression but undergo silencing, while elongation factor-1α (EF-1α) promoters resist inactivation. This study evaluated whether transitioning a previously established VHH-based CD19-redirected CAR construct to EF-1α promoter control compromises antitumor functionality. Lentiviral particles encoding identical second-generation CAR constructs (CD19-specific VHH, CD8α transmembrane, 4-1BB costimulatory, CD3ζ signaling domains) under CMV (HCAR-T) or EF-1α (ECAR-T) promoters transduced primary human T cells. Cytotoxicity (effector-to-target ratios 1:1-10:1), antigen-driven proliferation, and cytokine secretion against CD19⁺/CD19⁻ targets were quantified. Promoter substitution from CMV to EF-1α in the matched VHH-based CAR construct did not alter CAR-T cell functionality. ECAR-T and HCAR-T cells exhibited statistically comparable cytotoxicity against CD19⁺ Raji (81.6% ± 2.4 versus 81.8% ± 2.5 at 10:1, respectively) and NALM6 cells (82.2% ± 2.3 versus 80.7% ± 3.5 at 10:1, respectively). Proliferation against Raji (ECAR-T: 94.2% ± 7.54 versus HCAR-T: 91.1% ± 6.03) and NALM6 (ECAR-T: 94.9% ± 4.35 versus HCAR-T: 92.5% ± 6.34) was comparable. IFN-γ, IL-2, and TNF-α secretion against CD19⁺ targets was statistically comparable between ECAR-T and HCAR-T groups and strictly CD19-dependent. EF-1α preserved the antitumor potency of nanobody-based CD19-redirected CAR-T cells, supporting its use as a clinically relevant promoter for further development of this VHH-based CAR-T cell platform.
    Keywords:  CD19; CMV; Cancer immunotherapy; Chimeric antigen receptor; EF-1α; Nanobody
    DOI:  https://doi.org/10.1007/s11010-026-05623-w
  39. Leuk Lymphoma. 2026 Jul 16. 1-9
    The impact of radiotherapy on the therapeutic response of patients treated with CAR T-cell therapy for high-grade lymphoma: a systematic review.
    Maïfa Belghoul, Andrea Kuhnl, Timothy Chevassut, Robin Sanderson, George Mikhaeel, Reuben Benjamin, Piers Patton, John Jones.
      Chimeric antigen receptor T (CAR -T) cell therapy is a promising form of cancer treatment with proven efficacy in relapsed/refractory lymphomas. However, there are limitations, including toxicity, failure to achieve immunological memory, and immune evasion. The rationale for administering radiotherapy (RT) with CAR -T, includes increased antigen exposure and immune activation. We studied the current evidence for RT use in high-grade lymphoma patients treated with CD19 CAR-T therapy. The outcomes of interest included progression free survival, complete response rate, overall survival, and incidence of treatment associated toxicities. Five studies were included encompassing 1034 patients. The results indicate that RT is a safe and effective bridging strategy. The combination of RT and CAR-T is associated with improved complete remission rates, but the evidence is limited by cohort heterogeneity and possible selection bias. Further prospective trials are required to confirm this and to determine whether survival outcomes are affected.
    Keywords:  CAR-T cell therapy; High-grade Lymphoma; Radiotherapy
    DOI:  https://doi.org/10.1080/10428194.2026.2685253
  40. Br J Haematol. 2026 Jul 12.
    The development of novel chimeric antigen receptor gamma-delta T cells against multiple myeloma and single-cell RNA sequencing analysis.
    Yang Hong, Cuiling Zhang, Jue Wang, Jianhua Zhang, Yuanyuan Zhu, Yage Zhang, Bang Shao, Yongkun Yang, Taochao Tan, Peipei Xu, Bing Chen.
      Chimeric antigen receptor (CAR) gamma-delta (γδ) T cells offer a major histocompatibility complex-independent, off-the-shelf alternative to conventional CAR alpha-beta (αβ) Tcells, but their efficacy in multiple myeloma (MM) remains underexplored. In this work, we developed a series of novel CAR γδ T cells redirected to B-cell maturation antigen (BCMA) and performed functional assays compared to CAR αβ T cells. As a result, novel CAR γδ T cells demonstrated similar activation upon antigen stimulation compared with CAR αβ T cells but showed lower proliferative capacity and less durable cytotoxicity. In vivo, higher doses of CAR γδ T cells were required to achieve tumour control comparable to CAR αβ T cells. Among CAR constructs, those with cluster of differentiation 3 (CD3ε or CD3ζ) intracellular domain exhibited superior cytotoxicity and in vivo efficacy. Single-cell transcriptomic profiling revealed the low ratio of cycling CAR γδ T cells after antigen stimulation limited the persistence of CAR γδ T cells. In conclusion, our developed novel CAR γδ T cells effectively eliminated MM cells in vitro, but exhibited limited in vivo persistence compared to traditional CAR αβT cells. These findings establish a baseline for utilizing γδ T cells as an off-the-shelf platform and highlight that addressing the proliferation bottleneck through further engineering is essential for future clinical translation.
    Keywords:  CD3; chimeric antigen receptor; gamma‐delta T‐cell; multiple myeloma; single‐cell RNA sequencing
    DOI:  https://doi.org/10.1111/bjh.70660
  41. Int J Nanomedicine. 2026 ;21 612549
    Re-Arming the Immunological Radar: The Translational Landscape of Dendritic Cell-Centric Nanotherapeutics and Microenvironment Remodeling for Osteosarcoma.
    Zhi Zheng.
      For decades, survival rates in metastatic Osteosarcoma (OS) have starkly plateaued. The persistent failure of immune checkpoint blockade underscores a critical reality: the true therapeutic bottleneck is not merely exhausted T cells, but a profound upstream defect in antigen presentation by Dendritic cells (DCs). To overcome this, this review comprehensively outlines the translational landscape of DC-centric therapeutics in OS, tracing the paradigm shift from foundational ex vivo cellular vaccines to advanced in situ vaccination strategies. Specifically, we highlight how intelligent biomaterials and engineered endogenous vesicles bypass external manipulation to directly prime immunity within the tumor bed. Furthermore, we extensively evaluate state-of-the-art physicochemical nanomedicines-encompassing photothermal, sonodynamic, and metallo-immunologic modalities-engineered to force severe organellar stress, trigger robust immunogenic cell death, and actively reverse the spatial and metabolic paralysis of resident DCs. By coupling these interventions with targeted agents and adoptive cellular therapies, we map a synergistic roadmap for closing the cancer-immunity cycle. Despite remarkable preclinical successes, translating these ultra-complex nanoplatforms faces formidable scale-up challenges, and uncalibrated innate hyper-stimulation risks profound DC exhaustion. Moving forward, transitioning toward logic-gated, metabolically precise delivery systems is imperative to flawlessly repair the innate-adaptive immunity bridge and achieve durable OS eradication.
    Keywords:  dendritic cells; immunogenic cell death; in situ vaccination; nanotherapeutics; osteosarcoma
    DOI:  https://doi.org/10.2147/IJN.S612549
  42. Front Immunol. 2026 ;17 1776472
    Recent applications of artificial intelligence in cancer radiotherapy and immunotherapy: current status and future directions.
    Qingmiao Shi, Mengjuan Xuan, Chi Lv, Zhibo Zhang, Xiaonan Geng, Di Huang, Xinjun Hu.
      Artificial intelligence (AI) enhances the precision, personalization, and efficiency of cancer treatment through deep learning and machine learning techniques. This review comprehensively examines the evolution of AI and its expanding applications in cancer radiotherapy, immunotherapy, and drug discovery and repurposing. In radiotherapy, AI enables automated medical image segmentation, thereby facilitating the accurate delineation of tumor targets. Furthermore, AI-driven feedback systems support clinicians in developing individualized treatment plans by offering real-time assessment of treatment safety and potential efficacy. In the context of cancer immunotherapy, AI integrates multi-omics data to advance the discovery of novel biomarkers, analyze the tumor immune microenvironment, and accurately predict responses to immune checkpoint inhibitors. Moreover, AI accelerates drug discovery and repurposing through virtual screening, protein structure prediction, and the identification of novel therapeutic targets. However, the true clinical value of these AI models depends heavily on their generalizability across diverse patient cohorts and their performance compared to standard clinical baselines. Despite these promising prospects, AI still faces challenges in clinical applications, such as insufficient data standardization, poor model interpretability, and a lack of ethical oversight, delaying its formal inclusion into standardized clinical guidelines. With the rapid growth of data volume and computational power, AI is expected to play an increasingly central role in cancer management, holding immense promise for improving patient outcomes and advancing precision oncology.
    Keywords:  artificial intelligence; cancer; drug discovery; immunotherapy; radiotherapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1776472
  43. Mol Ther Oncol. 2026 Sep 17. 34(3): 201280
    Reversible control of CAR T cells through PROTAC compound targeting bromodomain mutant.
    Yeongrin Kim, Da Yeon Lee, Ji U Choi, Moonjung Jeun, Heung Kyoung Lee, Sang Un Choi, Chi Hoon Park.
      Proteolysis-targeting chimera (PROTAC) is an innovative strategy for selectively degrading target proteins. In this study, we demonstrate that a PROTAC compound, AGB1, specifically degrades a bromodomain L387V mutant (BD2m)-tagged chimeric antigen receptor (CAR-BD2m). Unlike ARV771, which degrades wild-type bromodomains, AGB1 does not impair normal T cell function, as it spares endogenous bromodomain-containing proteins such as BRD4. Notably, AGB1 degrades CAR-BD2m with approximately 10-fold higher efficiency than ARV771 targets the wild-type BD2-tagged CAR (CAR-BD2w). In vitro, AGB1 reversibly modulates the activity of CAR-BD2m T cells through targeted CAR degradation. In preclinical models, CAR-BD2m T cells exhibit potent antitumor activity comparable to that of conventional CAR T cells, and AGB1 effectively regulates the activity of CAR-BD2m T cells. Together, these results suggest that the BD2m system can serve as an efficient tagging platform for targeted CAR protein degradation, thereby enabling successful and reversible control of CAR T cell activity in patients.
    Keywords:  CAR T cells; PROTAC; adoptive immunotherapy; cancer; reversible control
    DOI:  https://doi.org/10.1016/j.omton.2026.201280
  44. Stat Methods Med Res. 2026 Jul 16. 9622802261458072
    Adaptive spline-based weighting functions for blended survival curve extrapolation.
    Hao Chen, Clara Grazian.
      Health technology assessment frequently requires survival predictions well beyond the observed trial follow-up, yet single parametric models fitted to short horizons can accumulate long-term bias. Current guidance also encourages the principled use of external evidence, such as registry summaries or expert anchors, while maintaining fidelity to the trial data. We introduce an adaptive spline-weighted blended extrapolation on the cumulative-hazard scale that unifies these aims. The observation side is fitted on the trial window using a piecewise-exponential Cox-type model with a smooth prior-driven continuation beyond the administrative cutoff, implemented via INLA. The external side is an anchored Gompertz tail identified by a prespecified survival level at a clinically relevant time. To blend the two components, we compare their cumulative hazards, learn a monotone P-spline score over time, and pass it through a logistic link to obtain a data-driven, time-varying weight. A simple "temperature" scaling controls the slope of this weight and provides a practical guarantee of non-negative blended hazards on a chosen grid, preserving adaptivity while ensuring feasibility. Across Monte Carlo scenarios spanning multiple tail shapes and censoring levels, the method delivers consistently lower absolute survival error, smaller restricted mean survival time error, and improved stability compared with fixed-schedule blending and single-family parametric models. In a SEER registry study with three-year observation and ten-year extrapolation, the blended curve tracks the Kaplan-Meier estimates within follow-up and transitions smoothly toward the anchored tail, yielding small long-horizon errors across cancer sites and age strata. The framework is modular, interpretable, and easily extended to alternative tails and multiple anchors. An open-source implementation is available in the R package survblendr at https://github.com/haohaostats/survblendr.
    Keywords:  Gompertz tail; Survival extrapolation; blended survival curves; health technology assessment; monotone P-splines; shape-constrained additive models; survival anchor
    DOI:  https://doi.org/10.1177/09622802261458072
  45. bioRxiv. 2026 Jul 09. pii: 2026.07.07.737099. [Epub ahead of print]
    Coordinated expansion of CD163⁺ monocytes and immature CD177⁺ neutrophils marks severe neurotoxicity after CD19 CAR T cell therapy.
    Tony Chour, Nikhita Poole, Hugh R MacMillan, Katelyn Burleigh, David R Glass, Emily C Liang, Ryan Basom, Bobbie-Jo M Webb-Robertson, Kelly Stratton, Derrik Gratz, Annalyssa N Long, Anna E Elz, Jennifer J Huang, Alexandre V Hirayama, Stanley R Riddell, Jordan Gauthier, Heather H Gustafson, Evan W Newell, Sylvain Simon.
      Immune effector cell-associated neurotoxicity syndrome (ICANS) is a major complication after CAR T cell therapy, but its underlying mechanisms remain poorly understood. We performed longitudinal immune profiling of paired whole blood and serum samples from patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) treated with CD19 CAR T cells. At peak neurotoxicity, high-dimensional mass cytometry and serum proteomics identified the expansion of CD163⁺ monocytes and immature CD10 low CD101 low neutrophils correlated with elevated serum ST2 and IL-2RA concentrations. Integrative immune module analysis identified these features among the strongest predictors of ICANS severity. Independent single-cell transcriptomic profiling validated the emergence of immunoregulatory CD163⁺ monocytes and identified CD177 as a biomarker of ICANS-associated immature neutrophils. Together, these findings reveal a coordinated myeloid inflammatory network associated with ICANS and nominate candidate biomarkers and therapeutic targets for improving the safety of CAR T cell therapy.
    Significance: We demonstrate that immunoregulatory CD163 + monocytes and immature, activated CD177 hi CD10 low CD101 low neutrophils emerge in patients with moderate to severe ICANS at peak toxicity following CD19 CAR T cell therapy. These findings identify an uncharacterized myeloid network potentially contributing towards ICANS pathogenesis.
    DOI:  https://doi.org/10.64898/2026.07.07.737099
  46. J Biopharm Stat. 2026 Jul 13. 1-23
    Overview of dose-finding designs and trials in cell and gene therapies.
    Revathi Ananthakrishnan, Bambang Adiwijaya, Alan Y Chiang, Cong Han, Qiuling Ally He, Andrew Lewandowski, Rong Liu, Frank Shen, Hao Sun, Daniel Li.
      This manuscript provides an overview of recent and relevant dose-finding designs for cell and gene therapies (CGT). We start with an introduction of dose-finding. We then provide a brief overview of CGT, what dose‑escalation designs have already been developed to determine the maximum tolerated dose (MTD) and the optimal biological dose (OBD), and what dose‑escalation designs have been used so far in CGT approvals. We then discuss dose-finding design considerations and challenges for dose-finding for CGT.
    Keywords:  Dose-finding; cell therapies; dose escalation designs used in approved cell or gene therapies; dose optimization; gene therapies
    DOI:  https://doi.org/10.1080/10543406.2026.2684622
  47. Leuk Lymphoma. 2026 Jul 16. 1-3
    The role of radiotherapy in bridging to CAR T-cell therapy for high-grade B-cell lymphoma.
    Michael MacManus, Mark Dowling.
      
    DOI:  https://doi.org/10.1080/10428194.2026.2694679
  48. J Prev Med Public Health. 2026 Apr 27.
    Protecting Informational Self-Determination in AI-driven Precision Oncology: Privacy, Ethics, and Governance Challenges.
    Minsoo Jung.
      Artificial intelligence (AI) is rapidly transforming cancer care, from diagnosis and risk prediction to treatment planning and drug development. These advances depend on the large-scale integration of genomic, imaging, and clinical data, intensifying privacy and ethical concerns. This study examines emerging challenges in AI-driven precision oncology and explores strategies for protecting patients' informational self-determination through a narrative ethical and policy analysis informed by recent empirical and technical research. Even data considered de-identified, including molecular and imaging profiles, may enable inference of sensitive attributes through machine-learning analytics. Although many patients support the clinical promise of AI, they express concerns about secondary data use without meaningful consent, commercialization, and security breaches. Privacy violations threaten autonomy, confidentiality, and trust and may exacerbate existing inequities. Current regulatory frameworks, including the General Data Protection Regulation and the Health Insurance Portability and Accountability Act, focus primarily on identifiability and the removal of explicit identifiers. However, AI systems generate risks not only through re-identification but also through inferential analytics that derive new privacy-relevant information, such as disease susceptibility or familial risk, from ostensibly anonymized data. Addressing these gaps requires multilayered governance that combines privacy-preserving technologies, dynamic consent, data minimization, transparency, and strengthened legal safeguards to sustain public trust.
    Keywords:  Artificial intelligence; Cancer ethics; Health data privacy; Informational self-determination; Precision oncology
    DOI:  https://doi.org/10.3961/jpmph.26.094
  49. bioRxiv. 2026 Jul 11. pii: 2026.07.08.737087. [Epub ahead of print]
    A Donor T-Cell Receptor Structural Signature Determines Alloreactive Potential and Predicts Acute Graft-Versus-Host Disease.
    Ximi K Wang, Ajna Uzuni, Lingting Shi, David W Harle, Rodney Macedo, Michael Pressler, Christian A Gordillo, Kirubel Belay, Shami Chakrabarti, Joshua Fuller, Elizabeth O Hexner, Alison W Loren, David L Porter, Markus Y Mapara, Megan Sykes, Elham Azizi, Ran Reshef.
      Acute graft-versus-host disease (GVHD) remains a lethal barrier to successful allogeneic hematopoietic cell transplantation, yet pre-transplant donor selection entirely ignores hypervariable T-cell receptor (TCR) architecture. Here, by characterizing over 64,000 alloreactive clonotypes, we demonstrate that human alloreactivity is dictated by a constrained, predictable baseline structural signature. Pathogenic, tissue-infiltrating alloreactive T cells exhibit significantly shortened CDR3β regions, altered antigen-facing biophysical features, biased VJ gene usage and extensive inter-donor sharing originating from public anti-pathogen memory reservoirs. These potent clones natively cluster within the high-frequency fraction of the unstimulated baseline donor repertoire. We introduce R50, an assay-independent metric quantifying this clonal dominance, which independently predicted a six-fold increased risk of acute GVHD in a cross-institutional cohort. This scalable in silico platform shifts pre-transplant risk stratification from HLA typing and demographic surrogates to precision immune-receptor modeling.
    DOI:  https://doi.org/10.64898/2026.07.08.737087
  50. Purinergic Signal. 2026 Jul 17. pii: 63. [Epub ahead of print]22(4):
    Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.
    Luca Antonioli, György Haskó.
      Over the past three decades, adenosine signalling has emerged as a fundamental regulatory system controlling immune responses, tissue homeostasis, metabolism, and repair processes. The identification of four adenosine receptor subtypes and the development of selective agonists and antagonists generated substantial enthusiasm for therapeutic targeting across a broad spectrum of inflammatory, autoimmune, metabolic, and neoplastic diseases. However, despite compelling preclinical evidence, the clinical translation of adenosine-based therapies has often yielded inconsistent or disappointing results. Increasing evidence suggests that these limitations may not primarily reflect inadequate pharmacological tools, but rather an incomplete understanding of the remarkable spatial, temporal, and cellular heterogeneity of adenosine signalling in human disease. Advances in immunology, systems biology, single-cell technologies, spatial transcriptomics, metabolomics, and artificial intelligence are revealing highly diverse purinergic landscapes across tissues and patient populations. These findings challenge the traditional "one receptor-one disease" paradigm and support a transition toward precision medicine approaches capable of identifying disease-specific and patient-specific purinergic signatures. In this commentary, we discuss how the field is moving beyond classical receptor pharmacology toward biomarker-driven patient stratification. We propose that the next generation of purinergic therapeutics will depend not only on improved drugs but also on the ability to define when, where, and in whom adenosine signalling should be manipulated. Such a shift may ultimately represent the long-awaited bridge between decades of successful experimental research and meaningful clinical implementation.
    Keywords:  Adenosine; Adenosine receptors; Biomarkers; Personalized therapy; Precision medicine; Purinergic signalling
    DOI:  https://doi.org/10.1007/s11302-026-10175-1
  51. Nat Cancer. 2026 Jul 15.
    A targetable micropeptide reprograms macrophages to suppress T cell anti-tumor immunity.
      
    DOI:  https://doi.org/10.1038/s43018-026-01196-1
  52. J Pharm Sci. 2026 Jul 14. pii: S0022-3549(26)00268-6. [Epub ahead of print] 104419
    From barriers to cloud-based regulatory collaboration: An industry perspective on accelerating innovation in pharmaceutical manufacturing.
    Nina S Cauchon, Marquerita Algorri, Kabir Ahluwalia, J Paul Kirwan, Brett Griswold, Michael J Abernathy, Ganesh Pawbake.
      Pharmaceutical manufacturing is changing rapidly as new therapeutic modalities, advanced manufacturing approaches, modern analytical tools, and novel drug-delivery technologies continue to emerge. While the scientific and technical potential of these innovations is clear, their adoption has often lagged due to regulatory challenges. Differences in regulatory expectations across regions, lengthy review timelines, and limited opportunities for coordinated engagement can slow or discourage the implementation of meaningful chemistry, manufacturing, and controls (CMC) advances. This review considers these barriers from an industry perspective, drawing attention to how cautious regulatory paradigms, fragmented guidance, and market-specific interpretations can reduce the incentive to introduce innovation, even when patient benefit is evident. Recent surveys, regulatory initiatives, and collaborative experiences suggest that progress is being made, particularly through innovation programs and reliance-based mechanisms; however, gaps remain in achieving consistent alignment and efficient lifecycle management. Looking ahead, greater use of cloud-based platforms to support real-time information sharing and collaborative regulatory review offers a practical path forward. Such approaches can improve transparency, reduce duplicate interactions, and encourage convergence without compromising regulatory rigor. By aligning regulatory practices more closely with scientific progress and the demands of today's advanced manufacturing, digital, and other 21st-century technologies, these collaborative models have the potential to accelerate innovation, support continuous improvement, and enable more timely global access to medicines.
    Keywords:  Analytical chemistry; Artificial intelligence; Automation; Continuous processing; Database(s); Drug delivery system(s); Regulatory science
    DOI:  https://doi.org/10.1016/j.xphs.2026.104419
  53. Cancers (Basel). 2026 Jun 24. pii: 2051. [Epub ahead of print]18(13):
    Chimeric Antigen Receptor-Immune Cell-Based Therapies for Clear Cell Renal Cell Carcinoma: Latest Advancements and Directions.
    Xuyuan Zhu, Yu Zhang, Yuxiang Chen, Shanda Li, Kun Wang, Tao Li, Xiaojie Ma, Zhuona Ni, Hongtao Jiang.
      Clear cell renal cell carcinoma (ccRCC) accounts for approximately 75% of renal cell carcinomas and is defined by near-universal VHL inactivation, leading to constitutive HIF stabilisation, metabolic reprogramming, and an immunologically distinct tumour microenvironment (TME). Although ccRCC is characterised by abundant immune infiltration, this paradoxically correlates with poor prognosis, reflecting a TME that imposes interconnected physical, immunological, and metabolic barriers to effective immunotherapy. Chimeric antigen receptor (CAR)-based therapies have revolutionised the treatment of haematological malignancies, but their translation to ccRCC has encountered substantial hurdles. The first-in-human trial targeting carbonic anhydrase IX (CAIX) was limited by on-target off-tumour toxicity and CAR immunogenicity-lessons that fundamentally reshaped the field. CD70 has since emerged as the dominant clinical target, expressed in over 80% of ccRCCs with a highly restricted normal tissue distribution. The phase I COBALT-RCC trial of CTX130, an allogeneic CRISPR-Cas9-edited CD70-directed CAR-T cell product, provided formal proof of concept, achieving disease control in 81.3% of heavily pretreated patients and a durable complete response now exceeding three years-the first such sustained remission reported for any CAR-T cell product in a solid malignancy. Nevertheless, the low frequency of durable responses and universal loss of CAR-T cell persistence by day 28 underscore that major barriers remain. Beyond CD70, the field has diversified across multiple platforms, including CAR-natural killer (NK) cells, CAR-natural killer T (NKT) cells, and CAR-macrophages, each offering distinct biological advantages. This review synthesises current knowledge of the ccRCC TME, the preclinical landscape of CAR-based therapies, and emerging clinical evidence from more than 30 registered trials. We discuss target antigens; engineering strategies to overcome TME barriers, including cytokine armouring, chemokine receptor co-expression, switch receptors, and metabolic reprogramming; and rational combination approaches. We argue that the convergence of optimised target selection, cellular engineering, combination strategies, and biomarker-driven trial design may ultimately improve outcomes for patients with ccRCC. However, achieving a cure remains an aspirational goal, and significant barriers must first be overcome.
    Keywords:  CAR-NK cells; CAR-NKT cells; chimeric antigen receptor T cells; clear cell renal cell carcinoma; immunotherapy; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers18132051
  54. Orthop Traumatol Surg Res. 2026 Jul 16. pii: S1877-0568(26)00217-3. [Epub ahead of print] 104796
    The Rise of AI Companions: From Prediction to Surgery in the Digital Twin Era.
    Marc-Olivier Gauci, Grégoire Duval, Louis Rony.
      Artificial intelligence (AI) is rapidly reshaping orthopaedic surgery, supported by advances in data science, computational power, and perioperative digitalization. Within this evolving landscape, five "AI companions" structure the surgeon's workflow. The "AI Scribe" maximizes administrative efficiency while preserving the surgeon-patient relationship. The "Strategic Assistant" supports the continuum from diagnosis to decision-making and personalized care. The "Surgical Co-pilot" integrates real-time data, digital twins, and vision-language-action synergy to enhance intraoperative guidance. The "Learning Sentinel" leverages collective experience to inform practice, education, and continuous improvement. The "Agile Trauma Vanguard" secures emergency decision-making while contributing to the decentralization of expertise. These systems rely on digital twins, task-specific, data-driven models continuously refined through patient outcomes via automated or semi-automated feedback loops. While early applications have demonstrated feasibility, their clinical value remains insufficiently established, highlighting the need for robust evaluation frameworks focused on patient-centered outcomes and real-world effectiveness. In parallel, economic models remain uncertain for technologies generating largely intangible returns. Their integration into practice will require surgeons to develop strong oversight capabilities and a clear understanding of model performance, scope, and limitations. Open science, data sharing, and digital sovereignty will be critical to ensure transparency, reproducibility, and equitable access. AI companions may ultimately redefine orthopaedic care, provided that their deployment is guided by rigorous validation and appropriate governance. LEVEL OF EVIDENCE: V; Expert opinion, Narrative review.
    Keywords:  AI companions (AI Scribe/Strategic Assistant/Surgical Co-pilot/Learning Sentinel/Agile Trauma Vanguard); AI-assisted decision-making (diagnosis/risk stratification/personalized care); Digital twin (computational surgery/augmented surgery/feedback loop); Learning health system (PROMs/ Real-World Data/RENACOT); Surgical co-pilot (robotics/navigation/augmented reality/; Trustworthy AI deployment (human-in-the-loop/data sovereignty/open science/governance); Vision-Language-Action models)
    DOI:  https://doi.org/10.1016/j.otsr.2026.104796
  55. Int J Pharm. 2026 Jul 11. pii: S0378-5173(26)00625-3. [Epub ahead of print]701 127177
    Digital and AI-enabled models in pharmaceutical development and manufacturing: a regulatory-focused industry survey.
    Graham Cook, Ian Houson, Chantal Mustoe, Andrew G P Maloney, Walkiria Schlindwein, Daniel Markl.
      Digital and artificial intelligence (AI)-enabled tools are increasingly being applied across pharmaceutical Chemistry, Manufacturing and Controls (CMC) activities, yet adoption, benefits and regulatory barriers remain incompletely characterised. The Digital CMC Centre of Excellence in Regulatory Science and Innovation (CERSI), led by the University of Strathclyde and supported by the UK Medicines and Healthcare products Regulatory Agency (MHRA), conducted a survey to assess the landscape and inform priorities. A survey was distributed to industry stakeholders, including innovator and generic manufacturers, non-prescription medicine manufacturers, and contract development and manufacturing organisations. Responses were analysed descriptively to evaluate adoption patterns, drivers, barriers, perceptions and support needs. Most respondents reported experience with digital CMC tools, and many reported experiences with AI-enabled tools, across small and large molecule drug substance (DS) and drug product (DP) development. Adoption was more prevalent in small molecule applications, with greater implementation in drug product than drug substance. Fewer than 15% of tools had been included in submissions. Key drivers included process robustness, efficiency, time to market and cost reduction. Principal challenges included culture change, skills gaps and uncertainty regarding regulatory expectations, particularly for AI-enabled applications and evidence requirements for submissions and inspections. Respondents generally agreed that identifiable patient data are not used in Quality/GMDP AI applications, but there was no consensus that current regulatory frameworks fully address AI governance principles. Strong support was expressed for harmonised guidance, training and dialogue. Digital CMC tool adoption is increasing but remains uneven; greater regulatory clarity, harmonisation and collaboration are critical for scalable implementation.
    Keywords:  Artificial intelligence; Digital CMC; Pharmaceutical manufacturing; Quality by digital design; Regulatory inspections; Regulatory submissions
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127177
  56. Clin Kidney J. 2026 Jul;19(7): sfag201
    Blockchain technology for secure and efficient nephrology data management.
    David R Evans, Ömer Tarik Özyilmaz, Huifang Xue, Michele Provenzano, Ning Qu, Stephan J L Bakker, Martin H de Borst, Uwe J F Tietge, Tamas Szili-Torok.
      Rapid advancements in digital healthcare technologies have created new opportunities in nephrology, but they have also increased the fragmentation of datasets, complexity of data sharing, data privacy and security risks, and a lack of data verifiability and reliability (provenance). While several technological solutions have been developed to address these concerns individually, blockchain has been suggested as a unified solution for secure and efficient data management through several features. These include immutability, interoperability, and programmability, which provide a powerful framework that extends the utility of blockchain beyond data governance in nephrology. Blockchain also has potential applications in pharmaceutical and biobanking quality assurance and in the reliability of medical devices through auditable maintenance logs, making it a promising candidate to address several challenges in patient care and nephrology research. Despite this promise, practical challenges arise between the features of blockchain, such as immutability, and legislation, including the General Data Protection Regulation (GDPR). Furthermore, the value of real-world adoption in nephrology remains uncertain due to scalability, computational overheads, and implementation costs that may outweigh its advantages in many settings.
    Keywords:  Blockchain; big data; data management; data science; smart contracts
    DOI:  https://doi.org/10.1093/ckj/sfag201
  57. Front Neurol. 2026 ;17 1835346
    Steroid-resistant bilateral facial nerve palsies, ophthalmoparesis, and multilevel thoracic radiculopathy as immune effector cell-associated late-onset neurotoxicity after cilta-cel CAR-T therapy: a case report and review of similar cases.
    James Reid Johnson, Tanya Gupta, Michelle Tavcar, Alex Glynn, Peter Hedera.
      The use of chimeric antigen receptor T-cell (CAR-T) therapy has become more widespread in recent years, most commonly for hematologic malignancies. This therapy can be potentially associated with neurotoxic side effects. We present a patient with refractory multiple myeloma who developed diplopia, bilateral upward gaze limitation, abducens palsy, bilateral facial nerve palsy, and thoracic sensory radiculopathy following a course of CAR-T therapy, which were suspected to represent delayed immune effector cell-associated nerve palsies (IEC-NPs). His symptoms progressed despite oral and intravenous steroids. Subsequent intrathecal methotrexate and systemic cyclophosphamide resulted in acute symptomatic improvement and eventual resolution of diplopia and gradual recovery of extraocular movements and facial nerve palsies.
    Keywords:  IEC-NP; bell’s palsy; cilta-cel CAR-T; immune effector-cell late onset neurotoxicities; ophthalmoplegia
    DOI:  https://doi.org/10.3389/fneur.2026.1835346
  58. Med Decis Making. 2026 Jul 16. 272989X261455060
    A Simulation and Case Study to Evaluate the Extrapolation Performance of Flexible Bayesian Survival Models when Incorporating Real-World Data.
    Iain R Timmins, Fatemeh Torabi, Christopher H Jackson, Paul C Lambert, Michael J Sweeting.
      BackgroundAssessment of long-term survival for health technology assessment often necessitates extrapolation beyond the duration of a clinical trial. Flexible Bayesian survival models that incorporate longer-term data sources, including registry data and population mortality, have been proposed as an alternative to using standard parametric models with trial data alone.MethodsThe performance of extrapolations from the survextrap Bayesian M-spline survival model was evaluated through simulation, with 5 years of trial data follow-up for our primary analysis. We assessed long-term survival and incremental effect estimates under a range of settings and assumed long-term real-world data informed the control arm. Comparisons were made with standard and flexible parametric models.ResultsWhen relevant long-term external data on the control arm were available, a flexible Bayesian approach substantially improved the precision and accuracy of extrapolations for that arm. Improvements in estimates of extrapolated treatment effects were more variable and sometimes deteriorated, reflecting sensitivity to assumptions about how hazards relate across arms. Compared with exponential and Weibull models, the survextrap Bayesian model had better within-trial fit and more plausible extrapolations, although a Royston-Parmar spline often provided comparable accuracy of incremental effects in many settings. We noted further that the survextrap Bayesian approach has the potential strength of explicitly quantifying the structural uncertainty, making transparent the strong assumptions required by any survival modeling approach to extrapolate.ConclusionsFlexible Bayesian survival models can potentially improve long-term survival extrapolation in the control arm when well-matched external data are available, but improvements in estimates of incremental treatment effects were often quite variable across scenarios and models. This highlights the need for careful consideration of appropriate modeling assumptions and real-world data quality when using this approach.HighlightsFlexible Bayesian models that incorporate both clinical trial and real-world data can improve the accuracy of control-arm survival extrapolations compared with using trial data alone.Estimates of incremental long-term treatment benefit were sensitive to assumptions about treatment-effect structure, highlighting the need for clinically motivated modeling choices and sensitivity analyses.Our simulation study guides users on the important modeling choices, sensitivity analyses, and software settings to consider when implementing these flexible Bayesian survival models.By allowing the hazard to vary smoothly outside the data, flexible Bayesian methods can enable better quantification of structural uncertainty in survival extrapolations.
    Keywords:  Bayesian; external evidence; health technology assessment; real-world evidence; splines; survival analysis; survival extrapolation
    DOI:  https://doi.org/10.1177/0272989X261455060
  59. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 102994
    Advances in ex vivo mRNA-based gene transfer for cell-based cancer immunotherapy.
    Florian Van Oers, Zoi Katana, Donovan Flumens, Eva Lion, Diana Campillo-Davo.
      Electroporation of messenger RNA (mRNA) is an ex vivo non-integrating gene transfer technique used in immune-cell-based trials for cancer to transiently supply immune cells with multiple proteins. This technique has been used to engineer dendritic cells and B cells with tumor-associated antigens to boost the immune system of cancer patients and to redirect the anti-tumor activity of T cells and natural killer cells with immune receptors. Although gene delivery via mRNA electroporation results only in transient expression of the protein of interest, many investigators and clinicians consider it as a feasible, flexible, and safe technique, compared with stable expression methods using viral vectors. In this review, we discuss the efficacy of mRNA electroporation for gene transfer and assess the strengths and limitations of this technique for redirecting and boosting immune responses against various tumor antigens in cancer immunotherapy.
    Keywords:  MT: Delivery Strategies; RNA electroporation; cell therapy; gene engineering; immunotherapy; messenger RNA
    DOI:  https://doi.org/10.1016/j.omtn.2026.102994
  60. Int J Mol Sci. 2026 Jun 28. pii: 5836. [Epub ahead of print]27(13):
    Cultivating Functional Natural Killer Cells from Mobilized Hematopoietic Stem Cells in Heavily Pretreated Hematologic Malignancies.
    Suppanut Komjakraphan, Poonnattha Anantasaeree, Kajornkiat Maneechai, Panarat Noiperm, Jakrawadee Julamanee.
      CD19 chimeric antigen receptor (CAR) T cells have demonstrated promising outcomes in B-cell malignancies. However, using pretreated autologous T cells currently faces limitations, including compromised T-cell fitness and the challenge of manufacturing sufficient cell numbers for treatment. Consequently, natural killer (NK) cells have emerged as an alternative due to their natural ability to mediate cytotoxicity and their favorable safety profile. This study aims to generate patient autologous hematopoietic stem cell-derived NK (HSC-NK) cells and assess their therapeutic potential compared to peripheral blood NK (PB-NK) cells. We successfully cultivated HSC-NK under a 28-day, two-step differentiation and expansion protocol, achieving a cumulative 290-fold expansion using optimized memory-like cytokines and feeder cell stimulation. The expanded HSC-NK cells demonstrated a distinct phenotype (CD56+CD16low), representing an immature differentiation state, characterized by a lower expression of inhibitory receptors (NKG2A, KIR2DL, and CD94) and the exhaustion markers (LAG3, PD-1, TIM-3, and CTLA-4) compared to PB-NK cells. Prominent expression of CD62L, alongside sustained expression of CD69 and CD107a, was observed, translating into NK cell proliferation, activation, and cytotoxicity against cancer cells comparable to PB-NK cells. In conclusion, generating HSC-NKs is feasible while preserving essential NK cell phenotypes and activities. Our findings emphasize the potential of HSCs as an alternative NK cell source for cancer immunotherapy.
    Keywords:  cancer; hematopoietic stem cell; immunotherapy; natural killer
    DOI:  https://doi.org/10.3390/ijms27135836
  61. J Transl Med. 2026 Jul 15. pii: 923. [Epub ahead of print]24(1):
    Development of a 3-day manufacturing method to generate CD19-CD20-CD22 trispecific CAR T-cells from whole blood.
    Isabella Vignola, Michaela Prochazkova, Lipei Shao, Tatyana Fuksenko, Sarmila Sarkar, Hong Lei, Jianjian Jin, Ying Xiong, Yanping Xie, Ibeawuchi Oparaocha, Oxana Slessareva, Megan Forrest, Rimas Orentas, Zhongyu Zhu, Boro Dropulic, Ping Jin, Robert P Somerville, David F Stroncek, Hannah W Song, Steven L Highfill.
       BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for many hematological malignancies. However, high relapse rates and limited accessibility remain significant challenges. We developed a 3-day streamlined process to address these limitations.
    METHODS: T-cells were isolated from whole blood collected from healthy donors via an automated density gradient separation that included a T-isopure™ antibody cocktail, which isolates T-cells through negative selection. T-cells were activated then transduced with a lentiviral vector encoding a trispecific CAR. T-cells were cultured in G-Rex vessels and harvested at day 3 or day 7 for analysis. CAR expression and T-cell phenotype were assessed by flow cytometry and gene expression analysis. Functional activity was evaluated by measuring cytotoxicity and cytokine secretion following co-culture with target cell lines.
    RESULTS: The T-isopure isolation enriched CD3+ T-cells in whole blood from 18.9% to 88.5% of CD45+ cells, with a mean recovery of 40.6%. RBCs were depleted with ≥ 99% efficiency, with monocytes and NK cells comprising the bulk of remaining CD45+ cells. The 3-day manufacturing process produced T-cells with > 95% viability, 53% transduction efficiency, and vector copy number < 3 copies/cell. Phenotypic analysis revealed a high proportion of stem/central memory T-cells at both timepoints, with no significant differences observed. Cytotoxicity assays demonstrated strong and sustained killing of NALM6 tumor cells, comparable between both products. Gene expression profiling indicated that day 3 products were less differentiated, exhibiting a memory-like phenotype and reduced inflammatory signaling, further supported by protein analysis of culture supernatants.
    CONCLUSION: This study establishes a rapid, GMP-compliant method for manufacturing polyfunctional, CAR T-cells directly from whole blood. The workflow outlined here achieved a potent, phenotypically favorable CAR T-cell product without compromising viability or cytotoxic function. Compared to the standard 7-day method, the 3-day approach resulted in expression of genes associated with a more stem-like phenotype while reducing manufacturing time and cost. This method may provide a practical alternative for decentralized CAR T-cell manufacturing, particularly in resource-limited settings.
    Keywords:  Cell manufacturing; Cellular therapy; Chimeric antigen receptor; Negative selection; Whole blood
    DOI:  https://doi.org/10.1186/s12967-026-08306-8
  62. Front Public Health. 2026 ;14 1854507
    A new paradigm for medical data circulation: research on medical data sharing based on evolutionary game theory.
    Bingjun Guo, Dandan Wang, Muqing Niu, Jun Ma.
      To address the challenge of redundant testing in medical data sharing and mutual recognition, this paper constructs an evolutionary game model involving three parties: government, medical institutions, and patients. By integrating three scenarios-pessimistic (high costs, low acceptance), baseline (cost-benefit equilibrium), and optimistic (low costs, high coordination)-the study explores the system's dynamic evolution through payoff matrix derivation, stability analysis, and MATLAB simulation. Findings indicate: Under the pessimistic scenario, the system lacks stable equilibrium, requiring external intervention to break the deadlock. In the benchmark scenario, the system converges toward weak government regulation, proactive sharing by medical institutions, and active acceptance by patients, reflecting a transition toward coordinated government regulation and market autonomy. Under the optimistic scenario, the system converges toward an ideal state of tripartite collaborative participation, fully unlocking the shared value of medical examination data. Parameter sensitivity analysis indicates that reducing sharing costs for medical institutions, regulatory costs for governments, and privacy costs for patients, while enhancing institutional network effects, are core variables driving medical examination data sharing. Based on these findings, recommendations include a tiered implementation strategy, diversified incentive mechanisms, technological empowerment, and regulatory refinement, providing theoretical foundations and practical pathways for medical examination data sharing and mutual recognition.
    Keywords:  evolutionary game theory; incentive mechanisms; medical examination data; sharing and mutual recognition; stability analysis
    DOI:  https://doi.org/10.3389/fpubh.2026.1854507
  63. Front Immunol. 2026 ;17 1803276
    Immunomodulatory effects of nematode-microbiota interactions in cancer therapy.
    Valentyn Oksenych, Marjan Rashidan, Meisam Khazaei, Hamed Tahmasebi.
      Among parasites, roundworms release substances that quietly reshape how the body's defences respond - a dance shaped by long evolution. One player, called p43 - also known as Tm-DLP-1 - (Trichuris muris Dorylaimia Lipid-carrying Protein-1), makes up nearly all of it. Scientists now see this protein not just as a worm tool but as something that can steer immune responses, possibly helping fight tumours. Here lies an exploration: how p43 alters immunity, teams up with gut microbes, and shows promise in early tests and trials against cancer. Beyond its role inside the parasite hauling lipids around, p43 works outside by grabbing tightly onto IL-13, a signal involved in fighting worms - and oddly enough - in feeding some cancers. Thanks to parts resembling the IL-13 receptor alpha-2 and sections like those found in thrombospondin, this protein binds IL-13 strongly while also attaching to sugar chains in the tissue scaffold, leaving pockets where immune behaviour shifts subtly. Despite strong results across several animal cancer models - slowed tumours, stronger CD8+ T cell attacks, weaker regulatory T cell activity - the path forward stays uncertain. Safety data in healthy humans come from trials using Trichuris suis ova, yet those with weakened immune systems face lingering risks. A molecule called p43/Tm-DLP-1 emerges here, not by chance, due to its ability to block IL-13 while shifting gut microbes. Still, progress demands more lab refinement, larger production methods, and human studies built with precision before any real impact can take hold.
    Keywords:  TM-DLP-1; Trichuris muris; cancer immunotherapy; excretory-secretory products; helminth therapy; microbiota; nematode; p43 protein
    DOI:  https://doi.org/10.3389/fimmu.2026.1803276
  64. Expert Opin Biol Ther. 2026 Jul 16.
    Beyond innovation: why rare disease gene therapy needs a reset.
    Maram E Abdalla Elsayed, Robert E MacLaren.
      
    Keywords:  Adeno-associated virus; European Medicines Agency; Food and Drug Administration; cell therapy; clinical trials; gene therapy; natural history; rare disease; translation; translational development
    DOI:  https://doi.org/10.1080/14712598.2026.2706035
  65. Nature. 2026 Jul 15.
    GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma.
    Qi Zhang, Qihan Fu, Yinan Shen, Wanyue Cao, Gaowei Jin, Yize Zhang, Jiangchao Wu, Cao Chen, Hongkan Wang, Xingyuan Xu, Ke Sun, Xing Xue, Attilio Bondanza, Daisy Cao, Nina Chu, Nick Durham, Mark Cobbold, Benedetto Farsaci, Maria Letizia Giardino Torchia, Yixin Hao, Yi Hong, Jiaqi Huang, Michael Humphries, Qijie Jian, Gordon Moody, John Stone, Lingyan Sun, Eric Tu, Fei Wang, Fuzhe Wang, Ye Yang, Yihong Yao, Andy Zou, Xueli Bai, Tingbo Liang.
      Glypican-3 (GPC3) is highly expressed in hepatocellular carcinoma (HCC), making it an attractive target for chimeric antigen receptor (CAR) T cell therapy; however, this approach has previously shown limited clinical efficacy, potentially owing to high levels of transforming growth factor-β (TGFβ) in the tumour microenvironment1-4. We therefore engineered CAR T cells with a dominant-negative TGFβ receptor II, which showed enhanced antitumour activity in preclinical studies5. Here we report findings from a first-in-human trial evaluating the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC ( NCT05155189 ). Thirty-six patients received CAR T infusions at four dose levels (from 0.75 × 106 to 4.0 × 106 cells per kg). Cytokine release syndrome was reported in 34 patients, of which two cases were grade 3. Nine patients had non-haematological adverse events of grade 3 or higher. Tumour regression was observed in 32 patients, with a median best tumour reduction from baseline of 41.6% (range: 3.4-94.4%) in target lesions. The objective response rate was 44.4%, and the median duration of response was 4.4 months (95% confidence interval: 2.9-7.4). Median progression-free survival and overall survival were 4.2 months (95% confidence interval: 2.9-4.8) and 14.2 months (95% confidence interval: 10.1 to not evaluable), respectively. High-throughput analyses of tumour samples and functional validation suggested that GPC3 antigen loss and increased TGFβ levels may contribute to C-CAR031 resistance. Collectively, these results indicate that C-CAR031 has a manageable safety profile and encouraging antitumour activity in heavily pretreated patients with advanced HCC.
    DOI:  https://doi.org/10.1038/s41586-026-10786-z
  66. Pharmaceut Med. 2026 Jul 14.
    Embracing Digital as a Paradigm Shift in Medical Affairs.
    Amit Lalwani, Jon Zdon, Maaike Addicks, Yacin Marzouki, Densearn Seo, Orin Chisholm.
      Digital transformation is increasingly shaping how the Medical Affairs (MA) function generates insights, engages stakeholders, and demonstrates value within the pharmaceutical industry. This article examines how MA professionals can navigate and lead the digital revolution reshaping healthcare delivery and stakeholder engagement. Digital maturity progresses from basic channel activation through tactical integration to advanced personalisation enabled by artificial intelligence (AI). Central to this transformation is the convergence of omnichannel engagement with real-world evidence generation, creating unprecedented opportunities to deliver personalised, scientifically rigorous interactions that enhance patient outcomes and healthcare professional (HCP) satisfaction. AI applications are creating new opportunities for MA to generate insights, communicate evidence, and measure impact across the healthcare ecosystem, enabling predictive analytics and intelligent content delivery at scale. Digital transformation is less likely to be effective when implemented through organisational silos. Important enablers include cross-functional collaboration, robust governance for responsible AI deployment, co-creation with external partners including HCPs and patient advocacy groups, and shared technology infrastructure that supports coordinated engagement. Best practices for digital communication strategies, fostering innovation cultures, and demonstrating measurable value are explored. As healthcare's digital evolution accelerates, MA has an important role in ensuring that digital tools are applied in ways that remain scientifically rigorous, ethically governed, and aligned with stakeholder needs. By treating digital as an enabler of high-quality scientific exchange rather than an end in itself, MA can support more relevant engagement and strengthen the translation of evidence into practice.
    DOI:  https://doi.org/10.1007/s40290-026-00623-z
  67. Ther Innov Regul Sci. 2026 Jul 14.
    A Regulatory-Ready Bayesian Evidence Framework across Clinical Development and Pharmacovigilance: Practical Expectations from FDA, EMA, and ICH Guidance.
    Carlos G Bernaus, Maria Lilia Bournissen.
      Bayesian methods are increasingly used in clinical development and pharmacovigilance, especially when evidence is sparse, accrues sequentially, or must incorporate external information. Translation of high-level regulatory principles into an auditable, submission-ready Bayesian package remains inconsistent. Publicly available FDA, EMA, and ICH documents relevant to Bayesian implementation were reviewed, including Bayesian-specific guidance and recommendations that materially shape Bayesian analyses (for example, adaptive designs, externally controlled trials, estimands/sensitivity analyses, and pharmacovigilance signal management). Findings are synthesized into a practical framework organized around four deliverables that repeatedly emerge as regulatory decision drivers: (1) governed external information and prior specification, including quantification of prior influence and safeguards for prior-data conflict; (2) decision criteria paired with simulation-based characterization of operating characteristics under realistic scenarios; (3) structured sensitivity analyses that probe priors, borrowing, model forms, estimand-related assumptions, and key pharmacovigilance definitions; and (4) transparency and reproducibility, including pre-specification, traceability of data sources and transformations, and clear interpretation of Bayesian outputs for the intended decision (triage vs. confirmation). These deliverables are mapped to post-authorization pharmacovigilance workflows, where Bayesian shrinkage and hierarchical modeling are frequently used despite method-neutral guidance. The resulting framework provides a concise "regulatory-ready" evidence blueprint applicable across development programs and pharmacovigilance systems. This synthesis incorporates FDA's January 2026 draft guidance on Bayesian methodology in clinical trials of drug and biological products [9], which increases cross-agency expectations for prior justification, prospective evaluation of operating characteristics, and computational transparency.
    Keywords:  Bayesian statistics; External data; Operating characteristics; Pharmacovigilance; Regulatory science; Sensitivity analysis
    DOI:  https://doi.org/10.1007/s43441-026-01014-x
  68. Int J Pharm. 2026 Jul 16. pii: S0378-5173(26)00643-5. [Epub ahead of print] 127195
    Life-saving therapies to patients in hours - the new algorithmic digital regulatory exchange model.
    Michael J Abernathy, Marquerita Algorri, Craig Anderson, Mohit Juneja.
      The growing scale and complexity of pharmaceutical quality data across the product lifecycle are outpacing the capabilities of today's document-centric regulatory paradigm. Current processes are slow, fragmented, and resource-intensive, constrained by unstructured file formats, inconsistent submission standards (eCTD and non-eCTD), and inefficient exchange mechanisms ranging from AS2 gateways to email and physical media. These limitations hinder data accessibility, reuse, and the scalability of regulatory review. Anderson et al. (2023) previously proposed a vision for real-time, data-driven regulatory exchange enabled by structured standards and interoperable digital infrastructure. However, practical implementation has remained largely theoretical. Here, we demonstrate that the concepts described in the prior work are both feasible and operational. In the present work, we describe a reference model that can support broader adoption. Using the Health Level Seven (HL7) Fast Healthcare Interoperability Resources (FHIR®) framework, structured data models were developed to connect heterogeneous sponsor systems, including both integrated and non-integrated environments. Chemistry, Manufacturing, and Controls (CMC) data were transformed into FHIR-conformant, machine-readable resources and exposed via standardized application programming interfaces (APIs), enabling automated assembly of regulatory submission content. Once represented as structured, interoperable data, regulatory information becomes a foundation for advanced analytics and artificial intelligence (AI). AI models can analyze content, generate potential regulatory questions, and support response development by querying authoritative data sources. This FHIR-based interoperability approach can enable timely data-centric regulatory workflows to reduce manual effort, improve efficiency, and ultimately accelerate patient access to high-quality innovative medicines.
    Keywords:  Analytics; Chemistry, Manufacturing & Controls (CMC); FHIR; Pharmaceutical quality; Pharmaceutical regulatory affairs; Regulatory affairs
    DOI:  https://doi.org/10.1016/j.ijpharm.2026.127195
  69. J Comp Eff Res. 2026 Jul 14. e260144
    R WE ready for reimbursement? A round-up of developments in real-world evidence relating to health technology assessment: part 27.
    Paul Arora, Sreeram V Ramagopalan.
      In this update, we review the US FDA's updated compendium of real-world evidence (RWE) use in medical device regulatory decisions, a comprehensive scan of RWE utilization in Canadian drug reimbursement submissions, and Institute for Clinical and Economic Review's use of RWE to inform US Medicare drug price negotiations under the Inflation Reduction Act.
    Keywords:  Canada’s Drug Agency; Center for Devices and Radiological Health; FDA; Inflation Reduction Act; Institute for Clinical and Economic Review; health technology assessment; medical devices; real-world data; real-world evidence
    DOI:  https://doi.org/10.57264/cer-2026-0144
  70. BMC Health Serv Res. 2026 Jul 13.
    Approval and delay status of United States -approved new drugs (2010-2023) in European Union, Japan, and China.
    Qihui Mo, Jiaqi He, Qixiang Guo, Haibo Wei, Yanxi Liu, Yue Yang.
       BACKGROUND: China has long been faced with a drug lag. A decade has passed since China launched its pharmaceutical regulatory reforms, and related policies have been continuously optimized, yet their effectiveness remains to be evaluated. This retrospective analysis uses the United States as a reference to compare drug lags among the European Union, Japan, and China, and investigates key factors underlying lags between the US and China.
    METHODS: This study examined new drugs first approved by the US Food and Drug Administration (FDA) between 2010 and 2023. We conducted a descriptive analysis of key characteristics, including approval dates, drug categories, and development strategies. We further investigated factors associated with drug approval lag using the Mann-Whitney U test and analysis of covariance (ANCOVA).
    RESULTS: From 2010 to 2023, the FDA approved 516 new drugs. Of these, 399, 301, and 266 were authorized by the European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA), and the National Medical Products Administration (NMPA), respectively. China's drug approval lag decreased from 1,667 days in 2010-2014 to 635 days in 2020-2023. Furthermore, we found that the EMA's lag was mainly concentrated in the review phase, the PMDA's lag was mainly concentrated in the submission phase, and the NMPA showed a substantial lag in both phases. Factors influencing drug approval lag in China include whether conditional approval was granted by the NMPA, whether FDA breakthrough therapy designation was obtained, the region of the Marketing Authorization Holder whether a domestic development strategy in China was adopted, and whether external collaborative research and development was used. From a clinical development strategy perspective, drugs undergoing Multi-Regional Clinical Trial and early bridging trials experience shorter approval lag.
    CONCLUSIONS: Since China's pharmaceutical regulatory reforms, the number of newly approved drugs has increased, and approval lag has shortened, although it remains longer than that of the EMA and PMDA. We recommend that the NMPA improve review efficiency to reduce approval lag and adopt more favorable policies to encourage earlier development and submission in China, thereby alleviating submission lag.
    Keywords:  China; Drug lag; European Union; Japan; United States
    DOI:  https://doi.org/10.1186/s12913-026-15081-1
  71. Cancers (Basel). 2026 Jun 25. pii: 2057. [Epub ahead of print]18(13):
    Economic Evidence on Biliary Tract Cancer: A Systematic Review.
    João Rocha-Gomes, Ana Sofia Teixeira, Marina Ruiz-Romeo, José Manuel Oliveira, Patrícia Ramos.
      Background: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma and gallbladder carcinoma, are aggressive malignancies with poor prognosis and increasing incidence in selected regions worldwide. Advances in imaging, biomarker profiling, immunotherapy, and targeted therapies have improved treatment options but have also increased the economic pressure on health systems. Understanding the economic evidence on BTC is therefore important for resource allocation and health technology assessment. Methods: We systematically searched PubMed/MEDLINE, Embase, Scopus, and Web of Science for peer-reviewed economic studies of BTC published from January 2010 to March 2025. Eligible studies included cost-effectiveness, cost-utility, cost-benefit, cost-of-illness, and resource-use analyses. The review followed PRISMA reporting principles. Reporting completeness was assessed using CHEERS 2022, and methodological credibility was appraised using the Drummond framework. Results: Twenty studies were included: 13 cost-effectiveness or cost-utility analyses and seven cost-of-illness or resource-use studies. Conventional chemotherapy strategies, including gemcitabine plus cisplatin in some settings and other cytotoxic combinations in selected jurisdictions, generally produced more favorable economic results than newer systemic therapies, although findings varied by country, threshold, comparator, and price assumptions. First-line immunotherapy combinations and biomarker-directed targeted therapies frequently produced ICERs above jurisdiction-specific willingness-to-pay thresholds at current prices, often requiring substantial price reductions to approach cost-effectiveness. Real-world studies showed high resource use and costs, particularly with hospitalizations and later treatment lines. Evidence on screening and prevention was limited, with one study suggesting that ultrasound surveillance may be cost-effective in a liver fluke-endemic region of Thailand. Discussion: The available economic evidence suggests that affordability and jurisdiction-specific value assessment are central to BTC policy decisions. Current prices for several immunotherapy and targeted agents limit cost-effectiveness in published models, while evidence on prevention, early detection, and care-pathway interventions remains sparse and context-specific.
    Keywords:  biliary tract cancer; cholangiocarcinoma; cost-effectiveness; gallbladder cancer; health economics; immunotherapy; screening; systematic review; targeted therapy
    DOI:  https://doi.org/10.3390/cancers18132057
  72. Front Bioeng Biotechnol. 2026 ;14 1866957
    Decision-grade digital twins for in situ bioremediation of contaminated soil and groundwater: a critical review.
    Mariusz Cycoń.
      Field claims about in situ bioremediation often fail because monitoring data are not mapped to the causal process they are intended to prove. This critical review defines decision-grade digital twins as inferential systems, not as visualization tools, data lakes, or calibrated trend models. A decision-grade twin must connect a living conceptual site model with evidence streams that test competing hypotheses, prediction models with stated admissibility limits, uncertainty updates, and auditable trigger logic. The review evaluates how geochemistry, compound-specific isotope analysis, functional genes and transcripts, flux measurements, geophysical imaging, toxicity endpoints, and high-frequency sensing can support claims about pathway activation, treatment limitation, rebound risk, secondary impacts, and closure readiness. It also distinguishes the decision value of reactive transport models, hybrid process-data models, surrogate models, data-driven surveillance, and microbial process representations. Across hydrocarbons and polycyclic aromatic hydrocarbons, chlorinated solvents, pesticides, pharmaceuticals, and per- and polyfluoroalkyl substances, decision value depends on whether the evidence can distinguish among reaction, retention, redistribution, metabolite formation, and durable risk reduction. The review concludes that digital twins deserve decision-grade status only when they reduce ambiguity that can affect intervention choice, operating intensity, switching criteria, monitoring design, secondary-risk management, or closure judgment.
    Keywords:  adaptive decision support; contaminated soil and groundwater; decision-grade digital twins; in situ bioremediation; microbial process monitoring; multiple lines of evidence
    DOI:  https://doi.org/10.3389/fbioe.2026.1866957
  73. ACS Biomater Sci Eng. 2026 Jul 14.
    Pharmaceutical Engineering of Lipid-Based Nanocarriers for Cancer Nanomedicines: From Doxorubicin to mRNA Platforms.
    Liam Gillman, Djordji Suleski, Mark E Graham, Samantha L Ginn, Md Musfizur Hassan.
      Designing therapeutic payloads to deliver drug molecules to the desired target site is challenging and requires effective, stable, and safe delivery systems in cancer therapy. Lipid-based nanocarriers have gained substantial interest in preclinical and clinical studies in anticancer drugs, leveraging their potential for drug delivery over the last few decades. While lipid-based nanocarrier technology has achieved some commercial success in different therapeutics and vaccines, challenges persist in their design, development, and quality control in large-scale manufacturing, most notably a lack of robust and scalable lipid-based nanocarrier synthesis and formulation for chemotherapy. To overcome these limitations, it is crucial to understand the role of lipids and other constituents that are utilized in lipid-based nanocarrier synthesis. Along with the compositions of lipid-based nanocarriers, their preparation methods also play a critical role. The structural design of lipid-based nanocarriers aims to impart the desired physicochemical properties, stability, bioavailability, safety, and efficacy of the drug-loaded lipid-based nanocarriers. Initially, this review provides a brief overview of the classification of lipids and other essential components used in the preparation of lipid-based nanocarriers. We then examine critical formulation parameters, including composition ratios, physicochemical characteristics, and preparation methods. We also include the recent progress of cancer nanomedicine and clinical trials, regulatory approval, and future direction to improve the delivery efficiency of lipid-based nanocarriers in cancer nanomedicine. Finally, we summarize the formulation of five distinct types of lipid-based nanocarriers employed for anticancer drug delivery and draw a connection between these formulations and the development of mRNA-based lipid nanoparticles (LNPs).
    Keywords:  anticancer drug; drug-delivery; formulation; ionizable lipid; lipid; lipid nanoparticles; lipid-based nanocarriers; mRNA; stability; surfactants; therapeutic efficacy
    DOI:  https://doi.org/10.1021/acsbiomaterials.6c00618
  74. Int J Nanomedicine. 2026 ;21 590131
    Hydrogels in Autoimmune Disease: A Comprehensive Review of Current Research and Clinical Potentials.
    Yangyang Lu, Haodong Su, Xinying Fan, Jie Hu, Xiaoyu Tang, Jingjin Hu, Liyun Zhang, Dan Ma.
       Research Objective: Autoimmune diseases are chronic conditions in which the immune system abnormally attacks the body's own tissues. Their incidence is on the rise, and the pathogenesis remains incompletely understood. The clinical manifestations are complex and diverse. Despite active treatment, some patients still have poor therapeutic outcomes and rely on immunosuppressants for a long time. Although these drugs can control symptoms, they are associated with increased infection risks and serious side effects such as organ toxicity. Hydrogels are three-dimensional network structures with excellent water absorption properties, good biocompatibility, injectability, and physical and chemical properties. By loading adjuvants, drugs, cells, and other substances, they are applied in the establishment of disease models, drug delivery, bioimaging and biosensors, tissue engineering, and other fields, providing new strategies for studying disease pathogenesis, drug screening, local targeted delivery, and immune regulation. This article aims to systematically review the mechanism of action and research progress of hydrogels in the treatment of autoimmune diseases and assess their potential for clinical translation.
    Research Methods: Relevant literature on the medical applications of hydrogels published from January 1, 2004 to October 31, 2025 was retrieved, and the scope was narrowed down to studies on their application in autoimmune diseases for summary and analysis.
    Main Results: The main findings are as follows: (1) Through bibliometric analysis, it was found that research on hydrogels in the medical field is increasingly prominent, with studies in autoimmune diseases mainly focusing on drug delivery; (2) By constructing injectable bioadhesive hydrogels, the adhesion of hydrogels to joint tissues is enhanced, prolonging drug retention time and improving treatment efficiency; (3) Specific hydrogel designs can actively regulate immune cell functions - for example, inhibiting inflammation-related signaling pathways to reverse M1 polarization of macrophages and ferritin autophagy/ferroptosis in chondrocytes, maintaining the integrity of cartilage structure, and inducing mitochondrial dysfunction to promote apoptosis of FLS and macrophages and regulate the inflammatory microenvironment; (4) Hydrogel microneedle systems, as transdermal drug delivery platforms, have shown good compliance and efficacy in rheumatoid arthritis.
    Summary: Hydrogel technology, through localized, controllable, and intelligent drug delivery, is expected to break through the bottlenecks of traditional autoimmune disease treatment. Current research is gradually evolving from passive carriers to active participants in immune regulation as "intelligent platforms", and their potential to reshape the inflammatory microenvironment has been verified in animal models. However, issues such as material degradability, long-term biological safety, and consistency in large-scale production still need to be further addressed in preclinical and clinical studies. Future interdisciplinary collaboration and translational medical research are key to promoting the development of this field.
    Keywords:  autoimmune diseases; hydrogels; medical applications
    DOI:  https://doi.org/10.2147/IJN.S590131
  75. Cancers (Basel). 2026 Jul 06. pii: 2163. [Epub ahead of print]18(13):
    Rational Immune Checkpoint Inhibitor-Based Combination Immunotherapy in Cancer: Mechanistic Design, Biomarker Selection, and Implications for Oncology Pharmacy.
    Mathias Sanchez Machado, Sangnya A Upadhyaya, Saipriya Gadiraju, Matthew Santhosh, John Gaba, Patrick J Mcdonnell, Jacobo Hincapie-Echeverri, Carlos A Barrero.
      Cancer immunotherapy has reshaped oncology, yet durable benefit remains limited for many patients because antitumor responses are constrained by multiple biological and clinical barriers. A targeted narrative review was conducted using peer-reviewed literature indexed in PubMed, Scopus, and Web of Science from January 2020 to April 2026, with additional landmark studies from earlier years included for essential mechanistic context. Priority was given to clinical, translational, and high-impact review articles examining combination strategies built on immune checkpoint blockade and related immune platforms. The evidence was synthesized by the main barriers each strategy aims to overcome, including poor immune priming, immune exclusion, immunosuppressive tumor microenvironments, adaptive resistance, and limited treatment durability. Across recent studies, combination immunotherapy is increasingly moving away from empiric regimen construction toward biologically rational approaches that integrate checkpoint blockade with chemotherapy, radiotherapy, antiangiogenic therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, vaccines, and cellular platforms. Increasing emphasis has also been placed on integrated biomarkers that combine tumor-intrinsic, immune, spatial, and dynamic features to improve patient selection. At the same time, growing regimen complexity continues to raise challenges related to overlapping toxicity, sequencing, polypharmacy, and multidisciplinary implementation. Overall, the field is evolving toward mechanism-matched, biomarker-guided, and clinically manageable strategies that may broaden and refine the benefit of cancer immunotherapy.
    Keywords:  antibody–drug conjugates; biomarkers; bispecific antibodies; cancer immunotherapy; combination therapy; immune checkpoint blockade; immune resistance; oncology pharmacy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18132163
  76. Int J Biol Macromol. 2026 Jul 13. pii: S0141-8130(26)03482-3. [Epub ahead of print] 153537
    Therapeutic platforms for cancer management centered on blocking the PD-L1/PD-1 interaction through the use of aptamers: A review.
    Abolfazl Marvizadeh, Elham Sameiyan, Amir Teymour Najjarkar, Mona Alibolandi, Mohammad Ramezani, Khalil Abnous, Seyed Mohammad Taghdisi.
      Blocking the PD-1/PD-L1 (Programmed Cell Death Protein-1/Programmed Cell Death Ligand-1) pathway represents a pivotal approach in cancer immunotherapy, effectively promoting sustained antitumor immune responses while alleviating immunosuppressive mechanisms. Advancing novel technologies to enhance the efficacy of PD-1/PD-L1 blockade remains a critical focus in medical research. Nonetheless, challenges such as immune-related adverse effects, therapeutic resistance, and high treatment costs highlight the urgent need for innovative strategies that optimize clinical outcomes and accessibility. Aptamers are short, single-stranded oligonucleotides characterized by their high affinity and specificity for target molecules. Emerging as promising alternatives to traditional antibody-based therapies, they offer new avenues in cancer treatment. This review provides a comprehensive analysis of aptamer-driven strategies aimed at inhibiting the PD-1/PD-L1 immune checkpoint pathway. It summarizes recent advances in the design of PD-1/PD-L1-targeted aptamer systems and evaluates their potential to enhance therapeutic efficacy while addressing challenges related to immune resistance.
    Keywords:  Aptamer; Immunotherapy; PD-L1/PD-1
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153537
  77. Healthcare (Basel). 2026 Jul 02. pii: 1975. [Epub ahead of print]14(13):
    Ethical and Governance Challenges of AI in Medical Imaging and Diagnostics: A Systematic Survey and Policy Framework Recommendations.
    Dulani Athukorala, Khandakar Ahmed, Raza Nowrozy.
      Background/Objectives: Artificial intelligence (AI) is increasingly embedded within diagnostic imaging workflows, reshaping clinical decision-making, health system governance, and regulatory oversight. While technical advances in radiological AI have accelerated, governance mechanisms have struggled to keep pace with issues of bias, transparency, accountability, and lifecycle oversight. This study examines ethical, regulatory, and implementation challenges in AI-enabled diagnostic imaging, building on prior reviews that have often emphasised technical performance by integrating ethical risk domains with governance responses across the AI lifecycle. Methods: This study presents a PRISMA-ScR-informed systematic survey of 156 sources, including peer-reviewed publications, regulatory documents, policy reports, and professional guidance materials (2018-2025), synthesised through thematic analysis and lifecycle mapping spanning data acquisition, model development, deployment, monitoring, and continuous learning. Results: Drawing on both thematic insights derived from the reviewed literature and established ethical and regulatory frameworks, we propose a literature-derived conceptual ethical-governance framework organised around five pillars: equity and bias mitigation, explainability and transparency, accountability and oversight, privacy-preserving infrastructure, and adaptive regulatory alignment. Although illustrated through the Australian healthcare context, the framework is designed to be transferable to federated and multi-jurisdictional health systems. This review further identifies trust quantification as an underdeveloped but essential dimension of clinical AI governance, emphasising the need to integrate measurable indicators such as calibration, clinician-AI concordance, and patient acceptance into lifecycle-based evaluation. Conclusions: By bridging technical, ethical, and policy perspectives, this review proposes a structured conceptual governance framework to support safe, equitable, and trustworthy AI integration in digital health systems.
    Keywords:  AI governance; algorithmic bias; artificial intelligence; clinical decision support; diagnostic imaging; digital health; ethical AI; explainability; healthcare regulation; medical imaging
    DOI:  https://doi.org/10.3390/healthcare14131975
  78. Front Immunol. 2026 ;17 1893099
    Hypoxia-driven tumor immune escape: mechanisms and therapeutic opportunities.
    Hongran Qin, Shuqiang Yang, Jiawei He, Meijia Zhao, Luqian Zhao, Jingjing Wang, Xiulin Jiang, Xiaowen Chen, Xin Xu.
      Hypoxia is a common feature of solid tumors and a major driver of tumor immune escape. It arises from abnormal tumor vasculature and rapid tumor growth, leading to persistent or fluctuating oxygen deprivation within the tumor microenvironment. Under hypoxic conditions, hypoxia-inducible factors, especially HIF-1α and HIF-2α, activate transcriptional programs that support tumor survival, angiogenesis, glycolytic metabolism, invasion, and therapy resistance. Beyond these tumor-intrinsic effects, hypoxia also reshapes antitumor immunity by suppressing CD8+ T cells, natural killer cells, and dendritic cell antigen presentation, while promoting regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. These changes establish a strongly immunosuppressive microenvironment and reduce the efficacy of immunotherapy. Hypoxia-driven immune escape is mediated by several interconnected mechanisms. HIF signaling promotes lactate accumulation, acidosis, adenosine signaling, PD-L1 expression, myeloid cell recruitment, and T cell exhaustion. In addition, emerging evidence indicates that RNA modifications, including m6A and ac4C, provide a post-transcriptional regulatory layer that links hypoxia signaling with immune checkpoint regulation, chemokine production, myeloid metabolism, and HIF-1α translation. Therapeutically, targeting hypoxia-related pathways may improve antitumor immunity, but single-agent approaches are often insufficient because hypoxic tumors use multiple overlapping escape mechanisms. Rational combinations involving HIF inhibitors, metabolic intervention, immune checkpoint blockade, cell therapy optimization, and RNA epitranscriptomic targeting may provide more effective strategies. In this review, we summarize how hypoxia coordinates metabolic barriers, immune remodeling, checkpoint activation, and RNA modification-dependent regulation to drive tumor immune escape, and discuss future directions for targeting the hypoxia-metabolism-immune axis in cancer immunotherapy.
    Keywords:  HIF-1α; RNA epitranscriptomics; cancer immunotherapy; hypoxia; immune checkpoints; immune escape; metabolic reprogramming; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1893099
  79. Int J Mol Sci. 2026 Jun 23. pii: 5660. [Epub ahead of print]27(13):
    A Comprehensive HLA-DR4 MHC Class II Tetramer Platform for the Detection and Functional Validation of Post-Translational Modification Neoantigens.
    Henghui Li, Jingyao Li, Ying Wang, Hongyan Ma, Fen Tang, Liang Chen.
      Post-translational modification (PTM) neoantigens have emerged as key drivers of autoimmune inflammation. However, standardized protocols for MHC Class II tetramer preparation for the detection of such antigen-specific T cells remain limited, hindering the broader application of this important discovery. This study systematically engineered an HLA-DR4 (HLA-DRB1*04:02 and HLA-DRA*01:01) tetramer platform based on carboxyethyl-modified neoantigen ITGA2B peptide (ITG-CE), a PTM associated with autoimmune diseases (AUIDs) such as Ankylosing Spondylitis (AS). The platform provides a major histocompatibility complex (MHC) Class II tetramer associated with the PTM neoantigen and integrates modular protein construct, a controllable PTM peptide exchange strategy, and a specific T cell receptor (TCR) validation model. It can be employed to investigate PTM neoantigen presentation and CD4+ T cell auto-reactivity, providing extensive application value for future research into the mechanisms of PTM-induced AUIDs and immune monitoring.
    Keywords:  HLA-DR4; T-cell receptor (TCR) recognition; antigen-specific CD4+ T cells; autoimmune diseases (AUIDs); fluorescence polarization (FP); high-throughput screening; major histocompatibility complex (MHC) class II tetramer; post-translational modification (PTM) neoantigens
    DOI:  https://doi.org/10.3390/ijms27135660
  80. Radiol Med. 2026 Jul 13.
    Digital infrastructures and data interoperability in radiology for prevention: from digital health to AI-enabled, quantitative imaging workflows.
    Luca Maria Sconfienza.
      Radiology is rapidly evolving from a service that produces images into a data-centric clinical platform that supports prevention, early diagnosis, and personalized care. This shift is accelerated by the convergence of digital health, artificial intelligence (AI), and quantitative imaging approaches such as radiomics. However, the clinical impact of these innovations depends less on algorithms alone and more on robust digital infrastructures and true interoperability across radiological, clinical, and-when available-molecular data. In practice, many implementations fail because data remain fragmented across heterogeneous systems, metadata are incomplete, workflows are not harmonized, and governance frameworks are insufficient to ensure quality, privacy, and accountability. This paper focuses on the radiology-centric requirements for interoperable data ecosystems, covering technical and semantic standards (e.g., DICOM, HL7 FHIR, IHE profiles, controlled terminologies), data governance and quality programs, and AI integration into real-world radiology workflows. Common practical barriers, including legacy IT debt, semantic inconsistencies, model drift, bias, medico-legal uncertainty, and hidden operational costs, are discussed. Last, pragmatic recommendations to enable scalable, secure, and clinically useful interoperability are proposed-supporting prevention pathways and the responsible deployment of AI and radiomics at institutional and network levels.
    Keywords:  Artificial intelligence; Data interoperability; Digital infrastructures; Radiology
    DOI:  https://doi.org/10.1007/s11547-026-02263-4
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