bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–09–20
sixty-six papers selected by
Luca Bolliger, lxBio
  1. Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference.
  2. Emerging CAR-Treg and regulatory T cell therapies for inflammatory bowel diseases: a systematic review of a new era of treatment.
  3. CAR T-cells for the treatment of CNS malignancies.
  4. Engineered Bacteriophages in Cancer Immunotherapy: Emerging Concepts and Potential Integration with CAR-T Cell Therapy.
  5. Engineering controllable CAR T-cell therapies: from binary safety switches to programmable immunity.
  6. Quantitative Characterization of Innate and Adaptive Pharmacology of Allogeneic anti-CD20 Chimeric Antigen Receptor (CAR) Vδ1 γδ T cells using Multiscale Mechanistic Modeling.
  7. Engineering next-generation CAR-T cells for glioblastoma treatment: a review of innovations in receptor design, antigen targeting, and therapeutic persistence.
  8. T-cell redirecting therapies in lung cancer - a comprehensive analysis of clinical trials.
  9. CAR-HEMATOTOX score as a predictor of hematotoxicity, infection, and survival after CAR T-cell therapy in hematologic malignancies: a systematic review and meta-analysis.
  10. Immune memory engineering in mRNA therapeutics.
  11. Advances in CAR-T Cell Therapy: From Structural Design Innovations to Clinical Translation Challenges.
  12. Real-world insights into genomic reprogramming during CAR-T cell manufacturing in India.
  13. Progress in reprogramming failed graft-versus-leukemia immunity in acute myeloid leukemia relapse after allogeneic transplantation.
  14. Relapse and progression after CAR-T cell therapy in large B-cell lymphoma: Patterns, mechanisms, and salvage strategies.
  15. T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?
  16. Comment on "Prolonged Cytokine Release Syndrome is Associated with Hypofibrinogenemia after CD19-Directed CAR T-Cell Therapy in Adult Patients with Relapsed/Refractory Lymphoma".
  17. Biomaterial Techniques for Enhancing CAR-T Cell Therapy of Solid Tumours.
  18. Chimeric antigen receptor T-cell therapy in autoimmune rheumatic diseases: defining the reset-opportunity window.
  19. Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma.
  20. Biological Foundation Models for Complex Disease Research and Clinical Translation.
  21. Artificial intelligence-driven digital twins in Pharma 4.0: transforming smart manufacturing, predictive quality assurance, and personalized drug delivery.
  22. The carbon footprint of Chimeric Antigen Receptor-T cell manufacturing processes.
  23. Spatial and Temporal Heterogeneity of Macrophage Efferocytosis in Tumors: Emerging Implications for Immunotherapy Biomarkers and Therapeutic Timing.
  24. Top advances of the year in autologous cellular therapy in melanoma and solid tumors.
  25. Nanomedicine and the tumor immune microenvironment in cancer immunotherapy: a bibliometric and knowledge-mapping analysis.
  26. Efficacy and safety of chimeric antigen receptor T-cell therapy in primary central nervous system lymphoma: a systematic review and meta-analysis.
  27. In vivo immune cell engineering from bench to clinical reality.
  28. Spatially instructed checkpoints in antitumor NK cell immunity.
  29. Seamless dose optimization design accounting for unknown patient heterogeneity in cancer clinical trials.
  30. Sino-US-DrugQA: A benchmark for evaluating large language models in cross-jurisdictional pharmaceutical regulation.
  31. Hierarchical Composite Endpoints for Dose Optimization in Early Phase Oncology Trials.
  32. Artificial Intelligence in Pharmaceutical Regulatory Science: Opportunities, Challenges, and Emerging Frameworks.
  33. A real-world analysis of adverse events and operational impacts of using T-cell engager therapy in an oncology setting.
  34. A bio-orthogonally engineered probiotic-T cell chimera amplifies adoptive cell therapy through spatial DC-T cell immune licensing.
  35. Vitamin C enhances cytotoxicity of CAR-and εTRuC-engineered γδ T cells and modulates Ca2+, NFAT, NF-κB and ERK signaling in human γδ T cells.
  36. Optimizing the Hinge Length of Chimeric Antigen Receptor with a DdFP-Based Immunological Synapse Biosensor.
  37. Autocrine PD-1-blocking nanobodies enhance the antitumor efficacy of TCR-like CAR-T cells by attenuating t cell exhaustion.
  38. From ICI Resistance to Therapeutic Vulnerability: A Resistance-State Framework for Appraising Antibody-Drug Conjugate Evidence in Solid Tumors.
  39. Multimodal medical diagnosis: a mini review of LLM-vision fusion models in low-resource healthcare settings.
  40. Incentivizing challenging drug discovery: from reducing failure to quantifying uncertainty.
  41. Targeting intracellular immune regulatory molecules for cancer immunotherapy in solid tumors.
  42. Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy. Reply.
  43. Therapeutic Cancer Vaccines: Classification, Mechanisms, Challenges and Future Perspectives.
  44. Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy.
  45. Gene regulatory elements determine efficacy of BCMA-targeted CAR-T cell products.
  46. FOXP1 Knockdown Reprograms Th9 CAR-T Cells to Overcome Antigen Escape.
  47. Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy.
  48. The spatial architecture of tumor immunity: Emerging predictive biomarkers across cancer.
  49. Continuing education needs of nurses caring for patients undergoing CAR T-cell therapy for hematological malignancies: A Canadian survey.
  50. Moonlighting ERAP Aminopeptidases in Cancer: Beyond Antigen Processing.
  51. Designing eligibility and evaluation criteria for antibacterial pull incentives: a comparative review of implemented and emerging initiatives.
  52. A hospital-based HTA model to assess the economic and organizational impact of intravenous-to-subcutaneous monoclonal antibody transitions in oncology.
  53. Accessing Germany's Electronic Patient Record Through Health Insurer-Provided Apps: Qualitative Interview Study.
  54. Rigorous, transparent and inconclusive: what Europe's first joint clinical assessment reveals about a framework trying to serve everyone.
  55. T-Cell Engagers in Lung Cancer: A Comprehensive Literature Review from Tarlatamab Approval to Next-Generation Strategies.
  56. mRNA-encoding CD19-targeting T cell engager for refractory immune thrombocytopenia.
  57. Toward adaptive therapeutic timing: integration of mechanistic pharmacology and artificial intelligence in precision dosing.
  58. Incidence rates of immune-related adverse events and their correlation with response in hematological malignancies treated with Chimeric Antigen Receptor T-Cells.
  59. Childhood adversity and autoimmune diseases: global research landscape, immune-related hotspots, and emerging trends from a bibliometric analysis of three databases.
  60. Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy.
  61. Bridging data and theory: hybrid modelling for pharmaceutical crystallisation process development.
  62. CAR T-Cell Therapy in Systemic Lupus Erythematosus: Mechanistic Rationale, Early Clinical Experience, and Future Challenges.
  63. Turing problems in otolaryngology: a scoping review of the principal challenges of artificial ıntelligence and large language models.
  64. Adaptive bandwidth of immunity: a systems-level framework for understanding immune regulation across time.
  65. Discovery and engineering of bispecific TCR-mimic antibodies targeting peptide-HLA complex.
  66. Nonclinical Safety Assessment of SBT777101, a CAR-Engineered Regulatory T Cell Therapy for Autoimmune Diseases.
  1. Front Immunol. 2026 ;17 1884854
    Recognition and management of early complications in CAR-T cell therapy and virus-specific T-lymphocyte therapy: a practical clinical reference.
    Marek Ussowicz, Ewa Jakubczyk, Tomasz Wróbel, Anna Czyż.
       Background: Cellular immunotherapies-including chimeric antigen receptor T-cell (CAR-T) therapies and adoptive transfer of virus-specific T lymphocytes (VSTs) - have transformed the treatment of refractory hematological malignancies and post-transplant infectious complications. Eight products are currently authorized by the European Medicines Agency, encompassing seven autologous CAR-T products targeting CD19 or BCMA and tabelecleucel (Ebvallo), the first approved allogeneic off-the-shelf EBV-specific T-cell product for EBV-positive post-transplant lymphoproliferative disease. Despite their clinical efficacy, both modalities carry distinct early toxicity profiles that differ from conventional cytotoxic chemotherapy.
    Objective: This review summarizes current recommendations for identifying, assessing, and treating early problems that can occur after CAR-T cell therapy and VST administration.
    Content: CAR-T-specific complications discussed include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), and immune effector cell-associated HLH-like syndrome (IEC-HS). CRS is graded by ASTCT consensus criteria and managed with tocilizumab as first-line pharmacological therapy; steroid-refractory ICANS is most commonly treated with high-dose intravenous anakinra (up to 12 mg/kg/day) which is currently the most studied second-line option, although the supporting evidence remains largely observational. ICAHT is classified using the validated EHA/EBMT grading framework, separating early (day 0-30) and late (post-day 30) neutropenia by depth and duration, with management escalating from prophylactic G-CSF through hematopoietic cell boost to allogeneic HSCT as the ultimate option. For VSTs, the principal early complications are tumor flare reaction (in approximately 20% of tabelecleucel recipients), GVHD (below 5% with enriched products), acute infusion reactions, and low-grade CRS-like cytokine release. We summarize a differential diagnosis of overlapping syndromes, pediatric-specific adaptations, ICU escalation criteria, and a clinical monitoring schedule.
    Conclusions: Internationally validated criteria grade the early complications of cellular immune effector therapies. Prompt recognition, early pharmacological intervention, and monitoring are essential to minimize non-relapse mortality. Expanding real-world experience and the integration of pre-treatment risk stratification tools will continue to refine evidence-based practice in this rapidly evolving field, ultimately leading to improved patient outcomes and reduced non-relapse mortality rates.
    Keywords:  CAR-T cell therapy; ICAHT; ICANS - immune effector cell-associated neurotoxicity syndrome; cytokine release syndrome (CRS); immunotherapy toxicity; tabelecleucel; virus-specific T lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1884854
  2. Front Immunol. 2026 ;17 1920203
    Emerging CAR-Treg and regulatory T cell therapies for inflammatory bowel diseases: a systematic review of a new era of treatment.
    Fabio Suarez-Trujillo, Theodore S Steiner, Javier P Gisbert, María Chaparro.
       Background: Inflammatory bowel disease (IBD) is a chronic immune-mediated disorder characterized by dysregulated mucosal immunity. Despite major advances in therapies, a high proportion of patients do not achieve or sustain remission. Cellular immunotherapies have emerged as a mechanistically distinct therapeutic strategy with potential relevance for refractory disease. In the present paper, the authors aim to evaluate the rationale and current evidence supporting chimeric antigen receptor (CAR)-engineered immune cells and regulatory T (Treg)-cell-based therapies in IBD. Preclinical studies and early translational data support biological plausibility and feasibility of these therapies. However, available human evidence remains limited, with sparse clinical experience and short follow-up.
    Methods: A systematic review was conducted according to PRISMA guidelines. Search was performed in PubMed and EMBASE databases from inception to February 2026 including terms like "IBD", "CAR-T", "CAR-Treg" and "Treg therapy" among others. Eligible studies included preclinical, translational and clinical reports evaluating CAR-engineered immune cells in IBD models.
    Results: A total of 11 studies met the inclusion criteria after the screening and were included in the review. CAR-Treg technologies build upon advances achieved with conventional CAR-T cells in oncology and enable antigen-specific immune regulation rather than cytotoxicity. Preclinical studies and early translational data support biological plausibility and feasibility. However, available human evidence remains limited, with sparse clinical experience and short follow-up. Major unresolved issues include cellular persistence, phenotypic stability (particularly for Tregs), optimal antigen selection, manufacturing scalability, and long-term safety.
    Conclusions: Cellular immunotherapies represent a promising but still investigational therapeutic paradigm in IBD. Robust clinical trials with standardized endpoints and long-term safety monitoring are needed before their clinical adoption.
    Keywords:  CAR-T; CAR-Treg; inflammatory bowel disease; regulatory T cells; regulatory T-cells therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1920203
  3. Front Immunol. 2026 ;17 1891659
    CAR T-cells for the treatment of CNS malignancies.
    Caleb A Kisamore, Paul J Owolabi, Claire O Kisamore, William H Walker.
      Chimeric antigen receptor (CAR) T-cell therapy has undergone great advances since the development of the first-generation CAR in the early 1990s. Currently there are seven FDA approved CAR T-cell therapies for the treatment of hematological malignancies, with marked clinical success. However, the application of CAR T-cell therapies to solid tumors, particularly CNS malignancies, provide unique challenges. This review provides historical perspective on CAR T-cell therapy, describes CAR structures and current generations, and details challenges with the application of CAR T-cells to CNS malignancies. In addition, an extensive summary of all clinical trials, as of March 2026, utilizing CAR T-cell therapy for primary and secondary CNS malignancies are provided. Specific attention is given to detailing CAR structure, route of administration, and dosing. Furthermore, outcomes and adverse events for each trial are described for completed studies and studies reporting interim results. As the application of CAR T-cell therapy continues to expand in CNS malignancies, it is imperative that clinical studies provide adequate details on CAR structures, try to more quickly adopt/act on preclinical successes, and seek novel application strategies to advance growth in the field.
    Keywords:  CAR T-cells; adoptive cell transfer; brain metastases; brain tumors; cancer immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1891659
  4. Folia Biol (Praha). 2026 Sep 14.
    Engineered Bacteriophages in Cancer Immunotherapy: Emerging Concepts and Potential Integration with CAR-T Cell Therapy.
    Jehan Alrahimi.
      Due to antigen heterogeneity, restricted immune cell trafficking and an immunosuppressive, nutrient-restricted tumour microenvironment, solid tumours remain resistant to modern immunotherapies. Engineered bacteriophages offer a modular framework to overcome these obstacles: programmable virus-like particles with scalable production. Through genome engineering, capsid decoration with mammalian cell-targeting ligands, or hybrid AAV/phage systems, engineered bacteriophages can display tumour-associated antigens, enhance receptor-mediated uptake and deliver therapeutic payloads such as cytokines, chemokines and suicide genes without naturally infecting mammalian cells. These features support their use as vaccine platforms, immunological adjuvants and targeted gene-delivery vehicles. These may enable more precise, tumour-localized therapeutic intervention. Phages can engage innate immune pathways, including TLR9, TLR3/7/8, cGAS-STING and AIM2, promoting dendritic cell maturation and inflammatory mediators that may convert immunologically "cold" tumours into inflamed microenvironments. Their multivalent antigen display enhances B- and T-cell priming, while cDC1-mediated cross-presentation supports cytotoxic CD8+ T-cell responses and immunological memory. In CAR-T therapy, engineered phages may improve tumour homing through chemokine modulation, support persistence through local cytokine delivery, reduce antigen escape by presenting multiple tumour epitopes, and limit T-cell exhaustion through dominant-negative receptor strategies or local checkpoint blockade. This review summarizes engineering approaches, delivery systems, manufacturing, biodistribution, dosing, and safety issues, including immunogenicity, pre-existing anti-phage antibodies and horizontal gene transfer. It also distinguishes therapeutic engineered phage particles from phage display technologies used for molecular discovery. Despite encouraging results integrating modified bacteriophages with CAR-T cell therapy, the evidence remains mostly preclinical, indicating both substantial translational prospects and crucial obstacles for future clinical development.
    Keywords:  CAR-T cell therapy; CRISPR selection; adaptive immunity; cancer immunotherapy; innate immunity; phage engineering; phage therapy; tumour microenvironment
    DOI:  https://doi.org/10.14712/fb2026.0018
  5. Front Immunol. 2026 ;17 1936293
    Engineering controllable CAR T-cell therapies: from binary safety switches to programmable immunity.
    Sergei Smirnov, Yuriy Zaritskey, Galina Salogub, Alexander Fonin.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionised cancer gene therapy, yet its expansion into solid tumours is hindered by a critical vulnerability: the autonomous, "always-on" nature of conventional CAR constructs. This unregulated activity drives severe toxicities, including cytokine release syndrome (CRS) and on-target/off-tumour damage, while constitutive signalling in hostile tumour microenvironments (TMEs) accelerates T-cell exhaustion. Early safety strategies relied on irreversible genetic "kill switches," which sacrifice the therapeutic cell population entirely. This review traces the conceptual evolution of CAR T-cell controllability from binary elimination towards platforms enabling graded, reversible, and spatiotemporally precise regulation. We examine the transition from calibrated signalling architectures and small-molecule-regulated split-CARs to advanced optogenetic and sonogenetic controllers, detailing the biophysics of photoreceptor pairs and their preclinical efficacy. Furthermore, we explore complementary architectures, including autonomous logic-gated receptors. Finally, we propose that the optimal next-generation CAR T product will integrate calibrated signalling, external control, and context-dependent armouring to achieve truly programmable, safe, and durable cellular immunotherapy.
    Keywords:  CAR T-cell therapy; controllable CAR; immunotherapy; logic-gated receptor; modular adaptor; optogenetics; safety switch; synthetic notch
    DOI:  https://doi.org/10.3389/fimmu.2026.1936293
  6. AAPS J. 2026 Sep 18. pii: 154. [Epub ahead of print]28(6):
    Quantitative Characterization of Innate and Adaptive Pharmacology of Allogeneic anti-CD20 Chimeric Antigen Receptor (CAR) Vδ1 γδ T cells using Multiscale Mechanistic Modeling.
    Devam A Desai, Omar Elashkar, Rodrigo Cristofoletti, Ganesh Mugundu, Aman P Singh.
      Gamma Delta (γδ) T Cells are currently being evaluated as a therapeutic alternative to traditional alpha-beta (αβ) T-cells due to their superior safety profile and enhanced tissue retention properties. The application of CAR technology to gamma delta (γδ) T cells presents a novel therapeutic avenue with the potential to overcome some limitations of conventional CAR T-cell therapies, such as targeting solid tumors and reducing on-target, off-tumor toxicities. The objective of this manuscript is development of a translational PK-PD framework to first characterize in vitro killing potential of un-transduced and CAR transduced anti- CD20 Vδ1 γδ T cells as well as development of an in vivo mechanistic CK-PD model designed to understand the complex dynamics of CAR γδ T cells and their interaction with IL-15 and tumor cells. All the preclinical and clinical datasets along with relevant information were digitized and obtained from the published work on Adicet Bio's AD-001. The developed model was able to estimate the in vitro killing potential of untransduced and CAR transduced anti- CD20 Vδ1 γδ T cells as well as expansion, tissue distribution, the impact of lymphodepletion and interleukin-15 (IL-15), and the tumor-killing potential of CAR-modified γδ T cells. These insights offer a deeper understanding of the potential therapeutic benefits and mechanisms of γδ T cells in immunotherapy, particularly in their application against various cancers. The development of this translational framework can be paramount in understanding the underlying dose-exposure-response relationship of CAR modified γδ T cell therapy and facilitate the discovery and development of these agents.
    Keywords:  CAR-T cell therapy; allogenetic cell theraphy; mechanism-based modeling; preclinical to clinical translation
    DOI:  https://doi.org/10.1208/s12248-026-01314-y
  7. Int Immunopharmacol. 2026 Sep 13. pii: S1567-5769(26)01263-4. [Epub ahead of print]189 117416
    Engineering next-generation CAR-T cells for glioblastoma treatment: a review of innovations in receptor design, antigen targeting, and therapeutic persistence.
    Aleksandra Królikowska, Katarzyna Białkowska.
      Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults and is characterized by poor prognosis, profound intratumoral heterogeneity, and a highly immunosuppressive tumor microenvironment (TME). Although chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy in hematologic malignancies, clinical responses in GBM remain inconsistent and rarely durable. This review critically evaluates how receptor architecture, antigen selection, multi-antigen targeting, TME- and exhaustion-resistant engineering, locoregional delivery, alternative CAR-cell platforms and computational design address the major biological and anatomical barriers of GBM. What should be given a particular attention is not only the translational gap between preclinical activity and limited clinical efficacy, but also differences in target specificity, antigen escape, safety, delivery route and CAR-T persistence. However, the available evidence indicates that no single engineering strategy is sufficient to overcome the interconnected barriers. The strongest approach is likely to combine several strategies. These should improve antigen coverage, maintain CAR-T cell function, increase safety and improve delivery within the CNS. Future progress in GBM CAR therapy will therefore depend on combining complementary solutions rather than improving only one CAR feature.
    Keywords:  Antigen escape; CAR-T cell therapy; Glioblastoma; Multi-antigen targeting; T-cell exhaustion; VHH domains
    DOI:  https://doi.org/10.1016/j.intimp.2026.117416
  8. Front Immunol. 2026 ;17 1917770
    T-cell redirecting therapies in lung cancer - a comprehensive analysis of clinical trials.
    Jiahe Zhao, Ayrton Bangolo, Lili Zhang, Martin Gutierrez, Miguel Gonzalez-Velez.
      Lung cancer remains the leading cause of cancer-related mortality worldwide, and despite the transformative impact of immune checkpoint inhibitors (ICIs), primary and acquired resistance, limited efficacy in immune-cold tumors such as extensive-stage small cell lung cancer (ES-SCLC), and the absence of durable responses in a substantial proportion of patients define the unmet need that T cell-redirected therapies aim to address. These strategies engage, engineer, and deliver cytotoxic T cells against tumor cells independently of preexisting immunity, and this review provides a comprehensive overview of the four major modalities under clinical development in lung cancer: bispecific T cell engagers (BiTEs), tumor-infiltrating lymphocyte (TIL) therapy, chimeric antigen receptor T cell (CAR-T) therapy, and T cell receptor-engineered T cell (TCR-T) therapy. Among these, tarlatamab, a DLL3×CD3 BiTE, has achieved the most advanced clinical validation, receiving traditional FDA approval in November 2025 for second-line ES-SCLC following Phase 3 DeLLphi-304 data demonstrating superior overall survival versus chemotherapy (median 13.6 vs. 8.3 months; HR 0.60). TIL therapy is the leading adoptive cell approach in non-small cell lung cancer (NSCLC), with lifileucel demonstrating a 25.6% ORR in anti-PD-1-resistant disease and a 64.3% ORR when combined with pembrolizumab in ICI-naïve patients, though manufacturing complexity and cost constrain broad access. CAR-T and TCR-T therapies remain in early proof-of-concept phases, limited by the absence of uniformly expressed tumor-restricted surface antigens in NSCLC, MHC class I downregulation, and the sub-1% eligibility rates imposed by HLA restriction in TCR-T programs, while generating important engineering insights around genome editing, armored cytokine payloads, and neoantigen targeting strategies. Shared challenges across all modalities include antigen loss under therapeutic pressure, T cell exhaustion driven by the immunosuppressive lung tumor microenvironment, and the absence of prospectively validated predictive biomarkers for patient selection. Combination strategies pairing T cell-redirected therapies with ICIs, antibody-drug conjugates, and allogeneic or innate immune effectors represent the most promising path toward durable benefit. As the field advances toward Phase 3 trials, biomarker-selected patient populations, and scalable allogeneic manufacturing platforms, T cell-redirected therapy is positioned to extend the survival frontier for patients whose lung cancer has escaped existing treatments.
    Keywords:  T-cell redirected therapy; TCR-engineered T cells; bispecific T cell engager; chimeric antigen receptor T (CAR T) therapy; lung cancer; tumor-infiltrating lymphocyte
    DOI:  https://doi.org/10.3389/fimmu.2026.1917770
  9. Front Oncol. 2026 ;16 1928438
    CAR-HEMATOTOX score as a predictor of hematotoxicity, infection, and survival after CAR T-cell therapy in hematologic malignancies: a systematic review and meta-analysis.
    Juncheng Wei, Ziyu Chen, Mengfei Li, Miao Jiang.
       Background: Immune effector cell-associated hematotoxicity (ICAHT) is a common and clinically important toxicity after chimeric antigen receptor (CAR) T-cell therapy. The CAR-HEMATOTOX score, also reported as CAR-HT, is a baseline risk score proposed to identify patients at higher risk of hematotoxicity and related adverse outcomes.
    Methods: We conducted a systematic search of PubMed, the Web of Science, and the Cochrane Library on June 19, 2026. Included studies compared high- and low-risk groups defined by the CAR-HEMATOTOX score after CAR T-cell therapy for hematologic malignancies and reported extractable data on hematologic toxicity, infection, survival, or other predefined clinical outcomes. Random-effects inverse-variance meta-analysis was performed only when at least three independent, clinically compatible estimates were available.
    Results: Twenty-three publications were included in the evidence inventory. For ICAHT, high risk was associated with higher odds (pooled OR 5.58, 95% CI 1.98 to 15.73; I²=60.8%). For overall survival (OS), high risk was associated with worse OS (pooled HR 3.36, 95% CI 2.20 to 5.11; I²=0.0%). For progression-free survival (PFS), high risk was associated with worse PFS (pooled HR 2.74, 95% CI 1.81 to 4.15; I²=32.3%). For severe infection, high-risk status was associated with higher odds (pooled OR 5.18, 95% CI 2.78 to 9.67; I²=37.8%). Exploratory analyses suggested higher early red blood cell and platelet transfusion requirements in high-risk patients, whereas severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were not significantly associated with high-risk status.
    Conclusion: A high CAR-HEMATOTOX score was associated with greater risk of ICAHT, higher odds of severe infection, and worse survival outcomes after CAR T-cell therapy for hematologic malignancies. These findings suggest that the CAR-HEMATOTOX score may be a clinically relevant risk-stratification marker, but the evidence remains observational and exploratory; standardized outcome definitions, prospective validation, and clearer handling of overlapping cohorts are needed before the score can be used as a stand-alone decision tool.
    Systematic Review Registration: https://www.crd.york.ac.uk/prospero/view/CRD420261435303, identifier 420261435303.
    Keywords:  CAR T-cell therapy; CAR-HEMATOTOX; hematologic malignancies; immune effector cell-associated hematotoxicity; infection; meta-analysis; survival
    DOI:  https://doi.org/10.3389/fonc.2026.1928438
  10. J Control Release. 2026 Sep 18. pii: S0168-3659(26)00774-1. [Epub ahead of print] 115370
    Immune memory engineering in mRNA therapeutics.
    Jianguo Wen, Wenjing Tao, Xiaobo Zhou.
      Messenger RNA (mRNA) therapeutics have revolutionized vaccine development and are rapidly expanding into cancer immunotherapy, infectious diseases, regenerative medicine, and protein replacement therapies. While considerable efforts have focused on maximizing antigen expression and short term immune responses, durable therapeutic efficacy ultimately depends on the establishment of long lasting immune memory. Emerging evidence suggests that immune memory is not merely a passive consequence of antigen expression but can be actively shaped through the rational engineering of antigen persistence, delivery, and immune programming. In this review, we propose immune memory engineering as a unifying framework for mRNA therapeutics that achieve durable immune protection. We examine three interconnected biological determinants of immune memory, including antigen persistence, antigen trafficking, and innate and spatial programming, and discuss how LNP engineering, formulation parameters, and tissue specific delivery quantitatively influence memory formation. We further highlight how artificial intelligence and multiomics approaches can integrate these determinants into predictive design strategies for optimizing durable immune responses. Together, these advances position immune memory engineering as an emerging design paradigm for developing next generation mRNA therapeutics with durable, controllable, and increasingly personalized immune protection.
    Keywords:  Antigen persistence; Antigen trafficking; Artificial intelligence; Immune engineering; Immune memory; Trained immunity; mRNA therapeutics
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115370
  11. J Cancer. 2026 ;17(9): 1684-1697
    Advances in CAR-T Cell Therapy: From Structural Design Innovations to Clinical Translation Challenges.
    Haixia Gao, Yuan Fang, Pingjing Zhang, Qijun Qian.
      Chimeric Antigen Receptor T cells (CAR-T) therapy represents a groundbreaking technology in the field of tumor immunotherapy. This innovative approach involves the genetic engineering of T cells to specifically identify and eradicate tumor cells, and it has been shown to yield remarkable efficacy in treating hematological malignancies. This article provides a comprehensive overview of the core advancements in CAR-T technology, emphasizing the evolution of the five generations of CAR structures. Furthermore, it explores the latest innovations in transfection techniques, highlighting optimizations and comparative advantages of viral and non-viral vectors. The future of CAR-T therapy is poised to focus on several validated translational directions: the development of universal off-the-shelf CAR-T cell products, the design of multi-target and logic-gated intelligent CAR architectures, innovative in vivo genetic reprogramming platforms, and synergistic combinatorial therapeutic regimens to overcome solid tumour immune suppression. These advancements aim to enhance the specificity, safety, and accessibility of CAR-T therapies. This article seeks to outline the current state of CAR-T technology while providing insights into potential theoretical frameworks and technical pathways for its future evolution.
    Keywords:  CAR design; CAR-T; in vivo CAR-T generation; transfection technology; universal CAR-T
    DOI:  https://doi.org/10.7150/jca.134677
  12. Front Immunol. 2026 ;17 1912690
    Real-world insights into genomic reprogramming during CAR-T cell manufacturing in India.
    Nupur Das, Prashant Mehta, Kusum Gupta, Rahul Katharia, Swati Pabbi, Pravas Mishra, Soni Morya.
       Background: While CAR-T cell therapy has transformed outcomes in B-cell malignancies, most genomic insights originate from clinical trials. There is a paucity of data describing molecular changes during CAR-T manufacturing in real-world practice, particularly for non-US CAR constructs.
    Methods: This was an observational study conducted at a tertiary care center in India where a total of 4 set of paired samples comprising leukapheresis starting material (n=4) and the corresponding final CAR-T cell product (n=4) were analyzed. Analysis was done using NanoString nCounter® platform with a targeted immune-oncology panel comprising 750 genes.
    Results: Comparative gene expression analysis between CAR-T product and leukapheresis sample revealed significant upregulation of genes associated with cell proliferation (MKI67, BUB1), cytokine responsiveness (IL2RA, IL12RB2, CISH), metabolic fitness (PHGDH, PSAT1), and effector differentiation (IRF4, BATF3, LIF) in final product as compared to leukapheresis sample. Concurrent downregulation of innate immune and myeloid lineage genes (CD14, FCGR3A/B, FCAR, CYBB, FPR1, LILRA5, TYROBP, S100A12) along with reduced expression of inflammatory mediators (FOS, DUSP1, S100A12) suggests a controlled activation state that may limit baseline inflammatory priming and effective enrichment of adaptive T cells.
    Conclusions: Indigenous CAR-T manufacturing processes induce significant transcriptomic remodeling and reflects a highly proliferative and cytokine-responsive CAR-T phenotype associated with improved functional fitness. These findings may reflect a baseline framework for CAR-T genomic characterization in real-world clinical settings to explore outcome-related analyses.
    Keywords:  CAR-T; NanoString; genomic profiling; immune cells; leukapheresis; reactome pathway
    DOI:  https://doi.org/10.3389/fimmu.2026.1912690
  13. Front Immunol. 2026 ;17 1910630
    Progress in reprogramming failed graft-versus-leukemia immunity in acute myeloid leukemia relapse after allogeneic transplantation.
    Naif I AlJohani, Ahlam Almasari, Zayed Alzahrani, Nahla Shihata, Binyam Usman, Bassim Albeirouti.
      Relapse of acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) affects 40-50% of recipients and remains the leading cause of posttransplant mortality; median overall survival is approximately 5 months and 1-year survival is below 20%. Conventional salvage-chemotherapy, immunosuppression withdrawal, donor lymphocyte infusion (DLI), hypomethylating agents, targeted agents, and second transplantation-benefits a minority and has improved only incrementally over two decades. Relapse in this setting reflects leukemia that has survived an engrafted allogeneic immune system. Documented escape mechanisms include genomic loss of the mismatched human leukocyte antigen (HLA) haplotype, epigenetic downregulation of class II HLA molecules, checkpoint ligand upregulation, microenvironmental suppression, and clonal evolution-each calling for targeted redirection of the graft-versus-leukemia (GVL) response rather than further nonspecific cytotoxicity. We propose a GVL Failure Framework that organizes posttransplant relapse into three biologically defined categories of immune escape, aligns matched cellular therapies with each, and overlays a separate clinical transplant-eligibility axis that sets the therapeutic goal. Several cellular strategies have matured: autologous and donor-derived chimeric antigen receptor T (CAR-T) cells targeting CD33, CD123, C-type lectin-like molecule 1 (CLL-1)/CD371, and CD117; armored CAR-T products secreting interleukin-18; CD83-directed CAR-T cells targeting blasts and alloreactive T cells simultaneously; HLA-DRB1-directed CAR-T and chimeric antigen receptor natural killer (CAR-NK) cells exploiting donor-recipient mismatch for leukemia specificity; and off-the-shelf CAR-NK platforms reprogramming innate rather than adaptive allogeneic immunity. We integrate the mechanistic rationale and early clinical evidence for each approach, propose a four-pathway treatment algorithm built around relapse-clone HLA typing before DLI, and outline the gaps that must close before cellular therapy enters standard practice.
    Keywords:  CAR-NK; CAR-T; CD83; HLA-directed therapy; acute myeloid leukemia; allogeneic stem cell transplantation; posttransplant relapse
    DOI:  https://doi.org/10.3389/fimmu.2026.1910630
  14. Cancer Treat Res Commun. 2026 Sep 12. pii: S2468-2942(26)00335-7. [Epub ahead of print]49 101425
    Relapse and progression after CAR-T cell therapy in large B-cell lymphoma: Patterns, mechanisms, and salvage strategies.
    Lingzhi Wang, Qing Li, Xiaojian Zhu.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for large B-cell lymphoma (LBCL), particularly in the relapsed or refractory. However, relapse after CAR-T cell therapy remains a major barrier to durable remission and long-term survival because post-CAR-T relapse is biologically and clinically heterogeneous and lacks standardized management strategies. In this narrative review, we provide a clinically oriented synthesis of the current evidence on relapse or progression after CAR-T cell therapy in LBCL, focusing on relapse patterns, underlying biological mechanisms, risk factors, and evolving salvage strategies. Evidence from other B-cell lymphoma subtypes is included selectively when it provides relevant biological or clinical context, but it is not considered directly interchangeable with findings from LBCL. We delineate the heterogeneity of post-CAR-T cell recurrence across lymphoma subtypes, emphasizing differences in the timing, patterns of progression, and antigen expression. We then discuss the principal determinants of treatment failure, including patient-related factors, tumor-intrinsic features, impaired CAR-T cell expansion and persistence, an immunosuppressive tumor microenvironment, and treatment-induced selective pressures. We also summarize current salvage strategies, including bispecific antibodies, CAR-T cell reinfusion, allogeneic hematopoietic stem cell transplantation, and investigational approaches under clinical evaluation. Among these, bispecific antibodies have demonstrated promising efficacy in real-world settings and are increasingly being incorporated into post-CAR-T cell treatment algorithms. Overall, post-CAR-T cell relapse is a multifactorial process with important clinical implications. Integrating mechanistic insights with emerging therapeutic advances may enable more individualized salvage strategies. Future research should focus on improved risk stratification, biomarker-guided surveillance, optimization of treatment sequencing, and the development of next-generation cellular and combinatorial immunotherapies to improve long-term outcomes.
    Keywords:  CAR-T; Cell therapy; Large B-cell lymphoma; Progression; Relapse; Salvage therapy
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101425
  15. Haematologica. 2026 Sep 17.
    T-cell lymphoma following chimeric antigen receptor-T therapy: a cause for concern?
    Federico Stella, Joseph A Fraietta, Stephen J Schuster, Marco Ruella.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed or refractory B-cell malignancies and multiple myeloma, with tens of thousands of patients treated worldwide. As survival improves, long-term safety has come into focus, and rare reports of T-cell lymphomas occurring after CAR T-cell infusion have prompted regulatory scrutiny and heightened clinical attention. Drawing on pivotal trials, real-world registries, meta-analyses, pharmacovigilance data, and detailed molecular case reports, we review the incidence, biological plausibility, and clinical relevance of lymphomas arising after CAR T-cell therapy. Registry data and large institutional series consistently show that secondary T-cell malignancies are exceedingly rare, with reported incidences of approximately 0.03-0.3% depending on the cohort, and far less common than therapy-related myeloid neoplasms, solid tumors, and non-melanoma skin cancers in heavily pretreated populations. Most molecularly characterized post-CAR T-cell lymphomas lack evidence of CAR vector-driven transformation and appear to reflect pre-existing or therapyselected clonal T-cell populations in the context of clonal hematopoiesis, immune dysregulation, and, in some cases, viral reactivation. Nevertheless, rare CAR-positive cases with informative integration-site data confirm that vector-related transformation is biologically possible, although exceptional and probably dependent on cooperating host or clonal events. We also discuss pathogenetic mechanisms, diagnostic pitfalls, and practical recommendations for surveillance and patient counseling. In conclusion, secondary T-cell lymphomas represent a concerning but extremely uncommon complication of CAR T-cell therapy. Vigilance through standardized long-term follow-up and rigorous molecular investigation of suspected cases is warranted, but current evidence does not undermine the overwhelmingly favorable benefit-risk profile of CAR T-cell therapy.
    DOI:  https://doi.org/10.3324/haematol.2026.301592
  16. Transplant Cell Ther. 2026 Sep 18. pii: S2666-6367(26)00755-4. [Epub ahead of print]
    Comment on "Prolonged Cytokine Release Syndrome is Associated with Hypofibrinogenemia after CD19-Directed CAR T-Cell Therapy in Adult Patients with Relapsed/Refractory Lymphoma".
    Dr Danti Joseph.
      
    Keywords:  CAR T-cell therapy; CD19-directed therapy; Corticosteroids; Cytokine release syndrome; Hypofibrinogenemia; Lymphoma; Tocilizumab
    DOI:  https://doi.org/10.1016/j.jtct.2026.09.026
  17. Cancers (Basel). 2026 Aug 22. pii: 2727. [Epub ahead of print]18(17):
    Biomaterial Techniques for Enhancing CAR-T Cell Therapy of Solid Tumours.
    Kai Chilvers, John Maher.
       BACKGROUND/OBJECTIVES: Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in haematological malignancies but has shown limited efficacy against solid tumours. Key barriers include inadequate tumour trafficking, immunosuppressive tumour microenvironments, poor selectivity and heterogeneity of antigen expression, and challenges related to safety and manufacturing. Biomaterial-based technologies have emerged as a potential strategy to address many of these limitations. This review aims to critically evaluate biomaterial approaches designed to enhance CAR-T cell therapy of solid tumours and assess their translational potential.
    METHODS: A narrative review of recent pre-clinical translational studies was conducted, focussing on biomaterial platforms developed to improve CAR-T cell delivery, persistence, functionality, safety control, and manufacturing efficiency in solid-tumour settings. Approaches were analysed according to their mechanisms of action, therapeutic benefits, and stage of translational readiness.
    RESULTS: Biomaterial strategies, including nanoparticles, injectable and implantable hydrogels, scaffolds, and hybrid delivery systems, have improved CAR-T infiltration, survival, and therapeutic efficacy in several solid-tumour models. Localised delivery of cytokines and other immunomodulatory cues enabled improved spatio-temporal control of CAR-T activation, reducing systemic toxicity, and increasing persistence. Additional applications include amplified ex vivo CAR-T expansion and support for non-viral or in vivo CAR-T generation. However, increased material complexity was frequently associated with challenges in scalability, regulatory approval, and long-term safety.
    CONCLUSIONS: Biomaterial-enabled approaches offer a versatile toolkit to address key biological and translational barriers limiting CAR-T cell therapy of solid tumours. Strategies based on clinically familiar materials and simplified designs appear most suitable for near-term clinical translation, emphasising the need to balance engineering innovation with safety, scalability, and integration into existing clinical workflows.
    Keywords:  CAR-T cell therapy; biomaterials; drug delivery systems; immunotherapy; solid tumours; tumour microenvironment
    DOI:  https://doi.org/10.3390/cancers18172727
  18. Clin Exp Rheumatol. 2026 Aug 05.
    Chimeric antigen receptor T-cell therapy in autoimmune rheumatic diseases: defining the reset-opportunity window.
    Anna Gwóźdź-Broczkowska.
      The current challenge in autoimmune chimeric antigen receptor (CAR) T-cell therapy is no longer whether B cells can be depleted, but whether treatment is delivered before immune-mediated organ injury has become irreversible. This targeted narrative review appraises CD19-directed, dual CD19/B-cell maturation antigen, B-cell maturation antigen-directed and allogeneic approaches in systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myopathies. It proposes a reset-opportunity window: a pre-treatment state in which active immune injury, targetable B-lineage or plasma-cell biology and residual organ reserve coexist. Systemic lupus erythematosus is the clearest current test case because serology, complement, renal activity and remission can be followed serially. Systemic sclerosis and myositis require more cautious interpretation because fibrosis, vasculopathy and fatty muscle replacement may limit recovery despite immune control.To make partial and negative responses interpretable, the review defines five failure domains: cellular-product failure, target/plasma-cell escape, reconstitution failure, organ-reserve failure and comparator failure. The first four are patient-level mechanistic phenotypes; comparator failure is a trial-level interpretive domain. These domains are non-exclusive and may coexist within the same clinical course or dataset.Trials should make response and non-response mechanistically interpretable: they should report screened-but-not-infused patients, CAR T-cell expansion, B-cell and plasma-cell reconstitution, baseline damage, organ-specific recovery and relapse after immunereconstitution. Without these data, a clinical response cannot be distinguished from favourable selection, temporary depletion or damage-limited stabilisation.
    DOI:  https://doi.org/10.55563/clinexprheumatol/ggjis9
  19. Ann Hematol. 2026 Sep 15. pii: 421. [Epub ahead of print]105(10):
    Early deep response to cilta-cel as 2nd CAR T-Cell therapy after CELMoD-based bridging for advanced multiple myeloma.
    Henrik Niklas, Anna Bold, Simon Völkl, Nicola Lang, Marietta Truger, Knut Wendelin, Susanne Strifler, Johannes Gärtner, Stefan Knop.
      AbstractChimeric antigen receptor (CAR) T-cell therapy has emerged as an innovative and highly effective treatment option for patients with relapsed/refractory multiple myeloma (RRMM). This effect is based on redirecting modified T-cells towards plasma cells expressing target antigens, specifically B cell maturation antigen (BCMA). Despite high initial response rates, disease relapse remains a major clinical challenge. Therapeutic options after progression following prior BCMA-directed CAR T-cell therapy are limited, and prognosis is often poor. We report on a 58-year-old male with high-risk IgA kappa multiple myeloma who was heavily pretreated and received idecabtagene vicleucel as sixth-line therapy, achieving a deep response lasting for approximately one year. Following disease progression, the patient received bridging therapy with mezigdomide,carfilzomib, and dexamethasone, followed by a second BCMA-directed CAR T-cell infusion using ciltacabtagene autoleucel. Previous whole genome sequencing had confirmed preserved BCMA expression.Early post-infusion assessment showed a rapid and profound response, with marked declines in serum IgA and free kappa light chains, accompanied by robust CAR T-cell expansion. Treatment-related toxicities were manageable, including grade II cytokine release syndrome and prolonged cytopenias, without evidence of neurotoxicity.This case provides additional knowledge that retreatment with BCMA-directed CAR T-cell therapy may be feasible and clinically effective in heavily pretreated multiple myeloma, particularly after a durable response to initial CAR T-cell therapy. Bridging therapy and the use of an alternative CAR T-cell construct may further improve outcomes. Prospective studies are needed to define optimal patient selection and treatment sequencing in this setting.
    Keywords:  BCMA; CAR T-cell therapy; High-risk cytogenetics; Multiple myeloma; Retreatment
    DOI:  https://doi.org/10.1007/s00277-026-07278-5
  20. Biology (Basel). 2026 Sep 03. pii: 1527. [Epub ahead of print]15(17):
    Biological Foundation Models for Complex Disease Research and Clinical Translation.
    Tiana Noll-Walker, Yong Chen.
      Complex diseases, including cancer, rare genetic disorders, neurodevelopmental and psychiatric conditions, and neurodegenerative diseases, arise from interactions among genetic variation, gene regulation, and cellular states that are difficult to capture using a single data type or biological scale. Biological foundation models address this challenge by treating nucleotides and genes as tokens and learning representations that can be transferred to downstream biomedical and clinical tasks. In this review, we examine two major model classes, genomic sequence foundation models and cell foundation models, and compare their tokenization strategies, model architectures, pretraining objectives, and adaptation methods. We summarize their emerging applications in regulatory variant interpretation, disease-associated cell-state analysis, drug-response prediction, and therapeutic target discovery across complex diseases. We distinguish applications supported by experimental or retrospective validation from those that remain primarily computational or conceptual. We further discuss key challenges to clinical translation, including multimodal data integration, model interpretability, benchmarking, patient-specific prediction, and privacy protection. We highlight future opportunities to integrate biological foundation models with emerging frameworks of medical digital twins, agentic AI, and federated learning. By linking model design to translational goals, this review provides a practical framework for evaluating biological foundation models and their readiness for complex disease research and clinical use.
    Keywords:  biological foundation model; complex disease; large language model; precision medicine; single-cell omics
    DOI:  https://doi.org/10.3390/biology15171527
  21. Daru. 2026 Sep 16. pii: 76. [Epub ahead of print]34(2):
    Artificial intelligence-driven digital twins in Pharma 4.0: transforming smart manufacturing, predictive quality assurance, and personalized drug delivery.
    Chetana Krushna Belkare, Omkar Vishnu Daware.
       PURPOSE: The rapid advancement of Pharma 4.0 has accelerated the integration of artificial intelligence (AI), digital twins, and data-driven technologies into pharmaceutical research, manufacturing, and healthcare. This review aims to critically evaluate the role of AI-driven digital twins across the pharmaceutical lifecycle, with emphasis on smart manufacturing, predictive quality assurance, continuous manufacturing, regulatory validation, personalized drug delivery, and precision medicine. The review addresses how AI-enabled digital twins can overcome limitations of conventional pharmaceutical systems and support predictive, adaptive, and patient-centric approaches.
    METHODS: A comprehensive literature-based review was conducted by analyzing recent scientific publications, regulatory perspectives, and technological developments related to digital twins, AI, Process Analytical Technology (PAT), Quality by Design (QbD), Pharma 4.0, and emerging Pharma 5.0 concepts. Relevant evidence from pharmaceutical manufacturing, bioprocessing, healthcare applications, and supporting industrial domains was critically evaluated.
    RESULTS: AI-driven digital twins enable real-time process monitoring, prediction of critical quality attributes, optimization of manufacturing operations, predictive maintenance, and support for real-time release testing. Integration with advanced technologies, including nanotechnology, biosensors, wearable devices, and computational modeling, provides new opportunities for personalized drug delivery and precision medicine. However, challenges associated with data integrity, model validation, interoperability, cybersecurity, regulatory acceptance, and limited pharmaceutical datasets remain significant barriers.
    CONCLUSION: AI-driven digital twins represent a transformative approach for developing intelligent pharmaceutical ecosystems. Their successful implementation requires robust validation frameworks, regulatory guidance, interdisciplinary collaboration, and continued advancement toward reliable, sustainable, and patient-centered pharmaceutical systems.
    Keywords:  Artificial intelligence; Continuous manufacturing; Digital twins; Narrative review; Pharma 4.0; Predictive quality assurance; Process analytical technology
    DOI:  https://doi.org/10.1007/s40199-026-00655-5
  22. Int J Pharm X. 2026 Dec;12 100654
    The carbon footprint of Chimeric Antigen Receptor-T cell manufacturing processes.
    Wietske E van der Bijl, Bahez Gareb, Koen M Klomberg, Edwin Bremer, Tom van Meerten, Thijs H Oude Munnink, Bart G J Dekkers.
      Chimeric Antigen Receptor T (CAR-T) cell therapy is an established treatment for haematological malignancies, yet the environmental impact of its manufacturing and administration remains unexplored. As healthcare systems aim to reduce their carbon footprint, understanding the climate impact of CAR-T cell manufacturing is essential. The objective of this study was to quantify the carbon footprint, expressed in CO2-equivalents (CO2e), of CAR-T cell manufacturing and identify process steps that contribute most to CO2-emissions. A systematic life cycle assessment (LCA) comparing centralized and point-of-care (PoC) CAR-T cell manufacturing processes was conducted, according to ISO14044:2006 standards. All major processes were assessed, including leukapheresis, cryopreservation, transport, manufacturing, background facilities, quality controls, and infusion. Emissions were calculated using openLCA and open-access databases. Transport was the dominant contributor to total emissions, accounting for the higher footprint of centralized manufactured CAR-T cells (355.75 kg CO2e) compared to PoC CAR-T cells (72.85 kg CO2e). In addition, open system background facilities emitted substantially more CO2 compared to closed system background facilities (85.16 vs. 25.00 kg CO2e). Reducing travel distance and optimizing cleanroom use offer the greatest potential for emission reduction. This study provides the first assessment of differences in the carbon footprint of two established CAR-T cell manufacturing platforms and offers a framework that can be applied across a broad range of CAR-T products. It highlights transport and cleanroom energy use as key drivers of emissions, causing PoC manufacturing to substantially reduce the environmental impact by limiting long-distance transport.
    Keywords:  Carbon footprint; Chimeric Antigen Receptor T (CAR-T) cell therapy; Life cycle assessment
    DOI:  https://doi.org/10.1016/j.ijpx.2026.100654
  23. Cancer Med. 2026 Sep;15(9): e72195
    Spatial and Temporal Heterogeneity of Macrophage Efferocytosis in Tumors: Emerging Implications for Immunotherapy Biomarkers and Therapeutic Timing.
    Shanyi Li, Jilei Li, Zhenyu Zhang, Sizhe Wang, Chunzheng Ma.
      Resistance to immune checkpoint blockade (ICB) remains a major barrier in cancer therapy, reflecting the fact that tumor immunity is governed not only by cell type abundance but also by spatial organization and temporal dynamics within the tumor microenvironment (TME). In this review, we examine macrophage efferocytosis as a biologically and clinically actionable process that conditions immunosuppression or immune activation depending on niche context and treatment timing. The central question is whether apoptotic cell clearance by tumor-associated macrophages (TAMs) can serve as a biomarker-relevant regulator of therapeutic response, and more broadly, why conventional TAMs and efferocytosis reviews have been insufficient to explain spatial and temporal heterogeneity. Synthesizing evidence from spatial transcriptomics, single-cell atlas studies, multiplexed tissue imaging, and in vivo lineage tracing, we show that efferocytic macrophages concentrate in defined microanatomical compartments, including tumor margins, perivascular regions, and therapy-induced apoptotic zones, where they promote tolerogenic signaling and suppress antigen presentation. However, when efferocytosis is modulated in a delayed or spatially restricted manner, antigen persistence is prolonged and adaptive antitumor immunity is enhanced. Organ-specific differences in macrophage lineage, stromal architecture, and apoptotic burden further shape the functional meaning of efferocytosis across tumor types. On this basis, we propose a working model of efferocytosis-associated "hotspots" and "deserts" that may support biomarker-driven patient stratification: these spatial patterns are conceptualized as a model proposed in this review rather than a settled biological category. Overall, this work reframes macrophage efferocytosis as a spatially and temporally constrained determinant of immune contexture with important implications for precision immunotherapy, combination design, and trial optimization.
    Keywords:  immune checkpoint blockade; macrophage efferocytosis; spatial and temporal heterogeneity; tumor microenvironment; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/cam4.72195
  24. Cancer. 2026 Sep 15. 132(18): e70612
    Top advances of the year in autologous cellular therapy in melanoma and solid tumors.
    Kimberly Loo, Allison S Betof.
      The year 2025 marked significant advances in autologous cellular therapy for melanoma and solid tumors, building on landmark regulatory approvals in 2024. Lifileucel, the first Food and Drug Administration-approved tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, demonstrated durable efficacy in the 5-year analysis of the C-144-01 trial, with an objective response rate (ORR) of 31.4% and prolonged responses in a heavily pretreated population. Real world data further supported its effectiveness, with higher ORR likely reflecting earlier lines of therapy and differences in patient selection. Preferentially expressed antigen in melanoma (PRAME)-targeted T-cell receptor (TCR) T-cell therapy (anzu-cel, IMA203) showed promising activity in a phase 1 study, with ORR of approximately 50% in checkpoint inhibitor refractory melanoma, durable responses, and manageable toxicity, validating PRAME as a high value target across multiple tumor types. Next-generation engineered TIL approaches emerged to address limitations of high-dose IL-2. OBX-115, an IL-2 independent TIL platform expressing membrane-bound IL-15 regulated by acetazolamide, demonstrated early clinical activity with ORR of 67% in initial phase 1 data. Additional strategies, including CRISPR-mediated gene editing and checkpoint disruption, highlight a shift toward programmable, self-sustaining cellular therapies. Personalized neoantigen-based therapies advanced with early clinical validation of adoptive T-cell platforms and mRNA vaccines, demonstrating immune activation and improved recurrence-free survival in melanoma. Finally, afamitresgene autoleucel (afami-cel), a MAGE-A4 directed TCR-T therapy, showed durable efficacy in synovial sarcoma and expanding activity across solid tumors, establishing proof of concept for TCR-T approaches. Collectively, these advances position autologous cellular therapy as an evolving standard of care in melanoma and a promising modality across solid tumors, with ongoing efforts focused on improving accessibility, overcoming resistance, and optimizing combinatorial strategies.
    Keywords:  cellular therapy; melanoma; solid tumor
    DOI:  https://doi.org/10.1002/cncr.70612
  25. Front Oncol. 2026 ;16 1895225
    Nanomedicine and the tumor immune microenvironment in cancer immunotherapy: a bibliometric and knowledge-mapping analysis.
    Yanzhen Mai, Yaqin Wang, Weiwei Li, Jiajia Lu, Xi Luo, Xinli Zhuang, Xiaoran Duan, Ziyi Guo.
       Background: Nanomedicine can improve cancer immunotherapy by enabling tumor-selective delivery and active modulation of the tumor immune microenvironment (TIME), yet the global structure and translational trajectory of this interdisciplinary field remain unclear.
    Methods: The Web of Science Core Collection and Scopus were searched from inception to February 1, 2025. After deduplication and screening, 1,110 English-language articles and reviews were included. VOSviewer, CiteSpace, Bibliometrix, and Python were used to analyze publication trends, collaboration networks, journal relationships, co-citation structures, citation bursts, and keyword evolution. Non-negative matrix factorization was applied to citation-burst references to identify latent thematic structures.
    Results: Publication output increased sharply after 2022, and studies published during 2022-2025 accounted for 79.9% of the dataset. China led in publication volume and institutional productivity, whereas the United States showed strong citation influence. Soochow University, the Chinese Academy of Sciences, and Sichuan University were the most productive institutions. Three major themes emerged: photodynamic therapy combined with immune checkpoint blockade; tumor-microenvironment remodeling and melanoma immunotherapy; and nanomaterial-mediated immune activation involving cell death, antigen release, and adaptive antitumor responses. Temporal mapping demonstrated a shift from passive nanoparticle delivery toward active immune-regulatory nanoplatforms.
    Conclusion: By integrating dual-database bibliometrics, citation-burst analysis, temporal knowledge mapping, and topic modeling, this study clarifies the intellectual structure and evolution of nano-immuno-oncology. Future research should prioritize biologically predictive models, reproducible manufacturing, standardized characterization, long-term safety assessment, biomarker-guided patient selection, and clinically scalable designs.
    Keywords:  bibliometric analysis; cancer immunotherapy; immune regulation; knowledge mapping; nanomedicine; nanotechnology; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1895225
  26. Immunotherapy. 2026 Sep 16. 1-14
    Efficacy and safety of chimeric antigen receptor T-cell therapy in primary central nervous system lymphoma: a systematic review and meta-analysis.
    Abdulrahman F Al-Mashdali, Mujahid O Abdelraof, Rasha Kaddoura, Azza M Halfawi, Mohamed Elfatih M Yousif, Mohammed Abdulgayoom, Abdul Rashid Shah, Shehab F Mohamed.
       BACKGROUND: Evidence for chimeric antigen receptor T-cell (CAR-T) therapy in primary central nervous system lymphoma (PCNSL) remains limited and heterogeneous, with prior syntheses often combining primary and secondary CNS lymphoma.
    METHODS: We systematically searched PubMed, Scopus, and Web of Science through February 2026. The protocol was not registered in PROSPERO. Twenty-three reports were included: 15 studies in the quantitative synthesis (194 patients) and 8 reports in the qualitative synthesis (9 patients).
    RESULTS: The pooled overall response rate was 68% (95% CI, 59-76; I2=17%), including a complete response rate of 57% (95% CI, 49-65; I2=4%) and a partial response rate of 16% (95% CI, 11-22; I2=0%). Pooled overall survival rates were 79% at 6 months and 60% at 12 months; progression-free survival rates were 52% and 42%, respectively. Safety outcomes showed pooled rates of 72% for any-grade cytokine release syndrome (CRS) and 12% for grade ≥3 CRS, while any-grade and grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 46% and 16%, respectively. Treatment-related mortality was 5% (95% CI, 2-15; I2= 0%). Sensitivity analyses yielded comparable results.
    CONCLUSIONS: CAR-T therapy demonstrates promising efficacy with manageable toxicity in PCNSL. Although early disease control is encouraging, long-term durability remains limited.
    Keywords:  CAR T-cell therapy; CRS; ICANS; PCNSL; Primary CNS lymphoma; cytokine release syndrome
    DOI:  https://doi.org/10.1080/1750743X.2026.2722553
  27. Pharm Sci Adv. 2026 Dec;4 100131
    In vivo immune cell engineering from bench to clinical reality.
    Hui Yu, Maosen Han, Xiaotian Zhao, Chunwei Tang, Yanda Jia, Weiqiang Jing, Xinyi Jiang.
      Adoptive immune cell therapies, exemplified by chimeric antigen receptor T cells, have transformed the treatment of hematological malignancies. However, their broader clinical application is limited by complex ex vivo manufacturing, high cost, and safety concerns. In vivo immune cell engineering has emerged as an alternative strategy that delivers genetic instructions directly to immune cells, thereby generating or modulating therapeutic immune cells within the body and reducing the reliance on individualized in vitro operations. These advances underscore the need for a systematic evaluation of this emerging field. Therefore, this review systematically summarizes the mechanistic principles and delivery strategies underlying in vivo immune cell engineering, with an emphasis on in vivo CAR-T cell generation and the engineering of other immune cells. We then discuss major viral and non-viral delivery platforms and clarify how these platforms influence cargo delivery, cell specificity, and functional immune-cell programming. We further discuss recent preclinical and emerging clinical advances across cancer, autoimmune diseases, and degenerative diseases, while examining key translational challenges, including delivery specificity, off-target effects, controllability, persistence, and manufacturing standardization. Overall, although the field of in vivo immune cell engineering is advancing rapidly, its clinical success will depend on coordinated improvements in delivery precision, therapeutic efficacy, safety, and controllable immune-cell programming.
    Keywords:  Cancer immunotherapy; Genome engineering; Immune cell reprogramming; In vivo immune cell engineering; Targeted gene delivery
    DOI:  https://doi.org/10.1016/j.pscia.2026.100131
  28. Trends Immunol. 2026 Sep 14. pii: S1471-4906(26)00228-0. [Epub ahead of print]
    Spatially instructed checkpoints in antitumor NK cell immunity.
    Ruifeng Wang, Peng Sun, Cheng Sun.
      Natural killer (NK) cell immunotherapies remain less effective in solid tumors than in hematologic malignancies. Poor infiltration, checkpoint engagement, and metabolic stress contribute, but these mechanisms often operate within spatially organized niches. We develop the concept of spatially instructed checkpoints: inhibitory programs locally induced or maintained whose functional impact depends on position. We organize evidence across tissue-level exclusion, suppressive cellular neighborhoods, and the cytotoxic synapse, distinguishing causal findings from associations and hypotheses. Spatial organization is an integrating layer that interacts with, rather than replaces, intrinsic, soluble, metabolic, transcriptional, and epigenetic mechanisms. We propose a translational framework for converting spatial discoveries into deployable assays that identify the dominant barrier and guide mechanism-matched strategies to restore antitumor NK cell activity.
    Keywords:  NK cells; cancer immunotherapy; immune checkpoints; solid tumors; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2026.08.012
  29. Biometrics. 2026 Jul 01. pii: ujag161. [Epub ahead of print]82(3):
    Seamless dose optimization design accounting for unknown patient heterogeneity in cancer clinical trials.
    Rebecca B Silva, Bin Cheng, Shing M Lee.
      Project Optimus, an initiative by the FDA's Oncology Center of Excellence, seeks to reform the dose-optimization and dose-selection paradigm in oncology. We propose a dose-optimization design that considers plateau efficacy profiles, integrates pharmacokinetic data to inform the exposure-toxicity curve, and accounts for patient characteristics that may contribute to heterogeneity in response. The dose-optimization design is carried out in two stages. First, a toxicity-driven stage estimates a safe set of doses. Then, a dose-ranging efficacy-driven stage explores the set using response and patient characteristic data, employing Bayesian Sparse Group Selection to understand patient heterogeneity. Between stages, the design integrates pharmacokinetic data and uses futility assessments to identify the target population among the general phase I patient population. An optimal dose is recommended for each identified subpopulation within the target population. The simulation study demonstrates that a model-based approach to identifying the target population can be effective; patient characteristics relating to heterogeneity were identified, and different optimal doses were recommended for each identified target subpopulation. Most designs that account for patient heterogeneity are intended for trials where heterogeneity is known, and pre-defined subpopulations are specified. However, given the limited information at such an early stage, subpopulations should be learned through the design.
    Keywords:  biomarker identification; cancer clinical trial; dose optimization; patient heterogeneity; phase I/II
    DOI:  https://doi.org/10.1093/biomtc/ujag161
  30. PLoS One. 2026 ;21(9): e0343858
    Sino-US-DrugQA: A benchmark for evaluating large language models in cross-jurisdictional pharmaceutical regulation.
    Xuejing Fu, Zhen Chen, Wentao Lu.
      Cross-jurisdictional pharmaceutical compliance requires comparison of regulatory requirements across administrative systems such as the US Food and Drug Administration and China's National Medical Products Administration. Although large language models (LLMs) are increasingly explored for healthcare and regulatory applications, their performance in cross-jurisdictional pharmaceutical regulation has not been systematically evaluated using a dedicated benchmark. We introduce Sino-US-DrugQA, a bilingual multiple-choice benchmark covering Monolingual, Comparative, and Parallel regulatory question-answer tasks. The 11,871 candidate items underwent deterministic structural validation and full-dataset semantic quality screening, followed by risk-stratified independent review of 1,432 items by two regulatory experts. The final release comprised 11,444 items, including 10,122 classified as pass and 1,322 as borderline. Among 500 items sampled from the semantic screen-negative population, 18 were subsequently classified as material errors, corresponding to an observed residual material-error proportion of 3.60% (Wilson 95% confidence interval, 2.29%-5.62%). Four representative LLMs-gpt-5.6-terra, gemini-3.6-flash, deepseek-v4-flash, and qwen-3.5-max-were evaluated under a standardized zero-shot protocol. Overall accuracy ranged from 83.21% to 86.43%. Comparative accuracy was consistently lower than Monolingual accuracy, with absolute differences of 4.42-8.98 percentage points across models. The two highest-scoring models, GPT and Gemini, did not differ significantly after adjustment for multiple comparisons. These results indicate that explicit comparison across non-equivalent regulatory systems remains more challenging than single-jurisdiction question answering. Sino-US-DrugQA provides a validated and reproducible resource for evaluating bilingual regulatory reasoning. The findings support further investigation of expert-supervised decision-support workflows rather than autonomous regulatory interpretation. The stable dataset release and evaluation resources are available at https://github.com/DodgeLU/Sino-US-DrugQA.
    DOI:  https://doi.org/10.1371/journal.pone.0343858
  31. Pharm Stat. 2026 Sep-Oct;25(5):25(5): e70123
    Hierarchical Composite Endpoints for Dose Optimization in Early Phase Oncology Trials.
    Yuxiang Wu, Xiaohan Guo, Ray Li, Christophe Le Corre.
      The FDA-initiated Project Optimus has emphasized the need for dose optimization (DO) in oncology drug development, moving beyond the traditional maximum tolerated dose paradigm. Evaluating the balance of benefit and risk is central to DO. In this paper, we propose a novel benefit-risk assessment framework for DO in early-phase oncology trials, utilizing hierarchical composite endpoints (HCEs). The HCE approach enables integration of multiple endpoints within a clinically prioritized hierarchy. Generalized pairwise comparison is then used to compare patient outcomes across candidate dose levels in DO cohorts, providing interpretable metrics to guide dose selection. Our method addresses key practical challenges of existing methods by enabling straightforward, qualitative clinical inputs and integrating various DO-related evidence. The framework also supports uncertainty quantification and sensitivity analysis to ensure robust assessment. Additionally, we extend the HCE method to incorporate pharmacokinetic data through a probabilistic index model, allowing drug exposure to support dose selection. Extensive simulation studies demonstrate that the proposed method achieves superior performance in selecting optimal doses compared to utility-score-based methods, particularly in scenarios requiring careful balancing of efficacy and safety. Application to real-world trial data for DO in HER-2 positive nonsmall cell lung cancer further illustrates the method's practical utility and robustness.
    Keywords:  benefit–risk assessment; dose optimization; generalized pairwise comparison; hierarchical composite endpoint; oncology
    DOI:  https://doi.org/10.1002/pst.70123
  32. AAPS J. 2026 Sep 18. pii: 156. [Epub ahead of print]28(6):
    Artificial Intelligence in Pharmaceutical Regulatory Science: Opportunities, Challenges, and Emerging Frameworks.
    Inês Lucas, João Sousa, Carla Vitorino.
      Digital transformation in pharmaceutical regulatory affairs is accelerating as global submissions grow in complexity and traditional document-based workflows reach their limits. Artificial intelligence (AI), particularly natural language processing (NLP), is increasingly being explored to support regulatory data management, document preparation, and decision support activities. This review examines AI adoption across pharmaceutical regulatory science, including initiatives from major regulatory agencies, AI-supported regulatory workflows, and emerging governance and interoperability frameworks. Current applications include document classification, data extraction, Common Technical Document (CTD) support, pharmacovigilance, and predictive analytics. Key implementation challenges, including explainability, traceability, validation, data quality, interoperability, cybersecurity, and Good Practice (GxP) compliance requirements, are critically discussed. The review further examines emerging regulatory data ecosystems and governance frameworks that may support the responsible integration of AI into regulatory processes. Collectively, these developments highlight the potential of AI to support more structured, interoperable, and efficient regulatory systems while maintaining regulatory oversight and accountability. Current evidence suggests that AI implementation has progressed from conceptual research toward early operational deployment. However, robust evidence demonstrating sustained improvements in regulatory performance and long-term operational impact remains limited.
    Keywords:  AI Governance; Artificial Intelligence; GxP Compliance; Natural language processing; Pharmacovigilance; Regulatory Science; Regulatory Submission
    DOI:  https://doi.org/10.1208/s12248-026-01283-2
  33. Can Oncol Nurs J. 2026 ;36(3): 350-356
    A real-world analysis of adverse events and operational impacts of using T-cell engager therapy in an oncology setting.
    Shalini Fernandes, Diya Nijjar, Lollita Rahaman, Shannon Farley, Sabiha Delawala.
       Background: T-cell engager (TCE) therapies are an emerging immunotherapy option for hematologic malignancies and small-cell lung cancer. While effective, they are associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), particularly during ramp-up dosing. Evidence to guide nursing assessment, monitoring, and operational planning in real-world settings remains limited.
    Purpose: To describe the frequency, severity, timing, and management of CRS and ICANS among patients receiving TCE therapy at a community hospital oncology program, and to explore operational impacts, such as length of stay and geographic considerations.
    Methods: A retrospective chart review of 30 patients who received TCE therapy at the Osler Oncology Program at Brampton Civic Hospital between August 2023 and May 2025 was conducted. Demographic, treatment, adverse event, and operational data were abstracted from electronic medical records using standardized forms. Cytokine release syndrome and ICANS were graded using American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Descriptive statistics were used to summarize outcomes.
    Results: Cytokine release syndrome occurred in 77% (23/30) of patients, predominantly Grade 1 (70% of CRS cases), with most events occurring within 24 hours of ramp-up dosing and primarily following Dose 1. Immune effector cell-associated neurotoxicity syndrome occurred in 27% (8/30) of patients, including one Grade 4 event. Seventy-five percent of ICANS cases occurred in patients who also experienced CRS. Early use of tocilizumab for Grade 1 CRS appeared to reduce progression to higher grades. Mean total length of stay across ramp-up dosing was 11.4 days, decreasing from 7.2 days for the initial visit to 1.6 days for Dose 3.
    Conclusions: T-cell engager therapy in a community oncology setting is feasible but requires structured nursing assessment protocols, intensive early monitoring, and evolving management strategies. Findings support exploration of risk-stratified outpatient models for selected patients.
    Keywords:  ICANS; T-cell engager therapy; cytokine release syndrome; oncology nursing; outpatient oncology; tocilizumab
    DOI:  https://doi.org/10.5737/23688076362350
  34. Sci Bull (Beijing). 2026 Sep 04. pii: S2095-9273(26)01015-7. [Epub ahead of print]
    A bio-orthogonally engineered probiotic-T cell chimera amplifies adoptive cell therapy through spatial DC-T cell immune licensing.
    Jingwen Shen, Yanhong Chu, Yan Wang, Xinyi Chen, Yaohua Ke, Da Huo, Junmeng Zhu, Sen Hong, Sizhe Qin, Baorui Liu, Qin Liu.
      Adoptive cell transfer (ACT) has achieved durable clinical responses in hematological malignancies, yet remains limited in solid tumors owing to poor T cell infiltration, inadequate persistence, and tumor-driven immunosuppression. Here, we report a bio-orthogonally engineered probiotic-T cell chimera (T-FOLactis) that creates a mutually reinforcing cellular-microbial system, in which FOLactis, an engineered Lactococcus lactis expressing a Flt3L-OX40L fusion protein, provides localized immunostimulatory cues to enhance T cell activation and effector function, while adoptively transferred T cells serve as cytotoxic effectors and mobile carriers that facilitate delivery of the bacterial payload to the tumor microenvironment. Using strain-promoted azide-alkyne cycloaddition chemistry, FOLactis bacteria were covalently anchored onto the surface of T cells, generating a cell-bound platform for spatially restricted immune modulation. In syngeneic colorectal cancer models, T-FOLactis reduced tumor burden by 78.1% compared with saline-treated controls and by 65.0% relative to conventional ACT, while prolonging median survival from 22 to 46 d without overt systemic toxicity. Mechanistically, T-FOLactis promoted dendritic cell (DC)-T cell proximity and established a spatially organized immune-licensing niche that amplified the functional impact of FOLactis-induced inflammatory cues, including IL-18. This spatial configuration was associated with enhanced coupling of cytokine availability, DC maturation, local co-stimulation and cytotoxic CD8+ T cell effector programming. IL-18 blockade impaired this licensing program and reduced therapeutic benefit, supporting IL-18 as a key functional mediator within the DC-T cell licensing niche. Together, these findings establish a modular cell-surface engineering strategy for augmenting ACT in colorectal cancer through coordinated immune network engagement.
    Keywords:  Adoptive cell therapy; Bio-orthogonal click chemistry; Cell-surface engineering; Engineered probiotics; Tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.scib.2026.09.009
  35. Front Immunol. 2026 ;17 1759941
    Vitamin C enhances cytotoxicity of CAR-and εTRuC-engineered γδ T cells and modulates Ca2+, NFAT, NF-κB and ERK signaling in human γδ T cells.
    Michal Zarobkiewicz, Lin Ma, Claudia Juraske, Lea Cierna, Léonce Kouakanou, Sonia Maria Krißmer, Gina J Fiala, Christian Peters, Wolfgang W Schamel, Dieter Kabelitz.
      γδ T cells have raised interest as effector cells in cancer immunotherapy, due to their broad and HLA-independent reactivity towards multiple tumor entities. Despite promising ongoing clinical studies, there is a need to improve the effector function and thereby the efficacy of γδ T cells. In addition to its role as anti-oxidant, Vitamin C is an epigenetic modifier and exerts multiple effects on T-cell differentiation. While Vitamin C enhances in vitro proliferation, cytokine production and cytotoxicity of γδ T cells, the associated signaling pathways have so far not been elucidated. Here we demonstrate that Vitamin C enhances the cytotoxic effector function of unmodified as well as anti-CD19 chimeric antigen receptor (CAR) and TCR fusion construct (εTRuC)-transduced zoledronate-expanded γδ T cells. This was associated with increased upregulation of CD25 and IFN-γ secretion. Vitamin C increased calcium influx and nuclear translocation of NFAT and NF-κB in short-term expanded γδ T-cell lines. Although Vitamin C did not alter CD3ζ phosphorylation following stimulation with anti-CD3 antibodies, it reduced phosphorylation of ERK1/2 without affecting p38 MAP kinases. Further analysis showed that Vitamin C did not modulate the expression of selected immune checkpoint molecules on γδ T cells. Our results identify important signaling events where Vitamin C enhances the effector activity of human γδ T cells.
    Keywords:  CAR; TRuC; adoptive cell therapy; immunotherapy; vitamin C; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1759941
  36. ACS Sens. 2026 Sep 18.
    Optimizing the Hinge Length of Chimeric Antigen Receptor with a DdFP-Based Immunological Synapse Biosensor.
    Hyunmin Jo, Seung Eun Lee, Hae Nim Lee, Jisu Hong, Chang-Han Lee, Hang-Rae Kim, Jihye Seong.
      Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative cancer immunotherapy, employing genetic engineering to express CARs in patient T cells. CARs are composed of a single-chain variable fragment (scFv), hinge, transmembrane, and intracellular signaling domains. While scFv directly recognizes tumor-associated antigens, the hinge domain connects the scFv to intracellular signaling domains, determining the formation of immunological synapse (IS). Because IS is critical for CAR activation, optimizing hinge length is crucial for successful CAR-T cell therapy. Here, we developed a novel dimerization-dependent fluorescent protein (ddFP)-based IS biosensor, named CAR-D, to investigate hinge length effects on CAR activation. CAR-D consists of a CAR fused to ddFP-A and a ZAP70-tSH2 domain fused to ddFP-B. Upon CAR engagement with the target antigen, CAR phosphorylation recruits ZAP70-tSH2, triggering ddFP-A/ddFP-B dimerization and generating a fluorescent signal that reports CAR activation at the IS in real time. Using the CAR-D system, we assessed CARs with different hinge lengths targeting distinct epitopes of two tumor-associated antigens, mesothelin (MSLN) and HER2, and determined threshold hinge lengths for CAR activation. Our results revealed a strong correlation between threshold hinge length and the distance from scFv to the target epitope, implying that hinge length optimization is crucial for effective CAR-T cell therapy. Furthermore, the CAR-D system provides a valuable tool for predicting CAR efficacy and guiding future CAR engineering strategies.
    Keywords:  biosensor; chimeric antigen receptor (CAR); dimerization-dependent fluorescent protein (ddFP); hinge length; immunological synapse (IS)
    DOI:  https://doi.org/10.1021/acssensors.5c04490
  37. J Transl Med. 2026 Aug 21. pii: 1187. [Epub ahead of print]24(1):
    Autocrine PD-1-blocking nanobodies enhance the antitumor efficacy of TCR-like CAR-T cells by attenuating t cell exhaustion.
    Wanjun He, Kai Cui, Yiwei Zeng, Weiqiang Yang, Na Huang, Songshan Zhu, Muhammad Asad Farooq, Dan Jiang, Guangxian Xu.
       BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematologic malignancies, but its efficacy against solid tumors is severely limited by two core barriers: the scarcity of uniformly expressed tumor-associated antigens (TAAs) and the immunosuppressive tumor microenvironment (TME), in which PD-1/PD-L1 signaling promotes irreversible T cell exhaustion. This study aimed to develop a novel T cell receptor-mimic (TCRm) CAR-T platform with autocrine anti-PD-1 nanobody secretion to simultaneously overcome antigen heterogeneity and TME immunosuppression.
    METHODS: A lentiviral vector encoding a TCRm CAR targeting HLA-A*02:01-restricted WT1 and a secreted anti-PD-1 nanobody was constructed to generate WT1-CAR-Nb T cells. WT1-CAR T cells (CAR-only control) and Mock T cells were also prepared. In vitro assays included antigen-specific cytotoxicity, proinflammatory cytokine (IFN-γ, TNF-α) detection, chronic antigen stimulation-induced T cell exhaustion model, and transcriptomic analysis. In vivo efficacy was evaluated in human ovarian cancer SKOV3-A2 xenograft mice via tumor growth monitoring, survival analysis, intratumoral T cell infiltration assessment, and safety evaluation.
    RESULTS: WT1-CAR-Nb T cells targeting the HLA-A*02:01-restricted WT1 and constitutively secreting anti-PD-1 nanobody were successfully generated. In vitro functional assays demonstrated that WT1-CAR-Nb T cells exhibited significantly enhanced antigen-specific cytotoxicity and secreted markedly higher levels of proinflammatory cytokines IFN-γ and TNF-α compared with conventional WT1-CAR T cells upon specific antigen stimulation. Critically, autocrine PD-1 nanobody blockade effectively alleviated TME immunosuppression, as reflected by downregulated expression of multiple exhaustion markers (TIM-3, CTLA-4, TIGIT) and preserved proliferative potential under chronic antigen stimulation. In the SKOV3-A2 solid tumor xenograft model, WT1-CAR-Nb T cells mediated superior tumor growth control and significantly prolonged overall survival, which was closely correlated with enhanced intratumoral T cell infiltration and persistent in vivo expansion of engineered T cells.
    CONCLUSION: Local autocrine PD-1 checkpoint blockade potently enhances the effector function and durability of TCRm CAR-T cells. This armored TCRm CAR-T strategy is a promising therapeutic approach for solid tumor immunotherapy, with broad translational potential for other TCRm CAR systems targeting distinct peptide-MHC epitopes.
    Keywords:  Chimeric antigen receptor T cells; PD‑1 nanobody; Solid tumor immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12967-026-08765-z
  38. Crit Rev Oncol Hematol. 2026 Sep 17. pii: S1040-8428(26)00479-8. [Epub ahead of print] 105592
    From ICI Resistance to Therapeutic Vulnerability: A Resistance-State Framework for Appraising Antibody-Drug Conjugate Evidence in Solid Tumors.
    Yaoyao Du, Xue Li, Ke Zheng, Yibo Sun, Junhong Zhu, Yuxiao Chen, Chunyu He.
      Antibody-drug conjugates (ADCs) can alter tumor-immune interactions, but activity in immune checkpoint inhibitor (ICI)-resistant disease, ADC-ICI combination benefit, functional checkpoint re-enablement, and causal resensitization are often conflated. We propose a resistance-state appraisal framework that distinguishes three outcomes. Re-enable denotes renewed therapeutic contribution from a previously ineffective checkpoint pathway in an ADC-containing context. Bypass denotes ADC activity in an ICI-resistant state without demonstrated restoration of that pathway. Prime denotes immune remodeling that lowers the threshold for checkpoint responsiveness when prior ICI resistance has not been established. We organize potentially actionable biology around immunogenic visibility and antigen presentation, T-cell competence, stromal access, suppressive cellular or metabolic states, effector trafficking, and adaptive checkpoint dependency. Current evidence supports functional re-enablement in selected preclinical models and provides clinical signals compatible with, but not establishing, functional re-enablement after documented PD-1/PD-L1 failure; causal, temporally separable restoration of intrinsic ICI sensitivity remains rarely demonstrated. We therefore propose an evidentiary hierarchy that progresses from concurrent combination activity to controlled incremental checkpoint contribution and, when feasible, temporally separated state-conversion and rechallenge designs. Interpretation is constrained by lesion-level heterogeneity, imperfect preclinical modeling and ADC pharmacokinetics, and the practical or ethical infeasibility of fully separated rechallenge designs. Secondary hypotheses concerning residual immune competence and dose-time alignment are treated as research constructs rather than validated biomarkers or dosing rules. The framework is intended to make resensitization claims auditable and to guide experiments and clinical trials that distinguish therapeutic activity from genuine restoration of checkpoint vulnerability.
    Keywords:  antibody–drug conjugate; causal resensitization; checkpoint re-enablement; evidence appraisal; immune checkpoint inhibitor; immunotherapy resistance; therapeutic vulnerability
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105592
  39. Front Digit Health. 2026 ;8 1862236
    Multimodal medical diagnosis: a mini review of LLM-vision fusion models in low-resource healthcare settings.
    Kahakashan Ashraf, Md Hamid Hosen, Nuzhat Tabassum Farah, Md Kishor Morol, Tze Hui Liew, Dip Nandi, Mashiour Rahman, Abdullah Al Jubair.
      Recent advances in large language models (LLMs) and vision transformers have enabled multimodal systems that integrate clinical text with medical imaging for diagnostic decision-making. While these systems show promising results on benchmark datasets in well-resourced research settings, their applicability in low-resource healthcare environments where diagnostic disparities are most severe remains limited and poorly understood. This mini review synthesizes key developments in LLM-vision fusion architectures from 2018 to 2026, with a focus on radiology-oriented visual question answering (VQA) and report generation systems viewed from a deployment perspective. Rather than comprehensively cataloguing multimodal medical AI, we synthesize the evolution of LLM-vision fusion architectures and discuss complementary deployment-enabling strategies, including parameter-efficient adaptation, post-training quantization, federated learning, and multilingual support, where they directly improve the feasibility of radiology AI in resource-constrained healthcare settings. Rather than focusing solely on performance benchmarks, we examine these approaches through a deployment-oriented lens, highlighting trade-offs between representational capacity, computational efficiency, interpretability, and memory footprint. We argue that current progress remains substantially shaped by model scaling and benchmark optimization, which often do not address the memory, connectivity, and annotation constraints of low-resource healthcare systems. While cross-modal transformer architectures provide strong representational alignment, their computational demands and reliance on large curated datasets limit real-world deployment. In contrast, emerging directions including parameter-efficient fine-tuning, post-training quantization, federated learning, and modular agent-based systems offer more tractable pathways toward clinical integration under hardware and data constraints. To bridge the gap between benchmark performance and clinical utility, we identify concrete challenges in data scarcity, multilingual coverage, and calibration, and propose a shift toward lightweight, interpretable, and hardware-aware multimodal AI. This perspective highlights the need to move beyond scaling-centric design toward models that can run on 4-8 GB VRAM, operate offline, and generalize across languages and imaging equipment.
    Keywords:  LLM-vision fusion; clinical AI deployment; low-resource healthcare; medical imaging; multimodal medical diagnosis; transformer architectures; vision-language models
    DOI:  https://doi.org/10.3389/fdgth.2026.1862236
  40. Expert Opin Drug Discov. 2026 Sep 17. 1-7
    Incentivizing challenging drug discovery: from reducing failure to quantifying uncertainty.
    Stefano Moro.
       INTRODUCTION: Drug discovery's central difficulty is less the elimination of failure than the measurement of uncertainty. This editorial argues that artificial intelligence (AI) helps mainly by converting unquantifiable uncertainty into measurable, priceable confidence, as one evidence stream among several.
    AREAS COVERED: It discusses the risk-uncertainty distinction, AI as a new layer in the computational drug-discovery stack, the cumulative nature of confidence (illustrated by KRAS, PCSK9 and the AI-discovered TNIK inhibitor rentosertib), discordant evidence, AI's limitations, and incentive design. Literature was identified from PubMed/MEDLINE, Scopus and Google Scholar to August 2026, with primary sources and trial registries; as an invited editorial, the search was narrative, not systematic.
    EXPERT OPINION: AI's deepest contribution is epistemic rather than algorithmic: unlikely to lower failure rates markedly, but by making uncertainty measurable it can improve portfolio decisions and render ambitious biology attemptable - given calibration, prospective validation, open negative data, and incentives that reward reducing uncertainty.
    Keywords:  Artificial intelligence; computer-aided drug design; drug discovery; incentives; portfolio decision-making; risk versus uncertainty; uncertainty quantification
    DOI:  https://doi.org/10.1080/17460441.2026.2733199
  41. Crit Rev Oncol Hematol. 2026 Sep 13. pii: S1040-8428(26)00480-4. [Epub ahead of print]227 105593
    Targeting intracellular immune regulatory molecules for cancer immunotherapy in solid tumors.
    Chunyan Zhang, Jianwei Zhu, Ziqin Zhou, Xianlan Li, Qin Su.
      Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but remain limited by primary and acquired resistance, highlighting the need for novel immunotherapeutic strategies beyond cell-surface receptors. Intracellular immune regulators integrate signaling downstream of immune receptors and therefore represent attractive therapeutic targets capable of simultaneously modulating multiple immunosuppressive pathways. In this review, we summarize recent advances in therapeutics targeting intracellular immunoregulatory proteins that entered or advanced in clinical development between 2022 and 2026, with emphasis on representative targets, biological rationale, clinical development, and emerging therapeutic opportunities. We discuss membrane-proximal signaling regulators, intracellular signaling hubs, and innate immune mediators, including HPK1, DGKα/ζ, SHP2, CBL-b, PTPN1/2, JAK1, PI3Kγ/δ, MALT1, STING, and RIPK2. Current evidence indicates that intracellular regulators downstream of immune receptors warrant particular investigation because they integrate convergent signaling from multiple immune checkpoints and co-stimulatory receptors. Among these targets, HPK1 inhibitors have demonstrated preliminary monotherapy activity in selected patients, whereas the strongest clinical signals for SHP2 inhibition have been observed in combination with KRASG12C-targeted therapy and may reflect both tumor-cell-intrinsic and immune-mediated effects. Across multiple programs, rational combination strategies, biomarker-guided patient selection, optimized pharmacokinetic properties, and treatment sequencing appear more important than monotherapy. We further discuss major challenges, including incomplete understanding of target biology, limited druggability of certain intracellular proteins, and the need for improved translational strategies. Collectively, intracellular immunomodulators substantially expand the therapeutic landscape beyond conventional ICIs and may contribute to next-generation precision cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Drug development; Immune checkpoints; Intracellular signaling; Small molecules; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105593
  42. N Engl J Med. 2026 Sep 17. pii: 10.1056/NEJMc2608825#sa3. [Epub ahead of print]395(11): 1142-1143
    Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy. Reply.
    Vijay G Bhoj, Mary Kaminski, Ali Naji.
      
    DOI:  https://doi.org/10.1056/NEJMc2608825
  43. Immunol Invest. 2026 Sep 16. 1-35
    Therapeutic Cancer Vaccines: Classification, Mechanisms, Challenges and Future Perspectives.
    Juwei Gao, Yue Sun, Zijing Han, Huiwen Zhang, Mingwei Sun, Shujun Liu, Bo Zhang.
       BACKGROUND: With the rapid advancements in oncology, immunology, and molecular biology, immunotherapy has emerged as a cornerstone of anti-tumor treatment, complementing traditional modalities such as surgery, radiotherapy, and chemotherapy. Therapeutic cancer vaccines are a promising immunotherapy strategy that deliver tumor-associated antigens or neoantigens to prime naive T cells and generate long-lived memory cells for durable anti-tumor immunity. Recent advances in neoantigen identification, mRNA technology, biomaterial delivery and combination immunotherapy accelerate the development of personalized cancer vaccines. However, their clinical efficacy remains suboptimal, limited by poor immunogenicity, tumor heterogeneity, immune escape and immunosuppressive TME.
    OBJECTIVES: This review classifies therapeutic cancer vaccines by antigen source and design strategy, analyzes key biological barriers limiting efficacy, summarizes clinical trial evidence, and discusses strategies to overcome these bottlenecks.
    METHODS: We systematically reviewed published literature regarding cancer vaccine design, delivery platforms, clinical trials and combination immunotherapy.
    RESULTS: Multiple biological obstacles restrict vaccine efficacy. Novel approaches including computational antigen design, advanced RNA platforms, optimized delivery, biomarker-guided vaccination and rational combination therapy can mitigate these barriers.
    CONCLUSIONS: These advances provide an integrated framework for developing next-generation therapeutic cancer vaccines and advancing precision cancer immunotherapy.
    Keywords:  Antigen presentation; cancer immunotherapy; clinical translation; therapeutic cancer vaccines; tumor immune microenvironment
    DOI:  https://doi.org/10.1080/08820139.2026.2733761
  44. N Engl J Med. 2026 Sep 17. pii: 10.1056/NEJMc2608825#sa2. [Epub ahead of print]395(11): 1142
    Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy.
    Saifu Yin, Tao Lin.
      
    DOI:  https://doi.org/10.1056/NEJMc2608825
  45. J Immunother Cancer. 2026 Sep 18. pii: e016839. [Epub ahead of print]14(9):
    Gene regulatory elements determine efficacy of BCMA-targeted CAR-T cell products.
    Viktoria Blumenberg, Kristen B June, Filippo Birocchi, Giulia Escobar, Charlotte Graham, Yueyang Fan, Merle K Phillips, Sangwoo Park, Deshea Harris, Henry Anderson, Amanda A Bouffard, Christopher Kelly, Magdi Elsallab, Trisha R Berger, Kathleen Me Gallagher, Mark B Leick, Adele Mucci, Marcela V Maus.
      In relapsed/refractory multiple myeloma, the approved B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cell product ciltacabtagene autoleucel (cilta-cel) shows higher response rates than idecabtagene vicleucel (ide-cel) in pivotal trials and real-world comparisons. This advantage has been attributed to the biparatopic dual-VHH (dVHH) binder of cilta-cel. However, the products also differ in the gene regulatory elements driving CAR expression: cilta-cel uses a human elongation factor α (EF1α) promoter in conjunction with a woodchuck hepatitis post-transcriptional regulatory element (EF1α+WPRE), whereas ide-cel uses a myeloproliferative sarcoma virus enhancer (MND) promoter without WPRE (MMD-WPRE). The role of these elements in CAR-T cell efficacy remains unexplored.We generated lentiviral vectors where the CAR transgene was composed of either a dVHH-based or a single-chain variable fragment (scFv)-based BCMA-CAR with a 4-1BB costimulatory and a CD3ζ signaling domain, expressed either by EF1α+WPRE or MND-WPRE Primary human T cells or a nuclear factor of activated T cells (NFAT)-GFP Jurkat reporter line were compared at matched vector copy numbers (VCN) or CAR surface expression. Antitumor efficacy was assessed in MM.1S-engrafted NSG mice.When transduced at the same multiplicities of infection, MND-WPRE CAR-T cells reached higher VCN and transduction rates than EF1α+WPRE regardless of the binder type. In an NFAT-GFP reporter assay, unstimulated MND-WPRE-driven cells showed higher NFAT and CD69 expression, consistent with greater tonic signaling compared with EF1α+WPRE In vivo, independently of the BCMA binder moiety, EF1α+WPRE-driven CAR-T cells demonstrated superior cytokine secretion and tumor control along with greater survival of mice treated with EF1α+WPREcompared with MND-WPRE-driven CAR-T cells.CAR-T cells expressing the CAR under MND-WPRE showed greater gene transfer during manufacturing, but this did not translate into superior function in vivo. The advantage attributed to cilta-cel's dual VHH binder was lost when expressed under MND-WPRE and, conversely, ide-cel's scFv binder achieved better antitumor activity when expressed under EF1α+WPRE than under MND-WPRE The efficacy difference between our CAR constructs in xenograft models therefore tracked with the choice of regulatory elements driving CAR expression independently of the binder. It may be better to choose gene regulatory elements based on the CAR-T cell function they confer rather than on expression strength alone.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Multiple Myeloma
    DOI:  https://doi.org/10.1136/jitc-2026-016839
  46. Adv Sci (Weinh). 2026 Sep 16. e77564
    FOXP1 Knockdown Reprograms Th9 CAR-T Cells to Overcome Antigen Escape.
    Yihan Zhu, Xingwei Xie, Xiaohuan Wu, Suidong Ouyang, Yang Zhou, Kang Wen, Yutong Zhong, Yuyang Chen, Handuo Wang, Yuan Gao, Ling Jiang, Hui Li, Wenli Zhao, Abai Xu, Enguang Bi.
      Antigen-loss variants (ALVs) are a major cause of relapse following chimeric antigen receptor (CAR) T cell therapy, particularly in solid tumors where antigen heterogeneity and immune suppression prevail. By integrating public single-cell RNA sequencing analysis with experimental validation, we identify the transcription factor FOXP1 as a critical brake limiting Th9 CAR-T cell differentiation and effector programming. FOXP1 knockdown reprograms Th9 CAR-T but not Tc9 cells toward a metabolically active, cytotoxic, and exhaustion-resistant phenotype, thereby enhancing their persistence and antitumor activity. CUT&Tag and transcriptomic profiling reveal that FOXP1 binds regulatory regions of Il9, Spi1, and Runx1, as well as effector loci such as Tnf and Gzmb, repressing both Th9-lineage and TCR-downstream transcriptional programs. Its depletion releases this repression, broadly activating MAPK, PI3K-Akt/mTOR, and NF-κB pathways that sustain cytokine production and memory formation. Functionally, FOXP1-deficient Th9 CAR-T cells eradicate both antigen-positive and antigen-loss tumor populations by recruiting dendritic cells and promoting endogenous CD8+ T cell clonal expansion via the CD6-Flt3L axis. Our findings establish FOXP1 as a transcriptional checkpoint integrating cytokine and signaling networks to control Th9 CAR-T cell function and provide a mechanistic rationale for engineering CAR-T therapies capable of overcoming antigen escape.
    Keywords:  FOXP1; Th9 CAR T cells; antigen escape
    DOI:  https://doi.org/10.1002/advs.77564
  47. Cancers (Basel). 2026 Sep 01. pii: 2818. [Epub ahead of print]18(17):
    Mitochondrial Fitness as a Functional Immune Checkpoint in Cancer: Metabolic Plasticity, Tumor Evolution, and Immunotherapy.
    Fortunato Morabito, Enrica Antonia Martino, Antonella Bruzzese, Nicola Amodio, Ernesto Vigna, Massimo Gentile.
      Mitochondria are increasingly recognized as dynamic regulators of cancer-cell adaptation, immune function, and therapeutic response. Beyond their canonical role in energy production, mitochondrial metabolism, dynamics, quality control, and stress signaling influence tumor-cell survival and the capacity of immune effector cells to sustain antitumor activity within the tumor microenvironment. In this narrative review, we examine mitochondrial fitness as a multidimensional functional property encompassing bioenergetic capacity, metabolic flexibility, redox homeostasis, mitochondrial quality control, and adaptation to cellular and therapeutic stress. We propose the mitochondrial functional immune checkpoint as a conceptual framework linking mitochondrial fitness in malignant and immune cells to tumor-immune interactions and immunotherapy response. We discuss how mitochondrial metabolic plasticity, mitochondrial stress and mtDNA signaling, reactive oxygen species, mitochondrial dynamics, and intercellular mitochondrial transfer contribute to immune escape and treatment resistance. We further examine the relevance of mitochondrial fitness to immune checkpoint blockade, CAR-T-cell therapy, and T-cell-redirecting bispecific antibodies, with particular attention to hematological malignancies, including acute myeloid leukemia and multiple myeloma, while incorporating selected evidence from solid tumors to highlight shared mitochondrial mechanisms and their broader oncologic relevance. Finally, we discuss emerging strategies for mitochondrial targeting and functional mitochondrial profiling and their potential integration with established molecular and measurable residual disease assessments. Current evidence supports mitochondrial biology as a complementary dimension of precision oncology, although important challenges remain regarding context dependence, biomarker standardization, therapeutic selectivity, and preservation of immune-cell fitness. Prospective studies are needed to determine whether functional mitochondrial profiling can improve patient stratification and guide rational therapeutic combinations that selectively exploit tumor mitochondrial vulnerabilities while preserving effective antitumor immunity.
    Keywords:  CAR-T cells; T-cell exhaustion; bispecific antibodies; cancer metabolism; immune escape; immunotherapy; mitochondria; oxidative phosphorylation; precision oncology; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18172818
  48. Immunol Res. 2026 Sep 12. pii: 110. [Epub ahead of print]74(1):
    The spatial architecture of tumor immunity: Emerging predictive biomarkers across cancer.
    Xiaoying Li, Ruizhen Li, Huanhuan Wang, Pei Zhang, Dan Cao, Fan Zhang.
      Tumor immunity is shaped not only by the cellular composition of the tumor microenvironment (TME), but also by its spatial architecture. Increasing evidence shows that immune function cannot be inferred from cell abundance alone, because the positioning and coordination of immune and stromal cells determine whether local immunity is activated, excluded, or suppressed. Advances in multiplex imaging, spatial proteomics, spatial transcriptomics, and AI-assisted tissue analysis now enable high-resolution mapping of these spatial states across clinically relevant scales. These approaches reveal that tumors are organized as recurrent microarchitectures that can function either as immune engines or as suppressive brakes. Immune-supportive structures, including mature tertiary lymphoid structures, dendritic cell-centered immune triads, high endothelial venule-associated recruitment corridors, and effector-tumor interfaces, promote antigen presentation, lymphocyte recruitment, and cytotoxic engagement. In contrast, exclusionary and suppressive architectures, such as CAF-mediated stromal barriers, SPP1 + macrophage-CAF niches, stalled T-cell zones, Treg-enriched suppressive niches, and NLRP3 + macrophage-rich regions, restrict infiltration and sustain immune dysfunction. Across cancer types, such spatial readouts are emerging as robust biomarkers. In this Review, we summarize recent progress in spatial tumor immunology and propose a conceptual framework for interpreting tumor immunity from composition to cellular neighborhoods. We further discuss how these spatial architectures shape tumor heterogeneity, therapeutic response, and resistance, and how they may be translated into actionable biomarkers for patient stratification, treatment monitoring, and next-generation precision immunotherapy.
    Keywords:  Immune exclusion; Predictive biomarkers; Spatial biology; Tertiary lymphoid structures; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12026-026-09844-5
  49. Can Oncol Nurs J. 2026 ;36(3): 365-374
    Continuing education needs of nurses caring for patients undergoing CAR T-cell therapy for hematological malignancies: A Canadian survey.
    Ines Ben Henda, Caroline Arbour, Karine Bilodeau.
      CAR T-cell therapy represents a major, ongoing advance in the treatment of hematological malignancies, but it requires complex, highly specialized care. Given the central role they play in managing this care, nurses need access to tailored continuing education. Unfortunately, little evidence exists to guide the development of these programs. This study presents the findings of the first Canadian survey designed to identify the continuing education needs of nurses involved in the care of adult patients receiving CAR T-cell therapy. A bilingual (French and English) survey developed using the competency framework proposed by He et al. (2024) and adapted to the Canadian context was sent to the members of the Canadian Association of Nurses in Oncology/Association canadienne des infirmières en oncologie (CANO/ACIO). The resulting data were analyzed using descriptive statistics and qualitative thematic analysis. A total of 88 nurses completed the questionnaire. Most were women (94%), aged 30 to 49 years (73%), working primarily in oncology (38%), or an outpatient centre (35%). The findings revealed significant needs in terms of theoretical knowledge (treatment processes, complications) and operational skills (therapy administration, management of side effects, outpatient follow-up, interdisciplinary communication). Notable differences were observed depending on practice setting, clinical experience and prior training. These findings emphasize the need to develop structured continuing education programs that are easy to access and adapted to suit various practice settings in order to support nurses in delivering safe, high-quality care to patients undergoing CAR T-cell therapy.
    Keywords:  CAR T-cell therapy; Canada; continuing education; hematological malignancies; nursing care; survey; training needs
    DOI:  https://doi.org/10.5737/23688076363365
  50. Cells. 2026 Sep 04. pii: 1609. [Epub ahead of print]15(17):
    Moonlighting ERAP Aminopeptidases in Cancer: Beyond Antigen Processing.
    Paula Gragera, Valentina Scaldaferri, Doriana Fruci.
      Cancer immunotherapy has transformed the treatment of multiple malignancies; however, primary and acquired resistance remain major clinical challenges. Because effective immune recognition depends on the repertoire of peptides presented by major histocompatibility complex class I (MHC-I) molecules, increasing attention has focused on the antigen processing and presentation pathway as a therapeutic target to enhance tumor immunogenicity. Among its key regulators, the endoplasmic reticulum (ER) aminopeptidases ERAP1 and ERAP2 shape the MHC-I immunopeptidome by trimming peptide precursors before antigen presentation. Beyond this canonical function, accumulating evidence indicates that ERAP aminopeptidases are multifunctional proteins involved in inflammation, angiogenesis, ER stress responses, cell migration, and tumor-intrinsic signaling. These moonlighting activities suggest that ERAP enzymes influence cancer progression through both immune-dependent and immune-independent mechanisms. Recent advances in medicinal chemistry have enabled the development of selective ERAP1 inhibitors, leading to the first clinical evaluation of this therapeutic strategy and providing early clinical evidence that pharmacological modulation of antigen processing may complement existing immunotherapies. In this review, we summarize the multiple functions of ERAP aminopeptidases in cancer, discuss their role in regulating adaptive and innate immune responses, and highlight emerging therapeutic strategies and future challenges for exploiting ERAP-targeted interventions in precision immuno-oncology.
    Keywords:  ERAP1; ERAP2; antigen processing; cancer; cancer immunotherapy; precision oncology; targeted therapy
    DOI:  https://doi.org/10.3390/cells15171609
  51. Lancet Reg Health Eur. 2026 Nov;70 101849
    Designing eligibility and evaluation criteria for antibacterial pull incentives: a comparative review of implemented and emerging initiatives.
    Michael Anderson, Emily O'Neill, Gunnar Ljungqvist, Avi Cherla, Zilke Claessens, Elise Schoefs, Nick Crabb, Warren Cowell, Jennifer Cohn, Deepali Patel, Elias Mossialos.
       Background: Pull incentives aim to improve the commercial viability of antibacterials, but the criteria determining which products and companies qualify have not been compared across countries. We compared product and company eligibility and evaluation criteria across these incentives.
    Methods: We conducted an umbrella review of MEDLINE and Embase for English-language reviews of pull incentives targeting antibacterial innovation and access (2014 to 14 October 2024), supplemented by grey literature searches and the Global AMR R&D Hub dashboard (December 2025). Two reviewers independently extracted criteria from official documentation, using a framework of six product domains (high-priority medical need, relative effectiveness, unmet clinical need, innovative characteristics, health-system impact, and other) and five company domains (antibacterial sustainability, patient access, environmental health, economic criteria, and other).
    Findings: We identified 28 pull incentives: 20 implemented (UK, Sweden, Germany, France, Italy, US, Japan, and EU) and 8 proposed or in development (US, Japan, Canada, Australia, Switzerland, and EU). As mechanisms overlapped within countries, the 20 implemented incentives were analysed as nine groups. All nine targeted high-priority medical need and seven (78%) included unmet clinical need. Relative effectiveness featured in six (67%), economic criteria in five (56%), and innovative characteristics, health-system impact, patient access, and antibacterial sustainability in four each (44%); environmental health in two (22%). The UK Subscription Model applied all 11 domains and Sweden's Annual Revenue Guarantee eight (73%). Priority pathogen lists were widely referenced but varied in breadth.
    Interpretation: Eligibility and evaluation criteria vary substantially across countries in scope and specificity. Company-level obligations on stewardship, access, and environmental safeguards are applied inconsistently, and most comprehensive in the UK and Swedish models. Greater international alignment around a shared core of criteria, while retaining flexibility for national context and operational feasibility, could reduce uncertainty for developers and strengthen the global incentive ecosystem.
    Funding: World Health Organization Regional Office for Europe.
    Keywords:  Antibiotic resistance; Antimicrobial resistance; Pharmaceutical reform; Reimbursement reforms; Research and development
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101849
  52. Int J Technol Assess Health Care. 2026 Sep 17. 42(1): e79
    A hospital-based HTA model to assess the economic and organizational impact of intravenous-to-subcutaneous monoclonal antibody transitions in oncology.
    Giorgia Zorzetto, Alberto Russi, Alessandro Giuriola, Giuseppe Di Blasio, Sara Lonardi, Valentina Guarneri, Marco Maruzzo, Maria Vittoria Dieci, Giulia Pasello, Michele Gottardi, Silvia Cognolato, Nicoletta Rigamonti, Chiara Mioni, Flavio Cazzador, Giulia Badaile, Francesca Pipitone, Daniela Grosso, Patrizia Simionato, Giovanna Scroccaro, Marina Coppola.
       OBJECTIVES: Subcutaneous (SC) formulations of monoclonal antibodies (mAbs) allow faster and less invasive administration than intravenous (IV) routes, with comparable efficacy and safety. Beyond clinical equivalence, SC administration may reduce hospital resource use, improve patient experience, and increase treatment capacity, contributing to the sustainability of oncology care. This study aimed to develop and apply a hospital-based, multidisciplinary model to assess the economic and organizational impact of IV-to-SC transitions in oncology.
    METHODS: A scenario-based economic and organizational analysis was conducted using real-world institutional data from a high-volume oncology center, collected before price renegotiations, to estimate the budget impact and resource implications of transitioning from intravenous to subcutaneous mAbs. The analysis included drug acquisition, pharmacy preparation, nursing administration, chair occupancy, and staff time, with preparation costs estimated using Time-Driven Activity-Based Costing (TDABC). The model was applied to two mAbs (X and Y); eligible patients were identified through institutional registries, and scenario analyses simulated partial and complete IV-to-SC substitution across clinical settings.
    RESULTS: For antibody X, a full transition to SC administration increased annual treatment capacity by ~36 percent, with an additional drug expenditure of €123,354 and an overall budget impact of €66,778. For antibody Y, full SC adoption increased treatment capacity by ~19 percent, with an additional drug expenditure of €42,473 and a total budget impact of €6,671.
    CONCLUSIONS: SC-related efficiency gains are highly context-dependent and are maximized in settings with latent capacity demand. The proposed hospital-based HTA framework supports evidence-based adoption strategies and informs sustainable pricing and organizational decision making in oncology.
    Keywords:  budget impact; health technology assessment; hospital-based HTA; subcutaneous monoclonal antibodies; time-driven activity-based costing
    DOI:  https://doi.org/10.1017/S0266462326104000
  53. JMIR Mhealth Uhealth. 2026 Sep 14. 14 e95294
    Accessing Germany's Electronic Patient Record Through Health Insurer-Provided Apps: Qualitative Interview Study.
    Susann May, Manuela Marquardt, Gina Barzen, Frances Seifert, Mary Nyarko, Antonia Niemeyer, Sonja Gscheidle, Liane Schenk, Sebastian Spethmann, Felix Muehlensiepen.
       BACKGROUND: Nationwide electronic health records (EHRs) are intended to strengthen patient empowerment and improve information continuity across health care settings. In Germany, the electronic patient record (elektronische Patientenakte [ePA]) transitioned from an opt-in to an opt-out model in 2025. Initial survey data suggest that technical complexity and access requirements may hinder engagement; yet, little is known about how users experience this access process.
    OBJECTIVE: This study explored users' experiences of setting up and authenticating access to insurer-provided ePA apps and examined the barriers affecting successful access.
    METHODS: We conducted a qualitative interview study with individuals covered by statutory health insurance. From 61 interviews conducted within the broader ePA4all project, 23 were selected because participants had attempted to access the ePA through an insurer-provided application and described at least 1 concrete action or event during setup or authentication. Semistructured telephone interviews were conducted between August and December 2025. Data were analyzed using Kuckartz's structured qualitative content analysis. The process phases were developed inductively from the material. All 23 interviews were independently coded by 2 researchers, with differences resolved through consensus. A second analytic step examined how barriers interacted and accumulated across the access pathway.
    RESULTS: The sample included 21 participants who had successfully accessed the ePA and 2 who had initiated but abandoned setup or authentication. Setup and authentication were experienced not as a single technical step but as an interdependent process comprising 5 phases: orientation, technical entry, verification, interruption, and transition to initial use. During orientation, incomplete or outdated information left requirements and procedural steps unclear. Technical entry required users to coordinate different apps, interfaces, and device requirements. Verification involved multiple credentials, identification services, and partly repeated security steps. Technical failures, administrative inconsistencies, postal procedures, and waiting periods interrupted progression and sometimes required users to repeat previously completed steps. After successful access, an unclear immediate benefit could limit the transition to initial use. Across phases, participants relied on digital competence, prior experience, persistence, and self-efficacy to navigate the process. Difficulties were also reported by participants with high affinity for technology. Barriers could accumulate across phases: insufficient orientation increased subsequent coordination work, failures produced interruptions and repeated attempts, and prolonged effort contributed to frustration or disengagement.
    CONCLUSIONS: Access to the opt-out ePA through insurer-provided apps is shaped by cumulative demands rather than by isolated technical problems. Formal provision of an EHR does not ensure that users can successfully complete the access process. Implementation should prioritize clear preregistration guidance, continuity across applications and identification services, resumable procedures, actionable error messages, and accessible support. More broadly, onboarding and authentication should be treated as integral stages in the implementation of patient-facing digital health infrastructures rather than as neutral technical prerequisites.
    TRIAL REGISTRATION: German Clinical Trials Register DRKS00037053; https://www.drks.de/search/de/trial/DRKS00037053.
    INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1177/20552076251407130.
    Keywords:  EHR; accessibility; digital health; electronic health record; health; patient empowerment; qualitative interviews
    DOI:  https://doi.org/10.2196/95294
  54. J Comp Eff Res. 2026 Sep 17. CER
    Rigorous, transparent and inconclusive: what Europe's first joint clinical assessment reveals about a framework trying to serve everyone.
    Ramiro Gilardino, Antonella Cardone, Carlos M Cossio.
      On 30 April 2026, the Member State Coordination Group on Health Technology Assessment endorsed Europe's first joint clinical assessment (JCA) under Regulation (EU) 2021/2282, evaluating tovorafenib (Ojemda) for pediatric low-grade glioma harboring BRAF alterations. This perspective analyses the inaugural JCA report as a diagnostic of the European Health Technology Assessment framework under conditions of structural evidentiary constraint. The assessment revealed two structural points. First, between evidentiary rigor and feasibility: seven of eight predefined PICO (Population, Intervention, Comparator, Outcome) questions could not be answered comparatively, reflecting both the unavoidable limits of single-arm trial design in ultra-rare pediatric oncology and addressable failures in submission quality. Second, a temporal: the JCA is a one-time assessment, yet the report repeatedly identifies uncertainties that future evidence could reduce, with no regulatory mechanism to update the record. Our perspective further examines how comparator selection risks encoding access inequality as a scientific requirement, how the framework's legislative scope renders caregiver and family burden invisible to assessment, and how the absence of explicit certainty grading limits the actionability of JCA outputs for national payers. We suggest some improvements organized across three tiers: better use of existing mechanisms, guidance development within the current framework and legislative revision where structural change is required.
    Keywords:  EU HTA; health technology assessment; joint clinical assessment; patient access
    DOI:  https://doi.org/10.57264/cer-2026-0141
  55. Cancers (Basel). 2026 Aug 22. pii: 2725. [Epub ahead of print]18(17):
    T-Cell Engagers in Lung Cancer: A Comprehensive Literature Review from Tarlatamab Approval to Next-Generation Strategies.
    Adnan Saydawi, Sameh Madanieh, Stephanie L Echeverria, Angad Gill, Sweta Modha, Beyan El Emin, Waqar Haider, Bsher Almaalouli, Mohamed Shanshal.
       BACKGROUND: Lung cancer remains the leading cause of cancer-related mortality worldwide, with five-year survival below 5% for metastatic small cell lung cancer (SCLC) and below 10% for metastatic non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors have improved outcomes, but primary and acquired resistance, driven by tumor microenvironment immunosuppression, antigen heterogeneity, and T-cell exhaustion, leaves a substantial unmet need. T-cell engagers (TCEs), bispecific antibodies that redirect cytotoxic T-cells to tumor cells independent of MHC-I-restricted antigen presentation, offer a mechanistically distinct approach.
    METHODS: We conducted a structured narrative review, without formal PRISMA methodology or meta-analytic pooling, of PubMed, Embase, and ClinicalTrials.gov through June 2026, supplemented by conference abstracts from ASCO, ESMO, AACR, and ATS, covering clinical, translational, and preclinical evidence for TCEs across established and emerging targets in thoracic malignancy.
    RESULTS: Tarlatamab, a DLL3/CD3 bispecific TCE, received full FDA approval in November 2025 based on DeLLphi-304 data showing a median overall survival benefit of 13.6 versus 8.3 months over chemotherapy (HR 0.60; p < 0.001), establishing proof-of-concept for the TCE platform in lung cancer and NCCN Category 1 status in ES-SCLC. Beyond DLL3, an expanding pipeline of targets, including Claudin-18.2, TROP-2, FOLR1, CD70, and HER2, is under active TCE development; several of these antigens have independently validated tumor-selective expression through approved or late-stage antibody-drug conjugates (ADCs), providing target-level clinical de-risking for TCE development, though the two modalities have distinct requirements for antigen density and internalization that must be independently validated. Novel tri-specific constructs incorporating costimulatory domains and combination strategies with checkpoint inhibitors are in early clinical development.
    CONCLUSIONS: Tarlatamab approval validates the TCE platform in lung cancer, but overcoming TME-mediated resistance, antigen heterogeneity, and class-specific toxicities including cytokine release syndrome remains the central challenge. Rational TCE design, incorporating costimulatory signaling, antigen selection informed by parallel ADC validation data, and evidence-based combination strategies, offers the most credible path toward expanding this platform's impact in metastatic lung cancer.
    Keywords:  DLL3; T-cell engager; bispecific antibody; cytokine release syndrome; immunotherapy; lung cancer; non-small cell lung cancer; small cell lung cancer; tarlatamab; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18172725
  56. Cell. 2026 Sep 18. pii: S0092-8674(26)01012-3. [Epub ahead of print]
    mRNA-encoding CD19-targeting T cell engager for refractory immune thrombocytopenia.
    Mengyan Wang, Tingting Liu, Qihua Dai, Jialin Teng, Yaping Wu, Jinchao Jia, Jianfen Meng, Yuning Ma, Hui Shi, Xiaobing Cheng, Honglei Liu, Yutong Su, Junna Ye, Huihui Chi, Zhuochao Zhou, Yue Sun, Yan Wu, Jia Chen, Wei Yin, Peng Gao, Wenjie Song, Rui Lin, Bo Ying, Chengde Yang, Qiongyi Hu.
      While T cell engagers (TCEs) and chimeric antigen receptor (CAR)-T cell therapy show clinical promise for B cell depletion, challenges regarding safety, efficacy, and durability persist. ABO2203 is a lipid nanoparticle-formulated messenger RNA (mRNA) encoding a CD19-targeting TCE. In transgenic mice, ABO2203 induced complete B cell depletion with attenuated cytokine release compared with TCE protein. In a first-in-human study involving three patients with refractory secondary immune thrombocytopenia, ABO2203 achieved rapid and complete peripheral B cell depletion, with sustained depletion in bone marrow. Patients exhibited durable platelet recovery, improved serology, and reduced disease activity through 6 months of follow-up. ABO2203 was well tolerated, presenting only grade 1 and 2 adverse events without cytokine release syndrome. B cell reconstitution was observed with predominant transitional and naive B cells. These findings establish mRNA-encoded TCEs as a potent and safer therapeutic modality for B cell-mediated autoimmune diseases.
    Keywords:  ABO2203; B cell depletion; CD19; Sjogren’s syndrome; T cell engager; antiphospholipid syndrome; immune thrombocytopenia; lipid nanoparticle; mRNA; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.cell.2026.08.039
  57. Front Pharmacol. 2026 ;17 1890846
    Toward adaptive therapeutic timing: integration of mechanistic pharmacology and artificial intelligence in precision dosing.
    Yufeng Gong, Wei Ren, Ziqin Xiong, Chutian Wu, Congyan Tan.
      Artificial intelligence (AI) is reshaping the dosing of medication. It is shifting practice from fixed schedules to flexible timing that better reflects the needs of individual patients. This review synthesizes recent work in which AI identifies improved windows for drug delivery. It spans multiple time horizons, ranging from minute-by-minute infusion control to regimen planning over weeks or months. These approaches integrate population pharmacokinetic modeling with machine learning and reinforcement learning. Each component serves a distinct purpose. Together, they can recommend the dose timing, adjust dosing intervals, and indicate when a planned treatment pause may be appropriate. The models link these recommendations to the physiological rhythms and current disease status of patients, so timing becomes a defined part of the dosing strategy rather than a simple clock-based rule. Recent advances cluster into three directions. First, reinforcement learning supports sequential dosing decisions in long-term therapies, where early choices shape later outcomes. Second, AI enables chronotherapy by aligning drug delivery with daily circadian biology. Third, hybrid models improve exposure prediction, which supports more accurate interval personalization for individual patients. However, key limitations remain. Many models show limited generalizability across clinical settings, and many methods still require rigorous clinical validation. Even with these constraints, the trajectory is consistent. AI is positioned to move therapeutic timing from a static calendar task to an adaptive, patient-centered element of precision medicine.
    Keywords:  PK/PD; artificial intelligence; machine learning; medication timing; reinforcement learning
    DOI:  https://doi.org/10.3389/fphar.2026.1890846
  58. Transplant Cell Ther. 2026 Sep 15. pii: S2666-6367(26)00725-6. [Epub ahead of print]
    Incidence rates of immune-related adverse events and their correlation with response in hematological malignancies treated with Chimeric Antigen Receptor T-Cells.
    Zihao Li, Wuyuan Tan, Shaorong Lei, Yingying Xiao, Yuming Sun.
       BACKGROUND: Chimeric antigen receptor T (CAR-T) cell therapy provides breakthrough efficacy for relapsed/refractory hematological malignancies, yet the role of cytokine release syndrome (CRS) as an efficacy predictor remains controversial and lacks large-scale validation. This pooled-analysis aimed to systematically evaluate the incidence of CAR-T-related adverse events (TRAEs) and their correlation with therapeutic efficacy.
    METHODS: We searched four major databases up to December 10, 2025, and included 222 prospective trials enrolling 7538 patients. Pooled analyses were performed using a random‑effects model, and Pearson correlation was used to assess the association between TRAE incidences and key efficacy endpoints.
    RESULTS: The pooled rates of all‑grade and grade ≥3 CRS were 78.07% and 7.67%, with objective response rate (ORR) 83.26% and complete response rate (CRR) 67.46%. CRS only showed a weak correlation with short‑term remission, while specific TRAEs had moderate‑to‑strong correlations with efficacy (r=0.6099-0.9677, P<0.05).
    CONCLUSION: CAR-T therapy exhibits remarkable efficacy and manageable toxicity in hematological malignancies. CRS is not a reliable efficacy marker; grade ≥3 dyspnea/hypotension/tremor and all‑grade encephalopathy/fatigue are potential early efficacy predictors.
    Keywords:  Chimeric antigen receptor T cell therapy; Efficacy; Hematologic malignancies; Pooled-analysis; Treatment-related adverse events
    DOI:  https://doi.org/10.1016/j.jtct.2026.09.020
  59. Front Immunol. 2026 ;17 1864301
    Childhood adversity and autoimmune diseases: global research landscape, immune-related hotspots, and emerging trends from a bibliometric analysis of three databases.
    Haisheng Xu, Liuyin Jin, Hanqing Jin, Bin Wang, Xiao Ding.
       Background: Childhood adversity is increasingly recognized as an important early-life psychosocial exposure that may shape long-term immune function and contribute to autoimmune diseases through chronic stress, neuroendocrine dysregulation, and inflammatory activation. However, the knowledge structure, research hotspots, and developmental trends in this field remain insufficiently characterized.
    Methods: Publications on childhood adversity and autoimmune diseases were retrieved from the Web of Science Core Collection, Scopus, and PubMed from database inception to December 31, 2025. After screening, standardization, and deduplication, 319 records were included. Bibliometric analyses were performed using R, VOSviewer, and CiteSpace to evaluate publication trends, contributions of countries, institutions, authors, and journals, collaboration networks, keyword co-occurrence, thematic clustering, and citation impact. Original articles and reviews were reported separately, and an article-only sensitivity analysis was conducted to assess the influence of reviews on the main findings.
    Results: Among the 319 publications, 257 (80.6%) were original articles and 62 (19.4%) were reviews. Publication output increased steadily, with rapid growth after 2021 and a peak in 2022. The United States led the field in publication output, citation impact, and international collaboration, while the United Kingdom, Canada, and Germany were also major contributors. Leading institutions included the University of California System, Harvard University, and the University of Manitoba. Major publication venues included Journal of Psychosomatic Research and Psychosomatic Medicine. Keyword analysis identified childhood adversity, depression, multiple sclerosis, rheumatoid arthritis, stress, autoimmune disease, and inflammation as major hotspots. Highly cited publications indicated that the field is rooted in stress biology, psychoneuroimmunology, inflammatory mechanisms, and disease-specific autoimmune research. Sensitivity analyses showed that major thematic and source-level patterns remained relatively stable after reviews were excluded, whereas reviews were disproportionately represented among highly cited publications.
    Conclusions: Research on childhood adversity and autoimmune diseases has developed into a growing interdisciplinary field linking psychosocial stress, immune-inflammatory dysregulation, and disease-specific outcomes. Future research should strengthen standardized definitions, longitudinal and causal evidence, and translational studies on risk stratification and early prevention.
    Keywords:  adverse childhood experiences; autoimmune diseases; bibliometric analysis; childhood adversity; immune dysregulation; inflammation; psychoneuroimmunology; research trends
    DOI:  https://doi.org/10.3389/fimmu.2026.1864301
  60. N Engl J Med. 2026 Sep 17. pii: 10.1056/NEJMc2608825#sa1. [Epub ahead of print]395(11): 1141-1142
    Kidney Transplantation in Highly Sensitized Persons after CAR T-Cell Therapy.
    Juliette Leon, Olivier Aubert, Julien Zuber.
      
    DOI:  https://doi.org/10.1056/NEJMc2608825
  61. Digit Discov. 2026 Sep 16. 5(9): 3449-3458
    Bridging data and theory: hybrid modelling for pharmaceutical crystallisation process development.
    Thomas Pickles, Christos Xiouras, Merve Öner, Cameron J Brown.
      Crystallisation remains a critical unit operation in pharmaceutical manufacturing, yet process development is often constrained by empirical approaches and data limitations. Mechanistic models such as population balance frameworks provide physical interpretability but require extensive parameterisation and struggle with complex, multiscale phenomena. Data-driven machine learning models offer strong predictive performance but lack transparency, limiting regulatory acceptance. Hybrid modelling, which integrates mechanistic theory with data-driven components, has emerged as a promising strategy to address these limitations. This review surveys the current modelling landscape and critically assesses recent case studies across batch cooling, antisolvent, and continuous crystallisation modes, covering population balance and machine learning combinations. Key open problems are identified, including the absence of agreed modelling and experimental design frameworks, data sparsity, poor scale-up transferability, unresolved regulatory requirements around uncertainty quantification and model. Practical technical recommendations and a proposed workflow are provided to guide future work, with the aim of moving the field beyond isolated case studies toward predictive, explainable, deployable and published crystallisation process development.
    DOI:  https://doi.org/10.1039/d6dd00342g
  62. Mediterr J Rheumatol. 2026 Sep;37(3): 506-513
    CAR T-Cell Therapy in Systemic Lupus Erythematosus: Mechanistic Rationale, Early Clinical Experience, and Future Challenges.
    Sabarinath Mahadevan, Saranya Chinnadurai, Balakrishnan Navaneethakrishnan.
      Systemic lupus erythematosus (SLE) remains a challenging multisystem autoimmune disease characterised by relapses and remissions, often necessitating lifelong immunosuppression. Over the past decades, the therapeutic landscape has evolved from broad-spectrum agents such as cyclophosphamide to more targeted biologics including rituximab, belimumab, and anifrolumab-each contributing to incremental improvements in disease control. More recently, cell-based therapies have emerged as a novel strategy to reprogramme immune responses, including haematopoietic stem cell transplantation, bispecific T-cell engager (BiTE) therapy, and chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy represents a potentially transformative approach in SLE, offering the prospect of sustained clinical and immunological remission without ongoing immunosuppression. In this narrative review, we searched the Medline/PubMed, Scopus, Web of Science, and Directory of Open Access Journals (DOAJ) and included relevant original articles, clinical trials, randomised controlled trials, case studies and case reports published in the last 7 years. In this review, we discuss the mechanistic rationale for CAR T-cell therapy in SLE, review the clinical outcomes reported to date, and explore its promise in ushering a new era of durable, drug-free remission in autoimmune disease.
    Keywords:  autoimmune diseases; chimeric; cytokine release syndrome; immunosuppression; lupus; stem cell
    DOI:  https://doi.org/10.31138/mjr.171125.mer
  63. Eur Arch Otorhinolaryngol. 2026 Sep 16.
    Turing problems in otolaryngology: a scoping review of the principal challenges of artificial ıntelligence and large language models.
    Nidanur Sinanoglu, Azada Ismayilova, Antiga Muradova, Rovsahana Hajiyeva, Natig Ahmadov, Yusif Hajiyev, Aynur Aliyeva.
       BACKGROUND: Artificial intelligence (AI) and large language models (LLMs) have rapidly entered otolaryngology-head and neck surgery (OHNS). Despite accelerating publication output, critical translational and safety challenges remain undercharacterized.
    METHODS: A scoping review was conducted, and PubMed/MEDLINE, Cochrane Library, Embase, Web of Science, and Scopus were searched from January 2020 to June 2025 using pre-specified terms encompassing AI, LLMs, machine learning, and deep learning in OHNS.
    RESULTS: Of 3,648 screened records, 68 met the final inclusion criteria. Six principal challenge domains were identified: (1) accuracy and validity (LLM correct-answer rates: 53-75% across studies); (2) hallucination and reference fabrication, including a 61.6% reference-to-prompt irrelevancy rate across the platforms evaluated in one study; (3) the 'AI Chasm' translational gap (99.3% of deep-learning studies remained in silico); (4) Black-Box/explainability failure; (5) algorithmic bias and demographic disparities; and (6) data privacy, regulatory compliance, and legal accountability. GPT-4-class models consistently outperformed GPT-3.5, and domain-specific models (e.g., ChatENT) achieved error reductions of 26-58%.
    CONCLUSIONS: Current AI and LLM tools in OHNS demonstrate promising but insufficient accuracy for unsupervised clinical deployment. Structured governance frameworks, mandatory clinical validation pipelines, and bias-audited datasets are urgently required.
    Keywords:  Algorithmic bias; Artificial ıntelligence; ChatGPT; Data privacy; Ethics; Explainability; Hallucination; Head and neck surgery; Large language models; Otolaryngology
    DOI:  https://doi.org/10.1007/s00405-026-10607-z
  64. Front Immunol. 2026 ;17 1848870
    Adaptive bandwidth of immunity: a systems-level framework for understanding immune regulation across time.
    Razvan Constantin Ionitescu.
      Immune-mediated diseases display substantial variability in clinical expression, treatment durability, relapse timing, and long-term trajectories that are not always fully explained by genetic predisposition, molecular pathways, or pharmacological exposure alone. Increasing observations from systems immunology suggest that immune behavior emerges through interactions across molecular, environmental, and temporal dimensions. This article introduces Adaptive Bandwidth of Immunity (ABI) as a conceptual systems-level framework describing the functional range within which immune regulatory networks preserve adaptive responsiveness, proportionality, reversibility, and coordinated recovery across biological perturbations. ABI is not proposed as a discrete biological pathway or a directly measurable variable. Instead, it is introduced as an emergent property inferred through longitudinal clinical trajectories, temporal response dynamics, and integrated biological observations. The framework draws upon concepts from immune homeostasis, trained immunity, immune tolerance, systems immunology, and environmental modulation while emphasizing preservation of adaptive flexibility across time. Within this interpretation, immune-mediated disease may be viewed not only through dysregulated activation but also through progressive restriction of adaptive regulatory capacity. The framework generates empirically approachable predictions and outlines potential directions for future operationalization through longitudinal cohorts, trajectory-based analyses, and integration of multi-omics with temporal clinical data. ABI is presented as a hypothesis-generating framework intended to support future investigation into adaptive regulation and dynamic immune behavior.
    Keywords:  adaptive bandwidth of immunity; adaptive regulation; immune adaptability; immune regulation; immune resilience; immune-mediated disease; longitudinal immune dynamics; multi-omics
    DOI:  https://doi.org/10.3389/fimmu.2026.1848870
  65. MAbs. 2026 Dec;18(1): 2731282
    Discovery and engineering of bispecific TCR-mimic antibodies targeting peptide-HLA complex.
    Jennifer Watkins-Yoon, Wei-Cheng Lu, Elyse M Petrunak, Noah J Tubo, Sara Halmos, William McConaughy, Rodolfo Ciuffa, Cédric Weber, Simon Friedensohn, Sune Justesen, Marie Skovgaard, Rennard Rachel, Caity Goshert, Lucy Liu, Piotr Bobrowicz, Jeffrey J Molldrem, Dongxing Zha.
      TCR-mimic (TCRm) antibodies represent a promising new frontier in cancer immunotherapy, enabling the targeting of intracellular targets previously considered undruggable with antibodies. We developed an integrated platform for generating human antibodies that mimic T-cell receptors (TCRs) and recognize peptide-HLA complexes with high specificity and affinity. These antibody binders were then engineered into highly potent bispecific antibodies capable of redirecting T cells to kill tumor cells. By leveraging high-quality pHLA immunogens, fully human transgenic mice, advanced single B-cell discovery, and whole proteome off-target screening (X-Scan) techniques, this end-to-end platform establishes a new benchmark in TCRm discovery. In this study, we highlight the successful identification and engineering of antibodies targeting the Wilms Tumor 1 (WT1) antigen, demonstrating superior performance compared to competitors' TCRm antibodies.
    Keywords:  Bispecific ab; T cell engager; TCR mimic antibodies; TCRm; WT1; pHLA
    DOI:  https://doi.org/10.1080/19420862.2026.2731282
  66. Toxicol Sci. 2026 Sep 15. pii: kfag125. [Epub ahead of print]
    Nonclinical Safety Assessment of SBT777101, a CAR-Engineered Regulatory T Cell Therapy for Autoimmune Diseases.
    Herve Lebrec, Jonathan M Clingan, Anne-Renee van der Vuurst de Vries, Lauren Mihalcik, Yuchi Honaker, Sara Charmsaz, Seonhwa Dura, Kathryn Hooper, Yuanyuan Xiao, Michelle Blake, Max Fiebiger, Radha Dhayal, Christine Saechao, Alexandre Iannello, Fred Ramsdell, Jeffrey A Bluestone, Josh Beilke.
      Chimeric antigen receptor (CAR)-regulatory T cell (Treg) therapies represent a promising approach for autoimmune diseases, but their nonclinical safety assessment remains challenging due to antigen-, disease-, and species-specific pharmacology that limits the relevance of conventional animal models. SBT777101, a CAR-Treg therapy targeting citrullinated proteins associated with rheumatoid arthritis and hidradenitis suppurativa, was evaluated using a nonclinical strategy centered on in vitro and ex vivo New Approach Methodologies (NAMs) and in vivo studies benchmarked against untransduced polyclonal Tregs which are manufactured identically but lack the CAR and have an established clinical safety record, complemented by immunodeficient mouse studies. We hypothesized that CAR engineering would not destabilize the Treg phenotype or introduce new toxicological liabilities relative to polyclonal Tregs. SBT777101 maintained phenotypic stability under repeated stimulation and pro-inflammatory conditions, produced minimal pro-inflammatory cytokines following activation, and demonstrated immunomodulatory activity comparable to untransduced Tregs. Tissue cross-reactivity and primary cell studies identified limited membrane-associated binding, no evidence of CAR-mediated cytotoxicity or activation in normal human tissues, and no off-target binding by broad protein array screening. Immunosuppressive activity toward natural killer and CD8+ T cell responses was limited and comparable to polyclonal Tregs. Lentiviral integration site analyses demonstrated polyclonal integration profiles without evidence of transformation or abnormal growth in a cytokine- and activation-independent growth assay. This study establishes a combination of in vivo and NAM-based nonclinical safety framework for CAR-Treg therapies and demonstrates that CAR engineering of SBT777101 does not introduce new safety liabilities relative to unmodified polyclonal Tregs. These findings supported progression of SBT777101 into Phase 1 clinical trials and offer a generalizable approach for evaluating the safety of future CAR-Treg therapeutics.
    Keywords:  Chimeric Antigen Receptor; Immunosuppression; New Approach Methodologies; Regulatory T cells
    DOI:  https://doi.org/10.1093/toxsci/kfag125
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