bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–08–16
76 papers selected by
Luca Bolliger, lxBio
  1. Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers.
  2. From T cell engagers to next-generation immune cell engagers for cancer immunotherapy.
  3. Endotheliopathy in CAR T-Cell Therapy: Mechanistic Insights into the VWF/ADAMTS13 Axis and the Angiopoietin-Tie2 Pathway.
  4. In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.
  5. Beyond exhaustion: T cell fitness for next generation of immunotherapy for hematological cancer.
  6. Leveraging chimeric antigen receptor-T cell therapy for the treatment of multiple sclerosis: Bridging oncology and neurology.
  7. CAR T cell therapy beyond cancer: current status, challenges and future prospects.
  8. Real-World Data from a Single-Center, Large Academic Centralized Manufacturing of CD19 CAR T Cells in an Industry Partnership.
  9. Nano meets CAR-T: A new era in cancer immunotherapy.
  10. Emerging Landscape of CAR-T Cell Therapy in Colon Cancer: Mechanistic Insights, Clinical Advances, Challenges, and Future Directions.
  11. Dual-module aCAR-iCAR NK cells for solid tumors: cascade resistance mechanisms, AI-driven engineering, and precision stratification.
  12. Review Article: Immune Effector Cell-Mediated Enterocolitis Following CAR-T Cell Therapy-Clinical Features, Pathophysiology and Management.
  13. Editorial: Advancing Treg cell therapy: a comprehensive review series.
  14. Rewriting CAR-T cell fate: CRISPR/Cas gene editing for solid tumor therapy.
  15. Mass Spectrometry in Allogeneic CAR-T Cell Manufacturing: From Cellular Starting Materials to Multi-Attribute Quality Control.
  16. The why, what, who and when of B cell depletion in systemic lupus erythematosus: Biological rationale, patient stratification and evolving therapeutic modalities.
  17. Quantitative Dose Optimization for Gene Therapy Trials: Implications for Project Optimus and Early-Phase Design.
  18. A Comprehensive Rehabilitation Framework to help optimize outcomes across the CAR-T Continuum - White Paper Report.
  19. Logic-gated CARs: a unified framework for programmable cell-based delivery systems.
  20. Health technology assessment in Eastern Europe and Central Asia: an updated SWOT analysis - CORRIGENDUM.
  21. A life-cycle approach to digital health technology assessment.
  22. A call for principle-based acceptance of synthetic patients: establishing the AI-driven foundation for regulatory submissions.
  23. Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells.
  24. Defining unmet medical need: mapping stakeholder perspectives in a multi-level framework for Europe.
  25. Gone but not forgotten: CAR-NK cells leave a lasting mark on autoimmunity.
  26. Rethinking Phase I units in the era of immuno-oncology: a three-layer framework.
  27. Establishment of a scalable engineered cell-line platform for direct, GMP-grade production of eVLP vectors enabling streamlined generation of gene-edited CAR-T/NK cells.
  28. Neoantigen cancer vaccines in the mRNA Era: antigen selection, platform engineering, and clinical translation.
  29. Rebalancing innovation, affordability, and access for orphan drugs in the European Union.
  30. Challenges with expansion of cell and gene therapy: A call for system-level action.
  31. Regulatory T cells: From Foxp3 to tolerance-inducing therapies.
  32. Predictive Models for Toxicities after CAR T-cell Therapy: Challenges and Opportunities.
  33. The Erosion of Proof in Paradigm Transitions: The Rise of Narrative Rationality in Health Technology Assessment.
  34. Drug Discovery's Blind Spot: Why Organoid-Artificial Intelligence Convergence Demands Integrated Governance.
  35. Cancer immunotherapy under immune pressure: Mechanisms of resistance and the shift toward precision immune engineering.
  36. Microbial influence on tryptophan metabolism in tumors:Mechanisms and potential clinical applications.
  37. Targeted delivery of mRNA to immune cells for in vivo cell therapy.
  38. A fluorescein-conjugated somatostatin receptor antagonist adapter for chimeric antigen receptor T cell therapy of meningioma.
  39. Encephalopathy Post CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Beyond ICANS.
  40. Closed-loop agentic AI in drug discovery.
  41. Lamotrigine and other therapy-associated HLH syndromes: a review.
  42. Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach.
  43. The Great Debate: CAR-T-Cell Therapy Versus Bispecific Antibodies in B-Cell Lymphoma.
  44. TA-TMA occurring after sequential CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation: a case report.
  45. Optimized ex vivo expansion and functional characterization of canine natural killer cells using genetically modified feeder cells.
  46. Ferroptosis in T cells: mechanisms, biology and translational opportunities.
  47. Obecabtagene Autoleucel in Relapsed/Refractory B-ALL: A Critical Review of Clinical Efficacy and Safety.
  48. Emerging trends and future outlook towards magnetic nanoparticles as frontiers in cancer immunotherapy.
  49. In vivo generation of CD19 CAR T cells for the treatment of mouse systemic lupus erythematosus.
  50. Lipid Nanoparticles Based Multi-Scale Systemic Immune Programming for Cancer Therapy.
  51. [Management of ICANS in Patient Treated with Anti-CD19 CAR T-Cell Therapy].
  52. Simultaneous gene engineering of T cells with multiple neoantigen-specific T cell receptors for adoptive cell transfer.
  53. TransTCR: Integrating TCRs and Transcriptomes Through Optimal Transport for Antigen Specificity Prediction.
  54. Redefining Regulatory Proof: The End of the Two-Trial Paradigm.
  55. Model Gateway: Management platform for model-driven drug discovery.
  56. An inherent T cell-activating mRNA delivery carrier for in vivo CAR T generation.
  57. Take Five: harmonization in personalized cancer vaccines for cancer immunotherapy.
  58. The interplay between oncolytic viruses, Toll-like receptor signaling, and chemotherapy in overcoming tumor immune tolerance.
  59. Molecular mechanisms of bacteria-mediated cancer immunotherapy: from intratumoral microbiota to engineered therapeutics.
  60. Cytomegalovirus-Cell-Mediated Immunity Assays for the Prevention and Management of Cytomegalovirus in Transplant Recipients and Patients Receiving Cellular Therapies.
  61. Enhancing stability and function of induced regulatory T cells through membrane-anchored transforming growth factor-β1 and interleukin-10 secretion to protect against graft-versus-host disease.
  62. Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.
  63. Integrating cryoablation with immunotherapy in non-small cell lung cancer: mechanisms, clinical evidence, and translational barriers.
  64. Unconventional T cells in urological cancers: catch them if you can.
  65. Decade-long persistence of CD19 CAR T cells in B cell lymphomas.
  66. Artificial Intelligence and Genomic Data Analysis: New Frontiers in Precision Medicine.
  67. Psychological distress as a putative host-state determinant of cancer immunotherapy response.
  68. Gut microbiota modulation of systemic immunity and cancer immunotherapy: mechanisms, evidence, and therapeutic implications.
  69. Medicine 4.0: the era of revolutionary access.
  70. Validation of an automated total and viable cell counting for GMP-compliant production of human bone marrow stromal cells.
  71. mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.
  72. Circular Logic: Engineering Next-Generation Circular RNA Therapeutics for Precision Oncology.
  73. Continuous assurance for AI-driven clinical decision support systems.
  74. Resetting immunometabolic set points in autoimmune disease.
  75. Organizational transitions in awareness: a framework of access, coordination, and regulation.
  76. Peripheral vision: Treg cell induction in the gut.
  1. Front Immunol. 2026 ;17 1891408
    Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers.
    Ziyan Kong, Jinke Wang.
      Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated remarkable clinical efficacy across a spectrum of hematological malignancies, with particularly profound responses observed in B-cell leukemias, lymphomas, and multiple myeloma. However, the clinical benefits of CAR-T cell therapy have not yet been effectively extended to most solid tumors. This limitation arises from multiple biological and structural barriers, including the paucity of truly tumor-specific antigens, variable antigen expression and loss, inefficient trafficking and infiltration, and the presence of a highly immunosuppressive tumor microenvironment (TME). These obstacles not only restrict tumor recognition and intratumoral accumulation but also impair CAR-T-cell persistence, cytotoxicity, and durable tumor control, while promoting immune escape and increasing the likelihood of on-target, off-tumor toxicity. To address these challenges, diverse engineering strategies are being developed to improve the safety, efficacy, and adaptability of CAR-T cell therapy in solid tumors. These include Boolean logic-gated receptors, multi-antigen and retargeting platforms, locoregional delivery and trafficking-enhancing approaches, checkpoint blockade, armored CAR-T cells, synthetic receptors that rewire inhibitory signals, and emerging in vivo engineering approaches. In this review, we discuss how these next-generation engineering strategies are being designed to overcome the obstacles that constrain CAR-T-cell efficacy in solid tumors and to guide the development of safer and more effective therapeutic platforms.
    Keywords:  CAR-T cell therapy; antigen heterogeneity; armored CAR-T cells; solid tumors; synthetic receptors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1891408
  2. Antib Ther. 2026 Jul;9(3): 381-394
    From T cell engagers to next-generation immune cell engagers for cancer immunotherapy.
    Zaopeng Yang, Yang-Xin Fu.
      Immune cell engagers have emerged as a powerful class of multi-specific therapeutics that redirect immune effector cells toward tumor cells to induce targeted cytotoxicity. Among these, T cell engagers (TCEs) represent the most clinically advanced platform, with multiple approved agents demonstrating substantial efficacy in hematologic malignancies. However, their broader application remains limited by systemic toxicities, antigen heterogeneity, and reduced efficacy in solid tumors. To address these challenges, next-generation TCEs are being engineered with improved selectivity, and optimized signaling properties. In parallel, increasing attention has shifted toward engaging alternative immune effectors, including γδ T cells, natural killer cells, and myeloid populations, which provide complementary mechanisms of tumor recognition and immune modulation. In this Review, we summarize the biological principles underlying T or other immune cell engagers, highlight emerging alternative platforms, and discuss evolving engineering strategies that are shaping the future of programmable cancer immunotherapy.
    Keywords:  NK cell engagers; T cell engagers; cancer immunotherapy; immune cell engagers; myeloid cell engagers; γδ T cells
    DOI:  https://doi.org/10.1093/abt/tbag030
  3. TH Open. 2026 ;10 a29231208
    Endotheliopathy in CAR T-Cell Therapy: Mechanistic Insights into the VWF/ADAMTS13 Axis and the Angiopoietin-Tie2 Pathway.
    Sévérine de Bruijn, Inge Vangenechten, Sébastien Anguille, Alain Gadisseur.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the management of hematologic malignancies, yet its clinical success is tempered by severe immune-mediated toxicities, including cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often accompanied by CAR T cell therapy-related coagulopathy (CARAC). Converging evidence identifies therapy-related endotheliopathy as a central pathophysiological link between cytokine excess, hemostatic dysregulation, capillary leak, and organ injury. Parallel efforts aim to identify circulating biomarkers that can signal emerging toxicity before clinical deterioration. This review summarizes the biological basis of endotheliopathy during CAR T cell therapy, with particular emphasis on two interconnected regulatory systems: the von Willebrand factor (VWF)/ADAMTS13 axis, which governs platelet adhesion and microvascular thrombosis, and the angiopoietin (Ang)-tyrosine kinase receptor Tie2 signaling pathway, which regulates endothelial stability and vascular permeability. Dysregulation of these pathways drives the shift from adaptive immunothrombosis to pathological endothelial injury, characterized by loss of anticoagulant control, barrier disruption, and microvascular instability. Clinical studies show that alterations in the VWF/ADAMTS13 balance and increases in the Ang-2/Ang-1 ratio correlate with CRS and ICANS severity and may precede overt toxicity, highlighting their potential as markers of endothelial vulnerability. Defining actionable biomarker thresholds and evaluating endothelial-targeted interventions are key priorities for improving the safety and precision of CAR T cell therapy.
    Keywords:  ADAMTS13; CAR T-cell therapy; CRS; ICANS; angiopoietins; coagulopathy; immunothrombosis; von Willebrand factor
    DOI:  https://doi.org/10.1055/a-2923-1208
  4. Int Immunopharmacol. 2026 Aug 10. pii: S1567-5769(26)01101-X. [Epub ahead of print]187 117255
    In vivo CAR-T therapy: The shift from ex vivo culturing to direct in situ immune reprogramming.
    Janani Gopalakrishnan, Bhagyashri Rathod, Sachin Puri.
      CAR T-cell therapy using chimeric antigen receptors (CARs) has provided a radical shift in the treatment of several hematological malignancies, producing high response rates and durable remissions. However, conventional ex vivo manufacturing is limited by complex processing steps, high costs, variability in product quality, and clinically relevant delays that restrict patient eligibility. In vivo manufacturing has emerged as a next-generation approach in which immune cells are reprogrammed directly within the patient, eliminating the need for exogenous handling and culture. This strategy uses viral and non-viral delivery platforms, including lentiviral vectors, adeno-associated viruses, lipid nanoparticles, and targeted polymer systems, together with DNA, mRNA, and genome editing tools such as CRISPR-based technologies. Early feasibility data are supported mainly by preclinical models and translational studies, while safety remains a central concern due to potential immunotoxicity, off-target transduction, and regulatory challenges. This review highlights key engineering strategies enabling in vivo CAR T-cell generation, summarizes emerging clinical research and development, and discusses future opportunities for expanding in vivo CAR T-cell therapies as scalable immunotherapy platforms.
    Keywords:  CAR-T cells; Ex vivo manufacturing; Genome editing (CRISPR); Hematological malignancies; In vivo delivery; Viral and non-viral platforms
    DOI:  https://doi.org/10.1016/j.intimp.2026.117255
  5. Front Immunol. 2026 ;17 1895434
    Beyond exhaustion: T cell fitness for next generation of immunotherapy for hematological cancer.
    Xiaoshuang Kong, Yuanhui Su, Hanxue Zheng, Zuxi Feng, Jianxia Huang, Liansheng Zhang, Lijuan Li.
      T cell-directed immunotherapies have transformed the treatment of hematological malignancies, but durable benefit remains limited by relapse, poor persistence, incomplete immune reconstitution and infection. These outcomes depend not only on target-antigen expression but also on the functional quality of the T cell compartment. In this Review, we define T cell fitness as a multidimensional capacity that includes cellular availability, memory reserve, proliferative competence, cytotoxic function, metabolic resilience, resistance to chronic stimulation and persistence. We distinguish exhaustion, senescence and terminal differentiation as overlapping but non-equivalent states and propose a measurable, modality-specific assessment framework rather than reliance on a single marker. We then compare how these states arise in multiple myeloma, lymphoma, acute lymphoblastic leukemia and acute myeloid leukemia, emphasizing the effects of age, tissue niche, disease burden and prior therapy. We critically appraise evidence from CAR-T cell therapy, bispecific antibodies and checkpoint blockade, including the limitations of predominantly retrospective, correlative and disease-specific datasets. Finally, we translate the fitness framework into clinical questions: when to collect cells, how to select bridging therapy, which biomarkers merit prospective testing, how treatment duration and sequencing may preserve immune competence, and where gene-edited products, CAR-NK cells and metabolic interventions may reduce dependence on compromised autologous T cells. A fitness-based approach may support more precise biomarker development and safer treatment selection, but prospective validation and modality-specific thresholds are still required.
    Keywords:  CAR-T cell therapy; T cell fitness; T cell senescence; biomarkers; bispecific antibodies; hematological malignancies; t cell exhaustion; treatment sequencing
    DOI:  https://doi.org/10.3389/fimmu.2026.1895434
  6. Curr Res Transl Med. 2026 Jul 25. pii: S2452-3186(26)00039-5. [Epub ahead of print]74(3): 103603
    Leveraging chimeric antigen receptor-T cell therapy for the treatment of multiple sclerosis: Bridging oncology and neurology.
    Matlyuba Sanoyeva, Nargiza Nasirdinova, Munisakhon Gulova, Nargiza Ortikova, Alexey Yumashev, Ro'zibek Tolmasov, Turgunbay Kholdarov, Zhanna R Gardanova.
      Multiple sclerosis (MS) is driven by complex interactions among B cells, autoreactive T cells, and compartmentalized inflammation behind the blood-brain barrier (BBB). Although treatment with B cell-targeting monoclonal antibodies (mAbs) has transformed MS management, their efficacy remains limited by inadequate penetration into the central nervous system (CNS), incomplete depletion of long-lived plasma cells, and development of treatment resistance in a significant number of patients. In recent years, chimeric antigen receptor (CAR)-T cell therapy has emerged as a new therapeutic approach to reset pathogenic immune circuits in MS. CAR-T cell therapy enables more profound and durable depletion of pathogenic B cell populations and, potentially, CNS-associated antibody-producing cells, allowing partial reconstitution of a more tolerant and less autoreactive humoral immune system and reducing intrathecal antibody-mediated inflammation. However, the extent to which CAR-T cells can eradicate deeply compartmentalized CNS-resident immune populations remains under investigation. Nonetheless, CAR-T cell therapy for MS has evolved beyond B cell-depleting strategies, and other types of CAR-T cell therapies with distinct mechanisms of action have also been developed. These strategies include chimeric autoantibody receptor (CAAR)-T cell therapy for selective depletion of autoreactive B cells, CAR-engineered regulatory T (CAR-Treg) cells to restore localized immune tolerance, and T cell receptor mimic CAR-T cells (TCRm CAR-T cells) to recognize autoantigenic peptide-MHC complexes. This review aims to discuss the progress of CAR-T cell therapy for MS and its existing challenges, including safety concerns, optimal antigen selection, and safe access to the CNS. Advances in dual-targeting strategies, chemokine receptor engineering, allogeneic platforms, tailoring strategies to the heterogeneous immunopathology of MS, and in vivo generation of CAR-T cells are also comprehensively discussed.
    Keywords:  B cell–depleting CAR-T; CAAR–T; CAR–Treg; Multiple sclerosis; TCRm CAR–T
    DOI:  https://doi.org/10.1016/j.retram.2026.103603
  7. Signal Transduct Target Ther. 2026 Aug 11. pii: 319. [Epub ahead of print]11(1):
    CAR T cell therapy beyond cancer: current status, challenges and future prospects.
    Saurabh Upadhyay, Sungwoo Cho, Kirti Upmanyu, Moustafa T Gabr.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic-precise antigen recognition coupled with durable effector activity-extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)-CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.
    DOI:  https://doi.org/10.1038/s41392-026-02873-4
  8. Hum Gene Ther. 2026 Aug;37(15-16): 802-804
    Real-World Data from a Single-Center, Large Academic Centralized Manufacturing of CD19 CAR T Cells in an Industry Partnership.
    Kati Kebbel, Gerno Schmiedeknecht, Andrea Quaiser, Susann Schumann, Carolin Poch, Manuela Haß, Andreas Grahnert, Margarida Rodrigues, Kristin Reiche, Markus Kreuz, Ulrike Koehl.
      To date, prediction of manufacturing failure for CAR T cells is still lacking. In a retrospective multivariate analysis of our 368 manufactured CAR-T cell batches (tisagenlecleucel), we investigated potential factors that might be associated with manufacturing failure. In this letter to the editor, we provide a summary of our findings and outline recommendations for future advanced quality control strategies.
    Keywords:  CD19 CAR T cells; manufacturing; product specification; production failure; quality control; tisagenlecleucel
    DOI:  https://doi.org/10.1177/10430342261472597
  9. Biochim Biophys Acta Rev Cancer. 2026 Aug 14. pii: S0304-419X(26)00157-5. [Epub ahead of print] 189685
    Nano meets CAR-T: A new era in cancer immunotherapy.
    Alaa Ibrahim, Maha Nasr.
      Chimeric antigen receptor (CAR)-T cell immunotherapy is one of the emerging advancements in personalized treatment of cancer, whose design is based on the genetic modification of T cells to express chimeric antigen receptors (CARs) to generate CAR-T cells, specifically targeting cancer tissues. Despite the fact that immunotherapy provides significant antitumor activity, only a limited number of therapies reached the market after their FDA approval because of the accompanying challenges including tumor resistance, side effects, high cost of production, possible toxicities during CAR-T cells engineering, and poor selectivity. Nanotechnology has emerged as a promising approach for improving drug targeting, selectivity and reducing their side effects. In this context, recent advances highlight the innovative integration of nanomaterials for enhancing CAR-T cell engineering, delivery, and in vivo functionality. Nanotechnology-enabled strategies such as nanoparticle-based gene delivery systems, nanoformulations for controlled CAR expression, and tumor microenvironment modulation have demonstrated significant potential in overcoming current therapeutic limitations. Therefore, substantial research efforts are currently focused on integrating this technology in developing CAR-T cell immunotherapy. This review article focuses on CAR-T cell bioengineering, antitumor mechanism of action, challenges and limitations, as well as the latest innovative nanotechnological solutions for complementing CAR-T cell immunotherapy. It also emphasizes the translational applications and design innovations of nanotechnology, including precision targeting platforms and multifunctional nanocarriers, highlighting that nanotechnology may play an important role in advancing the efficacy, safety, and clinical applicability of personalized CAR-T cancer immunotherapy.
    Keywords:  Antigens; CAR-T cell immunotherapy; Nanoparticles; Nanotechnology; Solid tumors; Tumor resistance
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189685
  10. Pathol Res Pract. 2026 Aug 10. pii: S0344-0338(26)00298-0. [Epub ahead of print]287 156645
    Emerging Landscape of CAR-T Cell Therapy in Colon Cancer: Mechanistic Insights, Clinical Advances, Challenges, and Future Directions.
    Arif Raza, Mohammad Adnan Raza, Junaid Khan, Ajazuddin.
      Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies; however, its clinical translation to solid tumors, including colon cancer, remains challenging. This review comprehensively examines the current landscape of CAR-T cell therapy for colon cancer, focusing on its underlying mechanisms, recent clinical advances, major challenges, and future perspectives. We provide an overview of CAR-T therapy, highlighting its significance in colorectal cancer and comparing its clinical performance in hematological malignancies and solid tumors. The review discusses the structural design and functional evolution of CAR-T cells, with particular emphasis on tumor-associated antigens such as epidermal growth factor receptor (EGFR), mucin-1 (MUC1), carcinoembryonic antigen (CEA), and Frizzled receptors. Mechanistic insights into the immunosuppressive tumor microenvironment and its impact on CAR-T cell efficacy are also presented. Despite promising preclinical and early clinical outcomes, several barriers continue to limit therapeutic success, including antigen heterogeneity, immune evasion, T-cell exhaustion, poor tumor infiltration, and manufacturing complexities. Current clinical trials targeting CEA, EGFR, and other emerging antigens are critically discussed to highlight recent progress and remaining limitations. In addition, we summarize emerging strategies to enhance CAR-T efficacy, including tumor microenvironment modulation, biomarker-guided patient selection, next-generation CAR designs, and combination therapies. Finally, we discuss future directions for optimizing CAR-T therapy through precision immunotherapy approaches, improved biomarker integration, and well-designed clinical trials. Overall, this review highlights the transformative potential of CAR-T cell therapy in colon cancer while providing a critical perspective on the challenges and opportunities that will shape its future clinical application.
    Keywords:  CAR T; Cellular Therapy; Colon Cancer; EGFR; MUC
    DOI:  https://doi.org/10.1016/j.prp.2026.156645
  11. Front Immunol. 2026 ;17 1863734
    Dual-module aCAR-iCAR NK cells for solid tumors: cascade resistance mechanisms, AI-driven engineering, and precision stratification.
    Chenru Ma, Yafei Zhuang, Songchen Han, Shuping Li, Qiang Dai.
      Chimeric antigen receptor-engineered natural killer (CAR-NK) cells have emerged as a promising off-the-shelf platform for cancer immunotherapy, with a favorable safety profile in early clinical trials and potent antitumor activity demonstrated in relapsed/refractory (R/R) hematologic malignancies. However, their clinical efficacy in solid tumors remains severely limited by interconnected resistance mechanisms. In this review, we systematically dissect the pathological basis of CAR-NK therapy failure in solid tumors and propose an integrative cascade resistance framework that delineates three core bottlenecks: tumor microenvironment (TME)-mediated functional exhaustion, structural defects of non-natural killer (NK)-cell-adapted chimeric antigen receptors (CARs), and trogocytosis-driven immune escape. We further characterize the context-dependent regulatory roles of the natural killer group 2 member A-human leukocyte antigen E (NKG2A-HLA-E) immune checkpoint axis and the intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 (ICAM-1/LFA-1) adhesion pathway within this cascade model, with clear stratification of evidence strength across all mechanistic conclusions. Centered on the activating-inhibitory dual-module CAR (aCAR-iCAR) system, we summarize its design principles, preclinical validation status, and potential to mitigate cascade resistance, with explicit distinction between killer cell immunoglobulin-like receptor (KIR)-based (Level 1 evidence) and NKG2A-based (Level 2-3 evidence) inhibitory CAR backbones. We then outline an end-to-end artificial intelligence (AI)-driven rational design framework covering target screening, structural optimization, and signaling balance calibration, and introduce the AI-nanosymbiont concept as an exogenous synergistic strategy to address TME delivery barriers. Building on the molecular heterogeneity of solid tumors, we propose a four-subtype precision stratification framework to match tumor features with tailored therapeutic regimens, and summarize core translational challenges including manufacturing constraints, regulatory gaps, and safety considerations. Overall, this review provides a balanced, evidence-graded theoretical framework for next-generation CAR-NK development against solid tumors, and generates testable hypotheses for future mechanistic and clinical investigations.
    Keywords:  CAR-NK cells; NKG2A-HLA-E; aCAR-iCAR; artificial intelligence; cascade resistance; dual-module CAR; precision immunotherapy; trogocytosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1863734
  12. Aliment Pharmacol Ther. 2026 Aug 13.
    Review Article: Immune Effector Cell-Mediated Enterocolitis Following CAR-T Cell Therapy-Clinical Features, Pathophysiology and Management.
    John A Damianos, Yi Lin, Zongming Eric Chen, Kenneth J C Lim, Navreet M Chowla.
       BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of hematologic malignancies, and its use is expanding rapidly into numerous other disease states including autoimmune diseases. However, CAR-T therapy is associated with a spectrum of immune-related toxicities. In addition to the already well characterized cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, it has become apparent that rarely, CAR-T can cause gastrointestinal mucosal inflammation, termed immune effector cell-mediated enterocolitis (IEC-EC).
    AIMS: This state-of-the-art review highlights the CAR-T mechanism and details the epidemiology, pathophysiology, clinical manifestations, endoscopic and histopathologic features, and management of IEC-EC.
    METHODS: This review presents the current state of knowledge through a comperhensive and detailed synthesis of all case series reported in the literature to date.
    RESULTS: Occurring in up to approximately 6% of patients typically following B cell maturation antigen-targeted CAR-T therapy, IEC-EC presents with severe diarrhoea and malabsorption, responds poorly to treatment, and portends a dire prognosis. Multi-disciplinary management should centre on early diagnosis, supportive cares, assessment and treatment of infections, and step-up pharmacotherapy, often featuring biologics and small molecules drawn from the inflammatory bowel disease pharmacologic armamentarium.
    CONCLUSIONS: Clinicians should maintain a high degree of vigilance for IEC-EC in patients presenting with gastrointestinal symptoms following CAR-T treatment. Early recognition and multi-disciplinary treatment may improve patient outcomes.
    DOI:  https://doi.org/10.1111/apt.70920
  13. Front Immunol. 2026 ;17 1923288
    Editorial: Advancing Treg cell therapy: a comprehensive review series.
    Fabien Depis, Devan Moodley, Seng-Lai Tan.
      
    Keywords:  Treg - regulatory T cell; autoimmune disease (AD); cell therapy (CT); immune tolerance; inflammatory disorders; transplantation
    DOI:  https://doi.org/10.3389/fimmu.2026.1923288
  14. Front Immunol. 2026 ;17 1910092
    Rewriting CAR-T cell fate: CRISPR/Cas gene editing for solid tumor therapy.
    Wenjing Liu, Jiayi Gu, Chenghao Xie, Bing Du, Mingyao Liu, Jiqin Zhang.
      Although chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematological malignancies, its therapeutic efficacy in solid tumors remains limited by several challenges, including insufficient tumor infiltration, T cell exhaustion and the immunosuppressive tumor microenvironment (TME). CRISPR/Cas, a third-generation gene editing technology developed in recent years, is characterized by its simplicity and high efficiency. This technology has demonstrated broad application potential across multiple fields and has emerged as a powerful tool for improving CAR-T cell therapy. In this review, we summarize recent advances in the application of CRISPR/Cas gene editing technology to enhance the antitumor activity of CAR-T cells against solid tumors. We also discuss the key challenges currently faced and systematically propose potential strategies for overcoming the limitations.
    Keywords:  CAR-T; CRISPR/Cas; gene editing; solid tumors; tumor immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1910092
  15. Cells. 2026 Jul 25. pii: 1333. [Epub ahead of print]15(15):
    Mass Spectrometry in Allogeneic CAR-T Cell Manufacturing: From Cellular Starting Materials to Multi-Attribute Quality Control.
    Naryeong Kim, Zhouyang Huang, Michael Born, Julien Camperi.
      Chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable clinical efficacy in hematological malignancies, yet their broader application is constrained by manufacturing complexity and variability, particularly in autologous settings. The development of allogeneic CAR T-cell therapies offers a promising alternative by enabling scalable, "off-the-shelf" production; however, these approaches introduce additional challenges related to donor variability, genome editing, and product consistency. Robust analytical strategies are therefore required to ensure safety, efficacy, and batch-to-batch reproducibility. Conventional analytical methods, such as flow cytometry and enzyme-linked immunosorbent assays, provide targeted, high-confidence measurements of predefined cellular and soluble markers but are inherently limited in their ability to capture the full molecular and functional complexity of CAR T-cell products. In current manufacturing paradigms, these assays are typically deployed as isolated quality control readouts rather than as components of an integrated control strategy that links donor variability, gene-editing material quality, in-process metabolic state, final product critical quality attributes, and clinical biomarker responses. In this context, mass spectrometry (MS) has emerged as a powerful platform for high-dimensional molecular characterization, enabling analysis of gene-editing reagents, proteins, metabolites, lipids, and both culture and spent-media composition across the CAR T-cell manufacturing workflow. In this review, we examine the various applications and tools of MS across key stages of the allogeneic CAR T-cell workflow, including donor characterization, analysis of gene-editing materials, in-process culture monitoring, drug product quality assessment, and post-infusion biomarker evaluation. Collectively, these approaches demonstrate the potential of MS-driven analytics to address current limitations in CAR T-cell manufacturing by improving process understanding, enabling comprehensive quality assessment, and supporting regulatory decision-making. The integration of MS into CAR T-cell workflows may ultimately facilitate the development of more consistent, scalable, and effective cell therapies.
    Keywords:  allogeneic CAR T-cell therapy; biomarker analysis; cell therapy manufacturing; mass spectrometry; metabolomics; proteomics; quality control
    DOI:  https://doi.org/10.3390/cells15151333
  16. Rheumatology (Oxford). 2026 Aug 14. pii: keag416. [Epub ahead of print]
    The why, what, who and when of B cell depletion in systemic lupus erythematosus: Biological rationale, patient stratification and evolving therapeutic modalities.
    Chris Wincup, Mariele Gatto, Marc Scherlinger, Georg Schett, Melanie Hagen.
      Systemic lupus erythematosus (SLE) is driven by interconnected immune circuits in which B cells function as antigen-presenting cells, cytokine producers and precursors of autoantibody-secreting plasma cells. Therapeutic targeting of B cells aims to disrupt these self-reinforcing circuits rather than simply reduce autoantibody titres alone. Clinical experience with anti-CD20 monoclonal antibodies has validated B cells as therapeutic targets, while exposing key biological constraints, including incomplete tissue depletion, persistence of long-lived plasma cells, and BAFF-driven B cell repopulation. Recent advances including next-generation anti-CD20 monoclonal antibodies, bispecific T cell engagers, and chimeric antigen receptor (CAR) T cell therapies have shown promise but questions remain relating to which patients should be treated with what modality of therapy and when this should be timed within the disease course. Herein, we evaluate the current landscape of B cell targeting therapies with particular focus on patient selection, timing of therapy and type of treatment.
    Keywords:  Autoimmunity; B cell depletion; B cells; Biologics; Biomarkers; CAR-T; Plasma cells; Precision medicine; Systemic lupus erythematosus; T cell engagers
    DOI:  https://doi.org/10.1093/rheumatology/keag416
  17. Pharm Stat. 2026 Sep-Oct;25(5):25(5): e70113
    Quantitative Dose Optimization for Gene Therapy Trials: Implications for Project Optimus and Early-Phase Design.
    Kevin Roberts, Jeffrey Palmer, Jessica Volpe, Wei Zhong, Avery McIntosh.
      Quantitative dose optimization in early phase clinical trials for investigational new drugs has been expanding across drug modalities and disease indications in response to the limitations of non-quantitative or algorithmic methods of dose progression. In the context of the FDA's Project Optimus Initiative, which emphasizes dose optimization rather than reliance on the maximum tolerated dose, these challenges motivate the development of alternative quantitative frameworks tailored to gene therapies. In this manuscript we describe the state of the art for quantitative dose optimization with an eye to applications in cell and gene therapy modalities. The application of quantitative dose progression methods in this setting poses unique challenges, but the regulatory, scientific, medical, and statistical environment has advanced to the point where new approaches can be employed to characterize the safety and efficacy profile of these powerful biopharmaceutical products. We discuss the current use of quantitative dose optimization, the limitations and pitfalls of these options for gene therapy indications, and provide a tutorial example of how an established Bayesian logistic regression framework can be adapted to distinguish clinically distinct toxicity classes. The example is intended to illustrate safety-constrained decision logic in a sparse early-phase setting, rather than to establish comparative superiority over existing dose-finding designs. The proposed framework should be viewed as one component of broader dose optimization that may also incorporate pharmacodynamic, exposure-response, efficacy, durability, and practical administration considerations.
    Keywords:  dose finding; dose optimization; early phase; gene therapy; project optimus
    DOI:  https://doi.org/10.1002/pst.70113
  18. Transplant Cell Ther. 2026 Aug 12. pii: S2666-6367(26)00596-8. [Epub ahead of print]
    A Comprehensive Rehabilitation Framework to help optimize outcomes across the CAR-T Continuum - White Paper Report.
    Jaleel A Mohammed, Zubaida Mohamed, Anne Gonzales, Mahmoud AlJurf, Mohamed A Kharfan-Dabja, Shahrukh K Hashmi.
       BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies but is associated with significant neuromusculoskeletal toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), fatigue, myopathy, arthralgia, and avascular necrosis. These complications profoundly impact functional status, mobility, and quality of life (QoL), yet structured rehabilitation remains inconsistently integrated into CAR-T care pathways.
    OBJECTIVE: To develop the first comprehensive, consensus-based recommendations outlining the role of rehabilitation team across the CAR-T treatment continuum, from pre-treatment assessment through long-term survivorship.
    METHODS: A systematic literature search of PubMed, Embase, Science Direct, Taylor & Francis, and CINAHL Ultimate was conducted for publications from 2015 to 2025. International expert consensus was obtained through collaboration with the Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) Group and the Rehabilitation Association for Hematopoietic Cell Transplant, specialist from a diverse clinical background including physical therapy, nurse practitioner and transplant consultants.
    RESULTS: Post CAR-T treatment patients can suffer from various neuromusculoskeletal manifestations including ICANS (20-60%), CRS-related musculoskeletal symptoms (up to 90%), persistent fatigue (up to 90%), cytokine-induced myopathy, peripheral neuropathies, arthralgias, and avascular necrosis. Pre-existing sarcopenia is associated with higher toxicity rates and reduced survival. A tiered rehabilitation model is proposed comprising: (1) comprehensive pre-CAR-T baseline assessment including functional, neurological, and QoL measures; (2) dynamic inpatient rehabilitation adapting to daily fluctuations in CRS/ICANS severity and cytopenias; and (3) structured outpatient follow-up for at least 12-18 months. Three service delivery levels (minimum essential, intermediate, and advanced/model care) are outlined, with recommendations for embedding rehabilitation services within multidisciplinary CAR-T teams and developing Advanced Clinical Practitioner (ACP) roles.
    CONCLUSIONS: Neuromusculoskeletal rehabilitation is an essential, yet underutilized, component of CAR-T therapy care. Systematic integration of rehabilitation across the treatment continuum, supported by specialized practitioner roles, has the potential to reduce morbidity, improve functional outcomes and QoL, and optimize healthcare resource utilization. Prospective trials validating these recommendations remain a priority.
    Keywords:  Chimeric antigen receptor T-cell therapy; cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; neuromusculoskeletal complications; physiotherapy; quality of life; rehabilitation
    DOI:  https://doi.org/10.1016/j.jtct.2026.07.034
  19. Trends Biotechnol. 2026 Aug 11. pii: S0167-7799(26)00292-1. [Epub ahead of print]
    Logic-gated CARs: a unified framework for programmable cell-based delivery systems.
    Pu-Sheng Wei, Zitao Ma, Evelyn Chang, Yu-Hsuan Tsai, Kuo-Ching Mei.
      Logic-gated chimeric antigen receptors (CARs) enable engineered immune cells to integrate multiple molecular and environmental inputs, improving therapeutic precision, safety, and resistance to antigen escape. As diverse logic-gated CAR architectures have emerged, differences in design principles and terminology have complicated comparisons across studies. This review presents a unified framework for classifying logic-gated CARs according to Boolean logic and biological signal integration, encompassing YES, OR, AND, INHIBIT (AND-NOT), sequential AND-YES/NOT, and hybrid architectures. We compare these systems based on computational logic, molecular mechanisms, reversibility, modularity, and clinical translatability and summarize the evolving clinical landscape of programmable immune cell therapies. This framework provides a practical reference for interpreting, designing, and translating next-generation logic-gated CAR systems.
    Keywords:  Boolean logic; CAR-T; cell therapy; immune cell engineering; logic-gated CAR; synthetic biology
    DOI:  https://doi.org/10.1016/j.tibtech.2026.07.013
  20. Int J Technol Assess Health Care. 2026 Aug 10. 42(1): e71
    Health technology assessment in Eastern Europe and Central Asia: an updated SWOT analysis - CORRIGENDUM.
    Rabia Sucu, Antonio Migliore, Nicola Vicari, Esra Meltem Koç, Alima Almadiyeva.
      
    DOI:  https://doi.org/10.1017/S0266462326103973
  21. Int J Technol Assess Health Care. 2026 Aug 10. 42(1): e70
    A life-cycle approach to digital health technology assessment.
    Ashwini Kanakapura Sriranga, Baptiste Vasey, Mateo Campos, Miguel Ángel Armengol de la Hoz, Ruben Casado Arroyo, Stephen Gilbert, Rebecca Mathias, Lucia Osoro, Peter McCulloch.
      The approach of Health Technology Assessment, which developed from the Evidence-Based Medicine movement of the 1990s, has proved its value in appraising the value of pharma products but presents methodological challenges when applied to medical devices and digital technologies, whose importance has increased enormously during the last 30 years. The concept of a single assessment, which can summarize relative effectiveness and cost-effectiveness, has been further challenged by the rapidly rising importance of software-driven devices, and latterly Artificial Intelligence. The need to adopt a broader evaluation approach based on product life cycles has been recognized by both regulators and HTA bodies, but practical frameworks for this have not yet been widely adopted. We describe a Life-Cycle-Based Evaluation (LCBE) approach to the assessment of Digital Health Technologies, developed as part of the ASSESS-DHT Horizon Europe 2020 project, EU project 101137347. The LCBE framework is currently being evaluated in pilot studies and aims to support early, proportionate, and continuous assessment and foster collaboration among developers, regulators, and HTA bodies to ensure timely, rigorous, and adaptive evaluations across the technology life cycle.
    Keywords:  evidence generation; health technology assessment; life-cycle evaluation
    DOI:  https://doi.org/10.1017/S0266462326104097
  22. Front Digit Health. 2026 ;8 1833779
    A call for principle-based acceptance of synthetic patients: establishing the AI-driven foundation for regulatory submissions.
    Jordi Guitart.
      The pharmaceutical industry stands at the precipice of an AI-driven data revolution, with synthetic patients emerging as a transformative tool to accelerate drug discovery and development while enhancing patient privacy. However, a critical regulatory gap persists: the absence of a standardized basis from leading regulatory bodies for accepting AI-generated patient populations as evidence in regulatory submissions. This manuscript addresses this void by proposing five foundational principles-Representativeness, Utility, Robustness, Privacy Preservation, and Transparency-anchored by the "Fit for Purpose" philosophy. We introduce the operational concept of a "Technical Validation Playbook" to facilitate the first wave of regulatory acceptances for synthetic patient data. We further outline actionable recommendations for regulatory agencies and pharmaceutical sponsors to advance the acceptance of synthetic patient populations through existing qualification and scientific advice mechanisms. By establishing a proactive, principle-based approach, this framework aims to catalyze regulatory-industry alignment and unlock the transformative potential of synthetic patients, particularly for populations with unmet medical needs such as rare diseases where traditional placebo-controlled trials face insurmountable ethical and recruitment challenges.
    Keywords:  GANs; VAEs; clinical trials; drug development; generative AI; rare diseases; regulatory framework; synthetic patient data
    DOI:  https://doi.org/10.3389/fdgth.2026.1833779
  23. Cancer Immunol Res. 2026 Aug 04.
    Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells.
    Cheng-Fu Kuo, Zhen Tong, Yi-Chiu Kuo, Miso Park, Jeremy King, Kevin Ly, Bea Parcutela, Lawrence A Stern, Zhiqiang Wang, Jonathan C Hibbard, Brenda Aguilar, Renate Starr, Wen-Chung Chang, Julie R Ostberg, Daniel Rossi, Mary C Clark, Darya Alizadeh, Stephen J Forman, John C Williams, Christine E Brown.
      Chimeric antigen receptor (CAR) T cells have transformed cancer treatment, yet challenges for achieving broader clinical success remain, including overcoming tumor antigen heterogeneity and limited T-cell fitness. To address these challenges and enhance CAR T-cell functionality, we leveraged meditope technology, a lock-and-key platform where Fab regions of antibodies are modified to bind a small cyclic peptide termed meditope (meP). We developed a panel of meditope-enabled Fab-based CARs (meCARs), which showed selective binding to the meP and comparable activity to traditional single-chain variable fragment (scFv)-based CARs. Focusing on HER2-targeted meCARs for evaluating platform utility, we exploited the modularity of the meditope platform to detect meCAR T cells using meP-fused fluorescent agents, promote meCAR T-cell expansion via meP-fused IL-15 cytokine, and broaden tumor antigen targeting through meP-fused antibodies to address tumor heterogeneity. These findings establish the meditope technology as a versatile strategy to augment CAR T-cell functionality and overcome key limitations of current CAR-based therapies.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1285
  24. Health Policy. 2026 Jul 30. pii: S0168-8510(26)00159-4. [Epub ahead of print]173 105722
    Defining unmet medical need: mapping stakeholder perspectives in a multi-level framework for Europe.
    Zilke Claessens, Anais Brouckaert, Isabelle Huys.
       BACKGROUND: In the context of the 2023 reform of the EU pharmaceutical legislation, the concept of unmet medical need (UMN) has gained renewed attention. The proposal introduces a new definition of UMN and calls for greater alignment across regulatory and health technology assessment (HTA) procedures. However, stakeholders remain divided on the concept's scope, purpose, and definition.
    OBJECTIVE: To explore stakeholder perspectives on the UMN concept, and to identify perceived application purposes and definitional parameters.
    METHODS: Semi-structured interviews were conducted with (i) healthcare providers, (ii) policy-makers/advisors (e.g., HTA bodies, regulators, payers), (iii) pharmaceutical industry representatives, and (iv) patients (representatives) across Europe. Interviews were transcribed verbatim and analysed thematically.
    RESULTS: Interviews (N = 38) revealed that a universally accepted, one-size-fits-all definition of UMN is viewed as unattainable, given the differing application purposes and stakeholder priorities. Analysis identified key sources of variation, categorised into five framing dimensions, five assessment criteria, and eight overarching application purposes. Framing dimensions establish the conceptual boundaries of UMN, including the type of need considered (pharmaceuticals, diagnostics, preventive measures, healthcare services), perspective of need (patient, caregiver, healthcare provider, society), and assessment level (population or individual). Assessment criteria provide factors for UMN evaluation, including the availability of alternatives, severity of the condition, population vulnerability, availability of information or research, and the intervention's therapeutic advantage.
    CONCLUSIONS: This study presents a multi-level framework for defining UMN, grounded in diverse stakeholder perspectives and designed for practical use. By explicitly outlining the underlying variables, the framework supports the development of transparent and context-sensitive UMN definitions.
    Keywords:  European Commission; Market access science; Pharmaceutical innovation; Pharmaceutical legislation; Public health; Regulatory science; Unmet medical need
    DOI:  https://doi.org/10.1016/j.healthpol.2026.105722
  25. Med. 2026 Aug 14. pii: S2666-6340(26)00268-0. [Epub ahead of print]7(8): 101265
    Gone but not forgotten: CAR-NK cells leave a lasting mark on autoimmunity.
    Rejeena Shrestha, Rafet Basar.
      In this phase 1 open-label trial, Zeng et al.1 show that umbilical cord blood-derived CD19 CAR NK-cell therapy is safe and effectively depletes autoreactive B cells in refractory systemic lupus erythematosus (SLE). Despite only transient CAR NK-cell persistence, patients experienced sustained clinical improvement and reconstitution of a predominantly naive B cell compartment, suggesting immune resetting rather than temporary immunosuppression.
    DOI:  https://doi.org/10.1016/j.medj.2026.101265
  26. J Immunother Cancer. 2026 Aug 11. pii: e015615. [Epub ahead of print]14(8):
    Rethinking Phase I units in the era of immuno-oncology: a three-layer framework.
    Liangjie Sun, Rongyang Xu, Shuhang Wang, Ning Li.
      The rapid expansion of immuno-oncology (I-O) and other advanced therapies is reshaping the complexity of early-phase clinical development. While core Phase I principles remain fundamental across oncology, emerging modalities introduce additional requirements for translational integration, specialized safety management, and therapeutic-specific infrastructure. However, the organizational functions of Phase I units have not evolved at the same pace and remain largely centered on conventional operational responsibilities. Drawing on the practices of leading Phase I units across the USA, Europe, and China, and comparing evolving regulatory frameworks of the US Food and Drug Administration, European Medicines Agency/Medicines and Healthcare products Regulatory Agency, and China's National Medical Products Administration, we propose a global perspective on the future development of Phase I units. We present a three-layer framework encompassing core Phase I foundations applicable across oncology, advanced translational capabilities, and ecosystem-level functions supporting emerging therapeutic development. Beyond ensuring patient safety and high-quality trial conduct, modern Phase I units should integrate translational research, artificial intelligence-enabled and model-informed drug development, regulatory science, and public engagement, while specialized centers may additionally support advanced therapy infrastructure, such as point-of-care manufacturing. Recognizing the diversity of institutional resources, we further propose a collaborative network model to facilitate scalable implementation and international harmonization. This framework positions Phase I units as integrated platforms connecting clinical investigation, translational science, regulatory innovation, and emerging therapy development, providing practical guidance for building future-ready early-phase clinical research infrastructure worldwide.
    Keywords:  Adoptive cell therapy - ACT; Biomarker; Cytokine release syndrome; Education; Immune related adverse event - irAE
    DOI:  https://doi.org/10.1136/jitc-2026-015615
  27. Front Immunol. 2026 ;17 1878099
    Establishment of a scalable engineered cell-line platform for direct, GMP-grade production of eVLP vectors enabling streamlined generation of gene-edited CAR-T/NK cells.
    Wei Lin, Jiaru Shi, Hanyi Chen, Ruikai Chai, Sha Zhu, Lili Chen, Shengshui Mo, Zhengbo Wang, Huaxiu Li, Yaru Feng, Lijun Zhao, Junhui Chen, Guohua Yu, Tao Lu, Jianxun Wang.
       Introduction: CRISPR-Cas9 has transformed the engineering of chimeric antigen receptor T (CAR-T) cells and chimeric antigen receptor NK (CAR-NK) cells; however, its clinical translation remains constrained by the high cost, batch-to-batch variability, and stringent regulatory requirements associated with current viral and electroporation-based manufacturing approaches.
    Methods: We report an industrial-grade platform based on monoclonal producer cell lines that enables the continuous and scalable generation of engineered virus-like particles (eVLPs) co-packaging Cas9-gRNA ribonucleoproteins (RNPs). A progenitor cell line was established by stably integrating three core modules-Gag-Pol, Gag-Cas9, and the baboon endogenous virus (BaEV) envelope-into a single HEK293T clone. Introduction of a self-inactivating (SIN) retroviral vector encoding the gRNA cassette (exemplified here by CD7) converted this progenitor into a dedicated eVLP producer within 10 days.
    Results: Using this platform, we generated CD7-knockout CAR-T/NK cells that retained robust in vitro cytotoxicity, confirming preserved functional activity. Owing to its modular architecture, the platform is readily extensible. For example, integration with Recombinant Adeno-associated Virus (rAAV) donor templates enables site-specific CAR insertion, while multiplexed eVLP cocktails allow simultaneous disruption of multiple genomic loci.
    Discussion: It is worth noting that this workflow eliminates the need for electroporation, reduces serum dependency, and significantly lowers the cost of reagent consumables. Collectively, this system provides a GMP-compliant and broadly adaptable strategy for the streamlined manufacturing of next-generation autologous and allogeneic gene-edited CAR-T/NK therapies.
    Keywords:  gene-edited CAR-NK therapy; gene-edited CAR-T therapy; large-scale eVLP preparation; scalable engineered cell-line; self-inactivating retrovirus
    DOI:  https://doi.org/10.3389/fimmu.2026.1878099
  28. Cancer Treat Res Commun. 2026 Aug 10. pii: S2468-2942(26)00269-8. [Epub ahead of print]48 101358
    Neoantigen cancer vaccines in the mRNA Era: antigen selection, platform engineering, and clinical translation.
    Minglu Ge, Ning Wu.
      Neoantigen vaccines have become a central direction in precision cancer immunotherapy because they aim to target tumor-specific peptide sequences generated by somatic alterations rather than self-antigens shared with normal tissues. This biological distinction reduces the barrier of central tolerance and creates a rational basis for individualized T-cell priming. The field has also changed technically. Tumor-normal sequencing, transcriptomic filtering, HLA typing, immunopeptidomics, and algorithmic prioritization now make it possible to move from a patient tumor sample to a ranked set of candidate vaccine targets within a clinically meaningful interval. Because durable vaccine responses frequently depend on CD4-positive T-cell help, we also give explicit attention to HLA class II prediction, which remains substantially less accurate than class I prediction. Among available delivery formats, mRNA platforms have become especially important because they can encode multiple patient-specific epitopes in a single product and can be redesigned rapidly as prediction and delivery methods improve, although synthetic long peptide, dendritic cell, viral vector, and DNA platforms retain specific advantages that we compare directly. This review re-examines neoantigen vaccines as a translational system rather than as a single technology. We first outline the biological basis of neoantigen recognition and classify the major antigen sources. We then discuss target discovery, HLA-restricted presentation, computational ranking, immunopeptidomic evidence, and functional validation. Next, we compare vaccine platforms, with particular emphasis on why personalized mRNA vaccines now dominate late-stage clinical development. Finally, we analyze current clinical evidence in melanoma, pancreatic ductal adenocarcinoma, renal cell carcinoma, glioblastoma, and other solid tumors-reporting primary efficacy endpoints, hazard ratios, patient numbers, and follow-up durations where available-and we identify the main barriers that still prevent broad clinical implementation. In our assessment-offered as an expert interpretation rather than as a conclusion derived from comparative or pooled analyses, because the supporting evidence still rests largely on single-arm and early-phase trials in heterogeneous tumor types-the strongest current signal supports use in adjuvant, perioperative, and minimal residual disease settings, usually in combination with checkpoint blockade or other immune-modifying strategies. Neoantigen vaccination is unlikely to become a universal standalone therapy. Its more realistic value is as a programmable immune-priming component within precision oncology.
    Keywords:  CD4+ T-cell help; Cancer immunotherapy; DNA vaccine; HLA; HLA class II; Immunopeptidomics; Neoantigen vaccine; Personalized cancer vaccine; Tumor immunology; mRNA vaccine
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101358
  29. Lancet Reg Health Eur. 2026 Sep;68 101778
    Rebalancing innovation, affordability, and access for orphan drugs in the European Union.
    Hilde Stevens, Georges Siotis, Micael Castanheira, Mathias Dewatripont, Sanae Akodad, Sam Daems, Alain Fischer, Michel Goldman.
      Orphan drug policy in the European Union faces a double price-and-innovation gap: a small fraction of rare diseases receive important resources while the overwhelming majority are under- or un-researched, leaving most rare disease patients facing high unmet medical needs. The European Commission's reform proposals, notably the Pharma Package and the European Biotech Act, seek to rebalance incentives by adjusting market exclusivity. We argue that, while these reforms move in the right direction, they are insufficient to foster meaningful innovation while safeguarding affordability, and that a broader, more structural approach is needed. We show how proposals from the Draghi Report could complement the reforms through an EU-level HTA Coordination Office, a US-style EU ARPA-H, and expanded regulatory sandboxing. We then propose two additional instruments: public-private Special Purpose Vehicles to de-risk high-need innovation, and EU-level joint procurement to strengthen affordability and create predictable demand. Ultimately, only a coherent, well-calibrated framework can align industrial policy with the EU's ambition of leaving no rare-disease patient behind.
    Keywords:  Access; Affordability; Draghi Report; Drug pricing; EU Biotech Act; EU Pharma Package reform; Innovation incentives; Market exclusivity; Orphan medicinal products (OMPs); Policy; Rare diseases; Regulation
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101778
  30. Transplant Cell Ther. 2026 Aug 12. pii: S2666-6367(26)00613-5. [Epub ahead of print]
    Challenges with expansion of cell and gene therapy: A call for system-level action.
    Jeffery J Auletta, Alvaro Urbano-Ispizua, Richard T Maziarz, Bronwen E Shaw, Anna Sureda, Sumithra Vasu, David L Porter.
      Cellular and gene therapy (CGT) has fundamentally reshaped the treatment landscape for a growing range of malignant and non-malignant diseases. Yet the rapid expansion of CGT has also exposed critical institutional and system-level pressures, including constraints in infrastructure and workforce capacity, product manufacturing, patient access, regulatory and data reporting compliance, and long-term healthcare affordability and sustainability. These opportunities and challenges framed the joint plenary session sponsored by the American Society for Transplantation and Cellular Therapy (ASTCT), the Center for International Blood and Marrow Transplant Research (CIBMTR), and the European Society for Blood and Marrow Transplantation (EBMT) at the 2026 ASTCT-CIBMTR Tandem Meetings. This proceedings manuscript summarizes the key challenges inherent to CGT expansion, identifies priority areas for coordinated action, and issues a call to the field to address these needs with urgency and shared commitment.
    Keywords:  Access; allogeneic hematopoietic cell transplantation; cell therapy; chimeric antigen receptor T-cell; gene therapy; real-world data; workforce constraints
    DOI:  https://doi.org/10.1016/j.jtct.2026.08.010
  31. J Invest Dermatol. 2026 Aug 15. pii: S0022-202X(26)01220-0. [Epub ahead of print]
    Regulatory T cells: From Foxp3 to tolerance-inducing therapies.
    Hisato Iriki, Miho Mukai, Hayato Takahashi, Masayuki Amagai.
      The immune system balances self-tolerance and threat defense; regulatory T cells (Tregs) enforce this equilibrium. This review follows their journey from the disputed suppressor T-cell era to the Foxp3-defined lineage and then integrates how Tregs recalibrate antigen-presenting cells and cytokine networks to sustain immune quiescence and restore homeostasis. These insights shape emerging therapies that expand endogenous Tregs in vivo with low-dose IL-2 or employ ex vivo-engineered cells to re-establish immune balance. We conclude by outlining key challenges-stability, tissue targeting, and scalability-for durable tolerance and therapeutic applications of recently clarified Treg-mediated tissue-specific homeostasis.
    Keywords:  Foxp3; Immune tolerance; Immunotherapy; Regulatory T cells; Regulatory T-cell therapy
    DOI:  https://doi.org/10.1016/j.jid.2026.05.009
  32. Blood Cancer Discov. 2026 Aug 11. OF1-OF23
    Predictive Models for Toxicities after CAR T-cell Therapy: Challenges and Opportunities.
    Julie Ma, August Culbert, Tian-Gen Chang, Mark L Solter, Eytan Ruppin, Kai Rejeski, Nirali N Shah.
      Chimeric antigen receptor (CAR) T-cell therapy is increasingly utilized with expanding indications beyond hematologic malignancies. Here, we review existing models developed for predicting toxicities in the CAR T-cell setting and identify both strengths and challenges emerging with their application. Predictive modeling approaches offer potential to guide risk stratification and inform clinical decision-making, but small sample sizes, overfitting, and poor data quality have limited model reproducibility and widespread adoption. As utilization of CAR T-cell therapy broadens, identifying additional biomarkers, developing context-specific models, standardizing guidelines for emerging toxicities, and leveraging federated learning to promote collaborative data sharing will be critical.
    SIGNIFICANCE: Predictive models integrating biomarkers and clinical variables are increasingly used to forecast potential toxicities after CAR T-cell therapy. However, due to heterogeneity in patient populations and cellular therapy products, the rapidly evolving nature of the field, and continued advancements in management of inflammatory toxicities, modeling in CAR T-cell therapy faces significant challenges. This comprehensive review of existing/emerging models serves to delineate components of developing predictive models including discrimination, calibration, biomarker integration, validation, and mitigation of overfitting while highlighting strengths, opportunities for improvement, and future directions applicable to CAR T-cell therapy.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0458
  33. J Clin Epidemiol. 2026 Aug 11. pii: S0895-4356(26)00334-3. [Epub ahead of print] 112458
    The Erosion of Proof in Paradigm Transitions: The Rise of Narrative Rationality in Health Technology Assessment.
    Jean-Christophe Lega, Arthur Gougeon, Claudina Michal, Steeve Provencher, Florian Naudet, Bruno Falissard, Sylvie Chevret, Remy Boussageon.
       OBJECTIVE: To describe and characterize three partly coexisting evidentiary configurations in drug regulation and health technology assessment (HTA), and to examine the inferential consequences of the progressive shift from replication-based to coherence-oriented standards of proof.
    STUDY DESIGN AND SETTING: Conceptual and methodological commentary drawing on regulatory history, published methodological and epidemiological literature, documented empirical trends in regulatory approval patterns, and illustrative regulatory cases. Three evidentiary configurations are formally defined and compared: the two-trial paradigm, the one-trial paradigm, and a narrative regime characterized by coherence-based justification when independent experimental replication is limited or absent.
    RESULTS: The two-trial paradigm emerged from the post-Kefauver-Harris regulatory emphasis on adequate and well-controlled investigations and was consolidated in U.S. FDA regulatory practice in the late 1980s and 1990s. Under realistic prior assumptions, this configuration may yield a posterior probability of false positive finding (PPFP) of approximately 0.3%. The one-trial paradigm was further legitimized by the FDA Modernization Act (1997), which allowed one adequate and well-controlled trial to be supported by confirmatory evidence, with estimated PPFPs of approximately 4-9% under comparable assumptions. A third configuration, here termed the narrative regime, has expanded progressively through accelerated approval pathways, surrogate endpoint reliance, single-arm trial designs, external controls, real-world evidence, and extrapolation strategies; under this configuration, PPFP may increase further (potentially >15-20%), depending on the prior probability, endpoint validity, and study design. Published trends document a decline in FDA approvals supported by at least two pivotal randomized trials, from 80.6% in 1995-1997 to 52.8% in 2015-2017. The development pathway of subcutaneous belimumab in pediatric systemic lupus erythematosus illustrates how replication-based evidence may be supplemented by pharmacokinetic bridging and extrapolation in selected settings. Regulatory agencies, HTA bodies, and guideline-development organizations operate under partly distinct institutional mandates and apply these configurations with different evidentiary thresholds and decision purposes.
    CONCLUSION: Maintaining the critical function of HTA requires flexible evidentiary frameworks to preserve independent comparative evaluation, analytical transparency, and explicit management of uncertainty. Without such safeguards, coherence-based inference may shift evidentiary standards toward plausibility and institutional acceptability rather than empirical testing. This shift should therefore be understood as a transformation in evidentiary standards, not merely as a technical adaptation of study designs.
    DOI:  https://doi.org/10.1016/j.jclinepi.2026.112458
  34. Am J Bioeth. 2026 Aug 11. 1-16
    Drug Discovery's Blind Spot: Why Organoid-Artificial Intelligence Convergence Demands Integrated Governance.
    Johnny Sakr.
      Organoid-artificial intelligence (AI) platforms are increasingly central to drug discovery, yet they sit between two governance regimes. AI frameworks presume stable, well-characterized inputs, while organoid ethics focuses on donor consent, moral status, and tissue use, leaving downstream computational uses of organoid-derived data underregulated. This article argues that the convergence of living biological variability with algorithmic decision-making creates a governance vacuum in high-stakes preclinical contexts. The organoid-AI case is distinctive because two mature governance traditions, built on incompatible assumptions, intersect at a decision-critical point, and because organoid-derived biological states are transient and often irrecoverable. The article maps the structural causes of this gap, illustrates its practical consequences through three failure scenarios assessing likely probability and impact, and proposes an integrated two-pillar framework: graduated AI validation indexed to organoid functional complexity and tamper-resistant audit trails linking biological and algorithmic metadata. It concludes that proactive governance is morally preferable to delayed, crisis-driven regulation.
    Keywords:  Organoid governance; artificial intelligence; bioethics; drug discovery; preclinical accountability; regulatory science
    DOI:  https://doi.org/10.1080/15265161.2026.2710282
  35. Int Immunopharmacol. 2026 Aug 12. pii: S1567-5769(26)01117-3. [Epub ahead of print]187 117271
    Cancer immunotherapy under immune pressure: Mechanisms of resistance and the shift toward precision immune engineering.
    Muneera Anwer.
      Cancer immunotherapy has transformed the treatment landscape across multiple malignancies; however, durable responses remain limited to a subset of patients due to the emergence of intrinsic and acquired resistance. Increasing evidence suggests that therapeutic immune pressure itself acts as a selective force that shapes tumour evolution, driving the outgrowth of resistant clones. In this review, we synthesise current understanding of the molecular and cellular mechanisms underlying resistance to major immunotherapeutic modalities, including immune checkpoint inhibitors, adoptive cell therapies, and cancer vaccines. We discuss tumour-intrinsic alterations such as defects in antigen presentation and immune signalling pathways, alongside tumour-extrinsic factors including immunosuppressive cell populations, metabolic constraints, and microbiome-mediated modulation. We further examine how these mechanisms converge within the tumour microenvironment to limit therapeutic efficacy. Emerging strategies to overcome resistance are highlighted, including rational combination therapies, next-generation engineered cellular platforms, and precision-guided approaches enabled by multi-omics profiling and artificial intelligence. Collectively, we propose that resistance should be understood as an adaptive consequence of therapeutic immune pressure. Building upon the principles of cancer immunoediting, we discuss how precision immune engineering, the rational design of personalised immunotherapeutic strategies informed by tumour biology, immune context, and predictive biomarkers, may be used to anticipate and overcome evolutionary escape mechanisms.
    Keywords:  CAR-T cell therapy; Cancer vaccines; Combination therapy; Immune checkpoint inhibitors; Immune resistance; Precision oncology; Tumour evolution; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2026.117271
  36. Biochim Biophys Acta Mol Basis Dis. 2026 Aug 04. pii: S0925-4439(26)00258-9. [Epub ahead of print]1873(1): 168395
    Microbial influence on tryptophan metabolism in tumors:Mechanisms and potential clinical applications.
    Rui Yang, Kaikai He, Yan Yang, Lisong Teng.
      Tryptophan (Trp) metabolism represents a major biochemical interface between the gut microbiota, host immunity, and tumor biology. Trp is metabolized through three interconnected routes: the kynurenine (Kyn) pathway, mainly regulated by indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2); the serotonin/5-hydroxytryptamine (5-HT) pathway; and the microbial indole derivative pathway. These metabolites regulate tumor development through multiple mechanisms, including aryl hydrocarbon receptor (AhR) activation, epithelial barrier modulation, immune checkpoint regulation, tumor-associated macrophage polarization, cytotoxic T-cell dysfunction, and treatment response. Importantly, Trp metabolites may exert either tumor-promoting or tumor-suppressive effects depending on microbial composition, metabolite concentration, receptor usage, immune contexture, tumor type, and therapeutic setting. In this review, we summarize recent advances in host- and microbiota-derived Trp metabolism, discuss mechanistic differences between Kyn-AhR and indole-AhR signaling, and critically evaluate therapeutic strategies targeting IDO1/TDO2, microbial metabolites, probiotics, diet, chemotherapy, and immune checkpoint blockade. We also highlight unresolved issues, including causality in microbiome studies, gut versus intratumoral microbiota, biomarker-guided patient selection, and the context-dependent nature of AhR signaling. Collectively, these findings support the concept that tryptophan metabolism functions as a context-dependent host-microbiota co-regulated network, and that its precise modulation may provide novel opportunities for biomarker-guided and mechanism-based cancer therapy.
    Keywords:  Cancer; Indole; Kynurenine; Microbiome; Tryptophan metabolism
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168395
  37. Drug Deliv. 2026 Dec 31. 33(1): 2716510
    Targeted delivery of mRNA to immune cells for in vivo cell therapy.
    Danyang Wang, Yumin Li, Jinfeng Deng, Mengxin Li, Lin-Ping Wu.
      Messenger RNA (mRNA) therapeutics have revolutionized biomedicine by enabling direct in vivo programming of immune cells. This strategy bypasses the complex manufacturing and high costs associated with ex vivo cell therapies. However, efficient and specific systemic delivery of mRNA to target immune cell subsets remains a major translational hurdle. This review systematically examines engineering strategies that address this challenge. We first outline the key biological barriers to mRNA delivery, such as serum instability, nonspecific biodistribution, cellular uptake heterogeneity, and inefficient endosomal escape. Next, we comprehensively review advances in lipid nanoparticle (LNP) engineering, including discovering novel lipids, modulating compositions, conjugating targeting ligands, and incorporating stimuli-responsive elements, to enable enhanced tropism toward specific immune cells. Representative applications in oncology, protein replacement, autoimmune disease, and tissue regeneration are highlighted. Finally, we address translational challenges in safety, scalable manufacturing, and regulatory issues. The integration of rational material design, high-throughput screening, artificial intelligence, and interdisciplinary collaboration will be essential to advance next-generation targeted in vivo mRNA cell therapies toward clinical translation.
    Keywords:  CAR-T; Targeted mRNA delivery; immune cell programming; in vivo cell therapy; lipid nanoparticles
    DOI:  https://doi.org/10.1080/10717544.2026.2716510
  38. Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag186
    A fluorescein-conjugated somatostatin receptor antagonist adapter for chimeric antigen receptor T cell therapy of meningioma.
    Jiawei Chen, Christian Pellegrino, Maximilian Mastall, Frank Szulzewsky, Mitchell Bijnen, Hannah J Van Hove, Nicholas Favalli, Gabriele Bassi, Vlad Moisoiu, Flavio Vasella, Luis Padevit, Marian C Neidert, Allison Shelbourn, Patrick J Cimino, Regina Reimann, Patrick Roth, Markus G Manz, Melanie Greter, Eric C Holland, Dario Neri, Michael Weller, Hans-Georg Wirsching.
       Background: A significant proportion of meningiomas are resistant to current treatments. Somatostatin receptor 2 (SSTR2) is highly and consistently expressed in most meningiomas, providing a promising target for localized chimeric antigen receptor (CAR)-T cell therapy. Short-lived small-molecule CAR adapters can potentially prevent CAR-T cell exhaustion in solid tumors by alternating between active and resting states.
    Methods: We developed the CAR adapter peptide Octofluo, which combines fluorescein-5-isothiocyanate (FITC) with a high-avidity SSTR2 antagonist. After determining its biodistribution, killing efficiency of CAR-T cells plus Octofluo against human meningioma was evaluated in vitro and ex vivo. Therapeutic capacity was assessed in vivo against xenograft and syngeneic genetically engineered mouse meningioma models.
    Results: We herein demonstrate rapid tissue diffusion and transient tumor persistence for only a few hours after intravenous administration of Octofluo, making a suitable switch for on-demand CAR-T cell activation. Nanomolar concentrations of Octofluo effectively directed FITC-specific CAR-T cells against SSTR2-expressing meningioma cells. Combined intratumoral CAR-T cell delivery and intravenous octofluo infusion at periodic intervals showed limited efficacy in an immunocompromised xenograft model but cured most mice with an intact immune system harboring highly aggressive, genetically induced higher grade meningiomas. Cures were accompanied by CAR-T cell expansion and an endogenous T cell response, suggesting a role for the host immune system in tumor elimination. Ex vivo lysis of patient-derived meningioma cells was observed.
    Conclusions: The combination of systemic octofluo administration and locally applied CAR-T cells is a promising strategy for future clinical development for patients with refractory meningiomas.
    Keywords:  CAR-T cells; brain tumor; cancer immunotherapy; genetically engineered meningioma mouse model
    DOI:  https://doi.org/10.1093/noajnl/vdag186
  39. J Investig Med High Impact Case Rep. 2026 Jan-Dec;14:14 23247096261478903
    Encephalopathy Post CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma: Beyond ICANS.
    Rita Ahmad, Mackenzie Wild, Tyler Friesen, Michael Hall, Sammantha Kouba, Seth Maliske.
      Human herpesvirus 6 (HHV-6) reactivation is a rare but serious complication of chimeric antigen receptor T-cell (CAR-T) therapy that can overlap with immune effector cell-associated neurotoxicity syndrome (ICANS) or cytokine release syndrome (CRS), making diagnosis and management challenging. We describe a 68-year-old man with relapsed/refractory IgA kappa multiple myeloma who received multiple prior therapies, including CyBorD, mVRD-lite, Dara-CyBorD, VD-ACE, and KPd, before undergoing lymphodepleting chemotherapy and CAR-T infusion. Early after infusion he developed grade 2 CRS and ICANS that improved with tocilizumab and corticosteroids, followed by recurrent encephalopathy with progressive neurologic decline. Initial infectious evaluation was negative, but repeat cerebrospinal fluid (CSF) and plasma polymerase chain reaction testing revealed HHV-6 reactivation. Antiviral therapy with foscarnet, later switched to ganciclovir, was initiated with corticosteroids and intravenous immunoglobulin. Although repeat CSF testing showed transient viral clearance, neurologic function continued to decline, and brain MRI demonstrated findings consistent with ICANS, including scattered white matter signal abnormalities and dural enhancement. Despite aggressive management, the patient developed multiorgan failure and died. This case illustrates the diagnostic complexity of HHV-6 reactivation during CAR-T therapy, where overlapping clinical and radiologic features with ICANS can obscure recognition; profound immunosuppression from prior treatment and CAR-T-induced immune dysregulation likely predisposed to viral reactivation. HHV-6 reactivation is a critical, underrecognized cause of neurotoxicity after CAR-T therapy, and clinicians should maintain a high index of suspicion in patients with delayed or atypical neurotoxicity, since early virologic testing and prompt antiviral therapy may improve outcomes in this vulnerable population.
    Keywords:  CAR-T therapy; HHV6; ICANS; multiple myeloma
    DOI:  https://doi.org/10.1177/23247096261478903
  40. RSC Med Chem. 2026 Jul 23.
    Closed-loop agentic AI in drug discovery.
    Pranal Chhetri.
      Drug discovery is undergoing a paradigm shift from isolated artificial intelligence (AI) tools to integrated, closed-loop, agent-driven systems that combine prediction with experimental execution. Recent advances in large language models (LLMs), generative frameworks, and self-driving systems are facilitating the emergence of adaptive, multi-agent ecosystems capable of hypothesis generation, iterative optimisation, and autonomous decision-making. Despite this progress, key challenges, including data bias, limited interpretability, coordination fragility, and regulatory misalignment, constrain the translation into reliable clinical outcomes. Here, the evolving landscape of agentic drug discovery is critically examined, illustrating the transition toward hybrid human AI intelligence, digital twins, and regulation-ready autonomous platforms. Resolving these challenges will determine whether the field remains tool-driven or advances into a truly self-evolving scientific enterprise.
    DOI:  https://doi.org/10.1039/d6md00319b
  41. Expert Rev Clin Immunol. 2026 Aug 11.
    Lamotrigine and other therapy-associated HLH syndromes: a review.
    Yaswanta K Gummadi, Ashley Sutherland, Steven Rowe, Luke Y C Chen.
       INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation that can occur secondary to medical interventions including immunomodulatory therapies such as immune checkpoint inhibitors and stem cell transplantation. However, lamotrigine and other anti-seizure medications (ASMs), which are not thought of as overtly immunogenic, are an important emerging cause and exploring the pathophysiology of lamotrigine-associated HLH may improve our understanding of secondary HLH.
    AREAS COVERED: We completed a literature search in EMBASE and MEDLINE for English language articles indexed between 1 January 1966, and 31 August 2025. We review the current understanding of the diagnosis and pathophysiology of known causes of immunomodulatory therapy-associated HLH including chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint inhibitors. We then discuss the clinical overlap between ASM-induced HLH & drug-induced hypersensitivity syndrome (DIHS) and explore underlying immune pathophysiology including mechanisms and potential contributors including host genetic factors and viral etiologies.
    EXPERT COMMENTARY: Lamotrigine-induced HLH has significant clinical overlap with DIHS, with common features of fever, diffuse skin rash, and multi-organ failure. Further advances in immune profiling of patients with ASM-associated HLH will improve our understanding of the pathogenesis and promote the development of novel immunotherapy agents for the treatment of the condition.
    Keywords:  DRESS; cytokine storm; eosinophilia; herpesviruses; severe cutaneous adverse reaction
    DOI:  https://doi.org/10.1080/1744666X.2026.2718332
  42. Front Pharmacol. 2026 ;17 1896516
    Repurposing mitochondrial-targeting drugs for management of ICANS in CAR T-cell therapy: a novel steroid-sparing approach.
    Atena Zahedi, Onwodi V Ifejeokwu, Shawn P Griffin, Erin A Dean.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory hematologic malignancies. However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains one of the most clinically significant and potentially life-threatening toxicities, limiting the broader applicability of this otherwise promising modality. Current standard-of-care (SOC) management of ICANS relies heavily on corticosteroids, which are not always effective and at high doses and with prolonged exposure may carry substantial risks for infectious complications, steroid-induced hyperglycemia, acute steroid myopathy, and steroid-induced psychosis. Steroid-sparing strategies are thus urgently needed. In this article, we emphasize the role of immune cell activation and mitochondrial dysfunction as a feedforward amplifier of neuroinflammation during ICANS and describe a structured framework for identifying and selecting mitochondrial-targeting drugs suitable for repurposing in ICANS prophylaxis and treatment. These agents are recommended based on mechanistic relevance, central nervous system bioavailability, oncological safety, and translational precedent. We apply this framework to generate a candidate landscape and highlight leflunomide as a prototype example. This work details leflunomide's dihydroorotate dehydrogenase-centered mitochondrial pharmacology, summarizes evidence from adjacent neuroinflammatory disease contexts, and outlines a proposed staged clinical evaluation pathway.
    Keywords:  CAR T-cell therapy; ICANS; drug repurposing; hematologic malignancies; leflunomide; mitochondria; neuroinflammation; steroid-sparing
    DOI:  https://doi.org/10.3389/fphar.2026.1896516
  43. Cancers (Basel). 2026 Aug 05. pii: 2513. [Epub ahead of print]18(15):
    The Great Debate: CAR-T-Cell Therapy Versus Bispecific Antibodies in B-Cell Lymphoma.
    Massimo Martino, Violetta Marafioti, Martina Pitea, Gaetana Porto, Giorgia Policastro, Filippo Antonio Canale, Virginia Naso, Caterina Alati.
      Background: The treatment paradigm for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 × CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended.
    Keywords:  CAR-T-cell therapy; axicabtagene ciloleucel; bispecific antibodies; diffuse large B-cell lymphoma; epcoritamab; glofitamab; lisocabtagene maraleucel; relapsed/refractory lymphoma; second-line therapy; third-line therapy
    DOI:  https://doi.org/10.3390/cancers18152513
  44. Front Immunol. 2026 ;17 1831641
    TA-TMA occurring after sequential CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation: a case report.
    Jinlin Zhang, Li Ma, Xiu Liu, Yuxin An, Mohan Zhao, Mengnan Li, Xiaomei Zhang, Jile Liu, Rui Zhang, Mingfeng Zhao.
      Currently, CAR-T cell therapy bridging to allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a pivotal therapeutic strategy for refractory/relapsed hematologic malignancies. Sequential therapy with CD7 chimeric antigen receptor T (CAR-T) cells combined with allo-HSCT provides a novel therapeutic approach for T-lymphoid malignancies, CD7-highly expressed acute myeloid leukemia (AML), and mixed phenotype acute leukemia (MPAL). This strategy circumvents the toxicities of conventional myeloablative conditioning chemotherapy and immunosuppressive agents, while achieving tumor eradication, hematopoietic reconstitution, and prevention of graft-versus-host disease (GVHD). Transplant-associated thrombotic microangiopathy (TA-TMA) is a rare but life-threatening complication following allo-HSCT, associated with elevated non-relapse mortality (NRM). This article reports a case of early-onset TA-TMA in a patient with MPAL after CD7 CAR-T bridging to allo-HSCT. This study aims to enhance clinicians' awareness of the diagnosis and management of TA-TMA following CAR-T bridging to allo-HSCT, provide a reference for early identification and timely intervention, and further improve patient outcomes.
    Keywords:  CD7 CAR-T cells; allogeneic hematopoietic stem cell transplantation; eculizumab; mixed phenotype acute leukemia; transplant-associated thrombotic microangiopathy
    DOI:  https://doi.org/10.3389/fimmu.2026.1831641
  45. J Vet Sci. 2026 Jul;27(4): e47
    Optimized ex vivo expansion and functional characterization of canine natural killer cells using genetically modified feeder cells.
    Yurim An, Geun-Seop Kim, YeonJu Baek, Jae-Hee Park, Jeong Won Hong, Phuoc Quang Huy Nguyen, Sang-Ki Kim.
       IMPORTANCE: Natural killer (NK) cells are critical effectors of innate immune surveillance and can eliminate malignant cells without prior sensitization. Given the biological and genetic parallels between canine and human cancers, NK cell-based immunotherapies have strong translational potential in veterinary oncology. However, the lack of an efficient and reproducible ex vivo expansion protocol for canine NK cells remains a major barrier to clinical application. Establishing culture conditions for expansion of functional canine NK cells would support adoptive NK cell therapy and translational research.
    OBJECTIVE: This study aimed to evaluate the effectiveness of genetically modified feeder cells and optimized culture media in expanding canine NK cells.
    METHODS: Canine peripheral blood mononuclear cells were co-cultured with irradiated genetically modified K562 or ARH77 cells in either RPMI-1640 or Dulbecco's Modified Eagle Medium (DMEM)/F12-based media. NK cell expansion, purity, cytotoxicity and expression of NK cell-associated receptors were evaluated using flow cytometry, cytotoxicity assays, and quantitative reverse transcription polymerase chain reaction.
    RESULTS: The combination of DMEM/F12-based medium and genetically modified ARH77 feeder cells yielded the highest NK cell expansion rate and purity among the tested conditions. Cytotoxicity differed significantly according to medium type, whereas no significant difference was observed between feeder cell types. In addition, the NK cell-associated receptors were significantly upregulated in expanded NK cells.
    CONCLUSIONS AND RELEVANCE: Genetically modified ARH77 feeder cells with DMEM/F12-based culture media demonstrated superior efficiency in promoting the ex vivo expansion of canine NK cells, achieving high purity and enhanced cytotoxic potential. These findings highlight a promising and reproducible platform for generating functional NK cells, offering a practical and scalable strategy to support the development of NK cell-based veterinary immunotherapy.
    Keywords:  ARH77 cells; Dogs; cell manufacturing; cytotoxicity, immunologic; immunotherapy, adoptive
    DOI:  https://doi.org/10.4142/jvs.24345
  46. Nat Rev Immunol. 2026 Aug 10.
    Ferroptosis in T cells: mechanisms, biology and translational opportunities.
    Jingshu Song, Qian Wu, Douglas R Green, Fudi Wang, Junxia Min.
      Ferroptosis is an iron-dependent form of regulated cell death driven by disrupted iron homeostasis and uncontrolled lipid peroxidation. Various metabolites and enzymes regulate cellular sensitivity to ferroptosis by affecting iron, lipid and redox metabolism. These pathways not only signal ferroptotic cell death but also affect the biology of T cells. The pathways include mechanisms by which iron metabolism regulates T cell activation via transferrin receptor 1-mTOR signalling, mechanisms by which lipid peroxidation drives vulnerability to ferroptosis in tumour-infiltrating CD8+ T cells, and mechanisms by which redox networks are balanced to maintain T cell survival. Here, we highlight the T cell subset-specific effects of ferroptosis-related pathways and ferroptosis susceptibility, and the implications for immunotherapy. We also discuss the emerging therapeutic strategies, including ferroptosis-resistant adoptive T cell therapy and ferroptosis-inducing approaches, that enhance the efficacy of immune checkpoint blockade for cancer treatment. Finally, we propose a framework for precision T cell-based immunotherapies, positioning ferroptosis as a tunable node linking T cell biology to clinical innovations.
    DOI:  https://doi.org/10.1038/s41577-026-01337-8
  47. Ann Pharmacother. 2026 Aug 10. 10600280261470829
    Obecabtagene Autoleucel in Relapsed/Refractory B-ALL: A Critical Review of Clinical Efficacy and Safety.
    Emily Hu, Sarah Johnson, Timber Abinsay, Michael Angelo Confiado, Grace Cobb, Kelli Corona, Lauren Carpenter, Jessica Huston.
       OBJECTIVE: This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of obecabtagene autoleucel, summarizing data from pivotal clinical studies and clinical relevance in the treatment of relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (B-ALL).
    DATA SOURCES: A literature review was conducted in PubMed and Clinicaltrials.gov from inception through May 2026, using terms "AUCATZYL®," "obecabtagene autoleucel," "obe-cel," "AUTO1," and "CAR-T cell therapy."
    STUDY SELECTION AND DATA EXTRACTION: Clinical data and studies were limited to those published in the English language which discussed the safety and efficacy of obecabtagene autoleucel.
    DATA SYNTHESIS: Obecabtagene autoleucel (obe-cel) is an autologous CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy using a novel CAT19 single-chain variable fragment designed with an intermediate affinity and fast binding off-rate mechanism. In the pivotal FELIX study, an overall remission rate of 77% was achieved in the primary adult cohort (IIa), with a median event-free survival rate of 11.9 months across all cohorts. Safety data indicate a manageable toxicity profile, and economic models suggest significant cost savings regarding adverse event management.Relevance to Patient Care and Clinical Practice in Comparison to Existing Agents:Obe-cel provides a new treatment option for adults with R/R B-ALL, a population that historically faces poor prognosis and high recurrence rates.
    CONCLUSION: While logistical complexities and high acquisition costs remain an access barrier to CAR-T cell therapies, obe-cel's molecular design and safety profile represent a significant advancement in the care of patients with R/R B-ALL.
    Keywords:  AUCATZYL; AUTO1; CAR-T cell therapy; obe-cel; obecabtagene autoleucel
    DOI:  https://doi.org/10.1177/10600280261470829
  48. Nanoscale. 2026 Aug 11.
    Emerging trends and future outlook towards magnetic nanoparticles as frontiers in cancer immunotherapy.
    Akshay Kumar, Vishal Singh, Kamal Kumar, Nitin Kumar Singhal, Sandeep Kumar.
      Magnetic nanoparticles (MNPs) are becoming significant assets in cancer immunotherapy. Their unique magnetic and surface-functional properties allow them to serve as multifunctional platforms capable of modulating immune responses at multiple levels. MNPs have the potential to enhance immune cell activation and targeting inside the tumor microenvironment. MNPs assist in transporting immune-stimulating agents and tumor antigens directly to antigen-presenting cells. This increases T cell activity and improves anti-tumor reactions. MNPs are additionally utilized to enhance checkpoint blockade and to overcome the immunosuppressive milieu that often hinders the therapeutic efficacy of immunotherapies. In certain preclinical models, MNPs facilitate local hyperthermia to stimulate local immune activation at tumor sites. The magnetic guidance of these nanoparticles also facilitates the delivery of cytotoxic lymphocytes such as CD8 T cells and natural killer (NK) cells to solid tumors, addressing the challenge of poor infiltration of immune effector cells into the tumor. Numerous designs currently integrate therapy with imaging for accurate monitoring of biodistribution. Although MNPs hold potential, challenges remain in terms of biodegradability, long-term biosafety, immune compatibility and clinical applications. This review covers recent advances in MNP-based cancer immunotherapy, including their mechanisms of immune modulation, innovative design strategies, and integration with existing therapies. It also discusses the current limitations and future perspectives that will guide the next generation of magnetically assisted immunotherapeutic platforms toward clinical success.
    DOI:  https://doi.org/10.1039/d6nr01113f
  49. Int Immunopharmacol. 2026 Aug 10. pii: S1567-5769(26)01102-1. [Epub ahead of print]187 117256
    In vivo generation of CD19 CAR T cells for the treatment of mouse systemic lupus erythematosus.
    Haojun Xie, Daxiang Chen, Ziyun Lin, Qi Luo, Wenfang Chen, Guiyang Zhang, Gang Yang, Tingyan Zhou, Tianyang Fu, Zheng Chen, Jing Lu, Zonghong Li, Hongyu Jie, Jinzhong Lin, Zhongfang Wang.
       OBJECTIVE: Systemic lupus erythematosus (SLE) is a severe autoimmune disease with significant health impacts, yet effective therapies remain elusive. Recent advances underscore the promise of chimeric antigen receptor (CAR) T-cell therapy for SLE. However, conventional CAR T cells manufacturing is complex, limiting its clinical application.
    METHODS: To overcome the limitations, we developed an in vivo engineered CAR-T system using CD5-targeted lipid nanoparticles (aCD5-CD19/LNP) delivering CD19-directed CAR mRNA.
    RESULTS: aCD5-CD19/LNP efficiently generates functional CAR T cells capable of targeting CD19+ B cells in vitro. In the MRL/lpr murine SLE model, aCD5-CD19/LNP-generated CAR T cells achieved robust B cell depletion, particularly eliminating pathogenic splenic plasmablasts (CD19+CD20-CD27+) and switched memory B cells (CD19+CD20+CD27+IgD-). This targeted depletion reduced autoreactive antibodies, reduced proinflammatory cytokines, and attenuated histopathological damage in renal and dermal tissues. Critically, this in vivo strategy induced sustained remission without requiring lymphodepletion preconditioning or ex vivo cell manipulation.
    CONCLUSION: Our findings support in vivo-generated CAR T cells as a potentially clinically viable, effective modality for SLE, offering a scalable pathway toward curative immunotherapy.
    Keywords:  CD19; In vivo CAR-T; Lipid nanoparticle; Systemic lupus erythematosus; mRNA
    DOI:  https://doi.org/10.1016/j.intimp.2026.117256
  50. Mol Ther. 2026 Aug 10. pii: S1525-0016(26)00688-X. [Epub ahead of print]
    Lipid Nanoparticles Based Multi-Scale Systemic Immune Programming for Cancer Therapy.
    Xinwen Lin, Yong Li, Xiling Shen, Bowen Li, Yue Xu.
      The clinical reach of cancer immunotherapy is currently limited by off-target toxicity, physical barriers in solid tumors, and the complex manufacturing of personalized cell therapies. This review presents multi-scale systemic immune programming as a transformative approach, in which lipid nanoparticles (LNPs) function not merely as delivery vehicles but as programmable platforms that direct immune responses across biological scales. At the molecular and cellular levels, LNP design and intracellular delivery regulate mRNA stability, translation, and antigen presentation. At the tissue level, intratumoral mRNA delivery reprograms the tumor microenvironment to overcome stromal barriers and immunosuppression. At the systemic level, LNPs coordinate immune responses, including in vivo CAR-T engineering and vaccine-driven immune memory. At the organismal level, liver-targeted LNPs restore metabolic regulators, reverse cachexia, and improve host resilience. Building on this framework, we propose a dual-track therapeutic paradigm that integrates tumor-directed immune activation with host physiological restoration. Together, this approach positions LNP-based therapies to treat cancer as a systemic immune-metabolic disorder rather than a localized disease.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.08.007
  51. Gan To Kagaku Ryoho. 2026 Jun;53(6): 367-372
    [Management of ICANS in Patient Treated with Anti-CD19 CAR T-Cell Therapy].
    Risa Nishiyama, Shinichi Makita.
      Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has been established as a standard of care in selected patients with relapsed or refractory large B-cell lymphoma (LBCL). Unlike conventional cytotoxic chemotherapy, CAR T-cell therapy has unique immune-related adverse events, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Therefore, successful management of these toxicities are crucial for the safe and effective delivery of CAR T-cell therapy. In particular, severe ICANS can be associated with life-threatening complications and poor neurological outcomes. ICANS is thought to develop as a result of excessive cytokine production associated with CAR T-cell activation, as well as on-target/off-tumor effect of CD19 expression. Clinically, it presents with a broad spectrum of neurological manifestations, ranging from mild symptoms such as cognitive impairment and aphasia to severe manifestations including seizures, depressed level of consciousness, and cerebral edema. Because clinical findings are often nonspecific, the diagnosis of ICANS can be challenging. Nevertheless, given its potential for rapid progression, early recognition and careful monitoring are essential for optimal clinical management. With regard to treatment corticosteroids have been the mainstay of treatment for ICANS in Japan. Recently, however, prophylactic and therapeutic interventions using the interleukin-1 receptor antagonist, anakinra, have attracted attention as a novel treatment option, particularly in Western countries. In this review, we summarize the currently available data on ICANS associated with anti-CD19 CAR T-cell therapy, focusing on its pathophysiology, clinical features, diagnostic approach, and management strategies.
  52. Mol Ther Adv. 2026 Sep 10. 34(3): 201810
    Simultaneous gene engineering of T cells with multiple neoantigen-specific T cell receptors for adoptive cell transfer.
    Melinda Magna, Lior Levy, Krisztian Csomos, Aaron J Dinerman, Abraham A Hakim, Noam Levin, Sanghyun P Kim, Nikolaos Zacharakis, Neilesh B Parikh, Brian D Bui, Aarushi Bhasin, Rachel K Beyer, Stephanie L Goff, Frank J Lowery, Steven A Rosenberg, Sri Krishna.
      T cell receptor (TCR) T cell therapy targeting tumor-specific antigens and neoantigens can mediate impressive tumor regressions in solid tumors. However, solid epithelial tumors are characterized by inherent tumor heterogeneity that can lead to tumor escape and thwart TCR T cell therapy. Targeting multiple cancer antigens in a single TCR T product may help overcome the antigen heterogeneity among metastatic deposits. However, the time and expense of preparing multiple TCR-transduced T cell populations under good manufacturing practice (GMP) for patient treatment has limited this approach to target 1 or 2 antigens. Here, we design strategies to enhance TCR T cell therapy efficacy by simultaneously targeting multiple neoantigens. We developed two novel manufacturing processes to introduce multiple neoantigen-specific TCRs into T cells, using gamma-retroviral delivery. These strategies resulted in multipotent neoantigen-reactive TCR T cell products, which demonstrated functionality against multiple tumor neoantigens and displayed cytotoxicity against heterogeneous tumor cells in vitro. High-dimensional single-cell and single-clone T cell analysis confirmed the presence of multiple TCR-expressing T cells in the products and demonstrated functional recognition of multiple neoantigens. This study, thus, addresses the challenges of tumor heterogeneity and immune escape mechanisms in solid tumors, paving the way for more effective TCR T cell therapies in cancer treatment.
    Keywords:  TCR T cell therapy; adoptive cell transfer; cancer; cell therapy manufacturing; engineered T cell; immunotherapy; mutated neoantigens; solid tumor
    DOI:  https://doi.org/10.1016/j.omta.2026.201810
  53. Interdiscip Sci. 2026 Aug 12.
    TransTCR: Integrating TCRs and Transcriptomes Through Optimal Transport for Antigen Specificity Prediction.
    Wenbing Li, Yuansong Zeng, Ruipeng Huang, Yuanze Chen, Jinyun Niu, Ningyuan Shangguan, Siyuan He, Yuedong Yang.
      Recent advances in single-cell immune profiling enable simultaneous measurement of T cell receptors (TCRs) and transcriptomes, offering unprecedented opportunities to characterize adaptive immunity at single-cell resolution. However, the substantial heterogeneity between these modalities poses challenges for effective integration, and existing approaches often rely on simplistic alignment assumptions that may overlook modality-specific biological signals. To address this challenge, we introduce TransTCR, a multimodal learning framework that integrates optimal transport (OT) with contrastive learning to align TCR and transcriptomic representations. Specifically, TransTCR first extracts informative features from each modality using pretrained foundation models, then performs OT-based projection into a shared latent space to achieve distribution-aware alignment. A bidirectional contrastive objective further refines instance-level correspondence by maximizing agreement between the paired TCR-RNA profiles. Extensive experiments demonstrate that TransTCR substantially outperforms existing single-modality and multimodal baselines across antigen specificity recognition tasks, achieving state-of-the-art performance in intra-donor antigen specificity prediction, inter-donor antigen specificity prediction, and clustering evaluations. Overall, TransTCR provides a powerful computational tool for integrating and analyzing multimodal T cell data, facilitating deeper insight into adaptive immune responses.
    Keywords:  Antigen specificity; Multimodal integration; Optimal transport; Single-cell omics; T cell receptor
    DOI:  https://doi.org/10.1007/s12539-026-00865-0
  54. Fundam Clin Pharmacol. 2026 Sep;40(5): e70110
    Redefining Regulatory Proof: The End of the Two-Trial Paradigm.
    Jean-Christophe Lega, Steeve Provencher, Bruno Falissard, Clara Locher, Matthieu Roustit, Arthur Gougeon, Rémy Boussageon, Sylvie Chevret.
      The recent decision to establish a single pivotal trial as the default evidentiary standard for Food and Drug Administration (FDA) approval marks a substantive shift in the architecture of regulatory proof. This marks a shift from replication-based validation to a coherence-based model of sufficiency, beyond a procedural adjustment. Because FDA standards likely influence global development strategies, this change will likely extend beyond the United States. Although accelerating access and reducing development costs are legitimate objectives, the reform raises methodological and epistemological concerns. The statistical rationale does not fully incorporate the contextual factors that influence false-positive risk, including prior plausibility and statistical power. Prior plausibility remains informal, and post-marketing evidence seldom restores the epistemic security provided by independent replication. Replication is not merely a statistical redundancy but rather a structural safeguard of robustness and external validity. Without explicit safeguards, increased regulatory flexibility may generate heterogeneity in evidentiary thresholds and progressively weaken the discriminative function of health technology assessment.
    DOI:  https://doi.org/10.1111/fcp.70110
  55. Drug Discov Today. 2026 Aug 14. pii: S1359-6446(26)00172-8. [Epub ahead of print] 104767
    Model Gateway: Management platform for model-driven drug discovery.
    Yan-Shiun Wu, Sai Mahit Vaddadi, Zachary A Rollins, Nathan A Morin.
      Pharmaceutical drug discovery demands machine learning (ML) infrastructure that goes beyond general-purpose Machine Learning Operations: inference-time composition of multiple models for multiparameter optimization, version management for physics-based models without serialized ML artifacts, enterprise compound library precomputation and governance structured around scientific organizational units rather than generic access controls. No existing commercial or open-source platform simultaneously addresses this full set of requirements. This review presents the Model Gateway, a cloud-based platform for managing ML and scientific computational models across drug discovery pipelines, providing centralized version control, pharma-structured governance, asynchronous execution, consensus model orchestration, automated retraining and a unified application programming interface service for heterogeneous clients, including molecular design suites and large language model agents. In production at Eli Lilly, the platform governs more than 200 deployed models spanning small-molecule, peptide and antibody modalities and serves more than five downstream applications across all phases of the Design-Make-Test-Analyze cycle.
    Keywords:  Generative AI; LLM agent; MLOps; drug discovery; large language models; machine learning; model registry; pharmaceuticals
    DOI:  https://doi.org/10.1016/j.drudis.2026.104767
  56. Nat Mater. 2026 Aug 12.
    An inherent T cell-activating mRNA delivery carrier for in vivo CAR T generation.
    Qiannan Cao, Yingli Yao, Wenming Zheng, Hongqian Liu, Mingxia Jiang, Dayang Xie, Siting Zhang, Pijun Su, Huilin Yuan, Xiaoyuan Chen, Huapan Fang, Huayu Tian.
      The clinical success of chimeric antigen receptor (CAR) T cell therapy requires scalable, non-invasive strategies for in vivo T cell engineering. Although mRNA delivery offers a promising alternative, lipid-nanoparticle-based carriers show limited efficiency for in vivo T cell transfection and typically require antibody conjugation. Here we report an inherent T cell-activating polymer-lipid nanoparticle that enables ligand-free, efficient mRNA transfection and activation of T cells in vivo. This mRNA delivery vehicle, composed of p-toluenesulfonyl arginine (RT)-modified oligoethylenimine-based lipid nanoparticles (ERTLNPs), preferentially mediated mRNA transfection in the spleen following systemic administration. Without exogenous stimulation, ERTLNPs intrinsically activated T cells, triggering robust mRNA expression and proliferation. Mechanistically, ERTLNPs engaged the PI3K/AKT/mTOR signalling axis to reprogram T cell metabolism, promoting expansion and restraining exhaustion. The systemic delivery of mRNA encoding fibroblast activation protein CAR via ERTLNPs contributed to the in situ generation of functional CAR T cells, which efficiently eliminated pathological fibroblasts in models of cancer and fibrosis, with minimal off-target effects. This ligand-free, metabolically reprogramming mRNA delivery system provides a clinically translatable approach for in vivo CAR T cell generation.
    DOI:  https://doi.org/10.1038/s41563-026-02675-7
  57. Exp Mol Med. 2026 Aug 13.
    Take Five: harmonization in personalized cancer vaccines for cancer immunotherapy.
    Seongje Cho, Jisun Lee, Young-Min Lee, Jae-Hwan Nam.
      Precision medicine provides a therapeutic framework that addresses the interindividual diversity in tumor genetics, immunological determinants of disease, and immune responsiveness. Among precision approaches, personalized cancer vaccines (PCVs) have gained attention as a promising strategy for inducing tumor-specific immunity by identifying patient-derived neoantigens. Despite encouraging clinical outcomes, the development of PCVs faces major challenges in optimizing antigen selection, delivery, immune activation, and clinical translation. This Review summarizes current advances in PCV research, covering tumor antigen classification, neoantigen prediction algorithms, and the evolution of delivery technologies such as peptide, dendritic cell, DNA, and mRNA-lipid nanoparticle platforms. We highlight the advantages of mRNA-lipid nanoparticle systems that enable rapid manufacturing, potent antigen expression, and integration with immunostimulatory cytokines. Furthermore, we discuss emerging combination strategies involving cytokine engineering and T cell modulation that provide new opportunities to enhance immunogenicity and therapeutic efficacy. Ultimately, we propose that the future maturation of PCVs will require a coordinated process across five interconnected dimensions: (1) advances in neoantigen prediction technologies, (2) rapid delivery of PCVs to patients, (3) an increase in anticancer efficacy through combination therapy strategies, (4) establishment of cost-effective manufacturing processes, and (5) regulatory innovation. In this Review, we conceptualize this multidimensional alignment as "Take Five," a unifying framework to bring precision, rhythm, and balance to next-generation cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s12276-026-01807-y
  58. Front Cell Infect Microbiol. 2026 ;16 1898807
    The interplay between oncolytic viruses, Toll-like receptor signaling, and chemotherapy in overcoming tumor immune tolerance.
    Yi-Ying Wu, Feng-Hsu Wu, Chen-Yuan Tseng, Pin-Kuan Chiang, Muhammad Muniri, Hung-Jen Liu.
      Oncolytic viruses (OVs) represent a unique therapeutic platform that combines tumor-selective replication with potent immunomodulatory capacity. In addition to direct oncolysis, OVs can convert tumors into inflammatory niches that support antigen release, dendritic cell activation, and cytotoxic T lymphocyte priming. However, durable responses remain inconsistent across tumor types and patient populations, largely due to tumor immune tolerance mechanisms that restrict both viral propagation and the development of effective anti-tumor immunity. Toll-like receptors (TLRs), as key pattern recognition receptors, play central roles in sensing viral nucleic acids and infection-associated danger signals, orchestrating type I interferon responses, NF-κB-driven inflammation, and downstream adaptive immunity. Notably, TLR signaling is a double-edged sword in virotherapy: it can promote antigen presentation and immune activation while simultaneously accelerating antiviral clearance and limiting intratumoral viral spread. Chemotherapy, a mainstay of cancer treatment, further shapes OV efficacy by altering lymphocyte availability, antigen presentation, myeloid composition, and the balance between immunogenic cell death and immunosuppression. Emerging evidence supports that rational OV-chemotherapy combinations can synergize by enhancing tumor antigen release, reprogramming suppressive myeloid compartments, and creating temporal windows for immune checkpoint blockade. In this review, we summarize the mechanisms underlying tumor immune tolerance, discuss how TLR-mediated innate sensing shapes OV-induced anti-tumor immunity, and evaluate how chemotherapy modulates these interactions. We propose mechanistic frameworks and translational considerations including scheduling, biomarkers, and immune monitoring to guide the development of next-generation OV combination strategies in chemotherapy-treated cancer patients.
    Keywords:  Toll-like receptors; chemotherapy; immune tolerance; immunogenic cell death; innate immunity; oncolytic viruses; tumor microenvironment; type I interferon
    DOI:  https://doi.org/10.3389/fcimb.2026.1898807
  59. Front Immunol. 2026 ;17 1878878
    Molecular mechanisms of bacteria-mediated cancer immunotherapy: from intratumoral microbiota to engineered therapeutics.
    Jinhu Guo, Yimeng Li, Yue Yang, Bobo Wang.
      Immunotherapy has redefined oncology, yet its efficacy remains constrained by low response rates, primary or acquired resistance, immune-related toxicities, and escalating costs. Bacteria-mediated cancer immunotherapy (BCIT), which exploits the intratumoral microbiota as a programmable immunotherapeutic platform, has therefore emerged as a promising strategy. Although anecdotal links between infection and tumor regression were documented over four millennia ago, the molecular underpinnings of BCIT have only recently become accessible through synthetic biology, single-cell sequencing, and gnotobiotic modeling. Here we synthesize current knowledge on how intratumoral bacteria either enhance or suppress malignancy via genotoxicity, epigenetic reprogramming, metabolic competition, and modulation of the tumor-immune interface. We dissect cutting-edge engineering approaches-quorum-sensing circuits, thermo-inducible switches, molecular mimicry, and biohybrid microrobots, that convert commensal or attenuated pathogenic strains into precision delivery vehicles for cytokines, checkpoint inhibitors, and neoantigens. Finally, we critically evaluate translational bottlenecks (safety, pharmacokinetics, regulatory science, inter-patient heterogeneity) and propose an AI-guided, microbiome-integrated framework to accelerate clinical translation. This Review provides a conceptual framework for harnessing living therapeutics to convert immunologically "cold" tumors into "hot", therapy-sensitive lesions, and discusses key directions for future microbiome-driven oncology trials.
    Keywords:  bacteria-mediated cancer immunotherapy; cancer; immunotherapy; intratumoral microbiota; tumor-immune interface
    DOI:  https://doi.org/10.3389/fimmu.2026.1878878
  60. Transpl Infect Dis. 2026 Aug 13. e70298
    Cytomegalovirus-Cell-Mediated Immunity Assays for the Prevention and Management of Cytomegalovirus in Transplant Recipients and Patients Receiving Cellular Therapies.
    Elisa Ruiz-Arabi, Madeleine R Heldman, Laurie D Snyder, Oriol Manuel, Eleftheria Kampouri.
      CMV cell-mediated immunity (CMV-CMI) testing has emerged as a promising tool to refine CMV risk stratification and inform prevention strategies in transplant recipients, while recent data assess its role in novel cellular therapies. By identifying patients with robust CMV-specific immune responses, these assays can reduce unnecessary antiviral exposure and support individualized decisions on prophylaxis and preemptive therapy. The strongest evidence comes from the solid organ transplant (SOT) setting, where immune-guided strategies can safely shorten prophylaxis duration, particularly in kidney and lung transplantation. In allogeneic hematopoietic cell transplant (HCT) recipients, CMV-CMI could also guide prophylaxis discontinuation and post-prophylaxis surveillance, although data remain more limited and its added value beyond established clinical markers unclear. In chimeric antigen receptor (CAR)-T-cell therapy recipients, CMV-CMI reaches a nadir at Week 2 post-infusion and recovers by Week 4, defining a window of increased vulnerability during which most CMV reactivation occurs. Assessment at this timepoint may help identify high-risk patients; however, the clinical impact of CMV reactivation, and as a result the need for preventive strategies, remain unclear in this setting. Importantly, the major strength of CMV-CMI lies in its consistently high negative predictive value of robust T-cell responses, while its ability to pinpoint highest-risk patients remains limited. Its widespread use is hindered by assay discordance, limited geographic access, and unproven cost-effectiveness. Despite these limitations, CMV-CMI remains the best-studied strategy for individualized CMV management; further standardization and prospective validation are needed to define its role in increasingly complex immunocompromised populations.
    Keywords:  CAR‐T‐cell therapies; CMV; CMV–CMI; ELISpot; HCT; SOT; cell‐mediated immunity; hematopoietic cell transplant; solid organ transplant
    DOI:  https://doi.org/10.1111/tid.70298
  61. Am J Transplant. 2026 Aug 11. pii: S1600-6135(26)02723-1. [Epub ahead of print]
    Enhancing stability and function of induced regulatory T cells through membrane-anchored transforming growth factor-β1 and interleukin-10 secretion to protect against graft-versus-host disease.
    Shuo Zhang, Ang Li, Xiangrong Li, Sen Li, Xiang Ji, Cuisong Zhu, Chenli Qiu, Xiaoyan Zhang, Jianqing Xu, Shuye Zhang.
      Graft-versus-host disease (GvHD) remains a key challenge in allogeneic transplantation, underscoring the need for effective therapies to establish immune tolerance. Adoptive regulatory T cell therapy shows promise but is restricted by the limited expansion of natural Tregs (nTregs) and the instability of induced Tregs (iTregs). The latter are prone to losing Foxp3 expression and suppressive function in inflammatory microenvironments. Here, we developed membrane-anchored TGF-β1 and IL-10-secreting iTregs (MAT-iTregs), a novel engineered iTreg platform designed to enhance lineage stability and suppressive potency. MAT-iTregs express membrane-anchored TGF-β1 and produce high levels of IL-10 to amplify immunosuppression and maintain functional stability. We optimized construct design and manufacture process to yield highly enriched MAT-iTregs. In preclinical studies, MAT-iTregs outperformed conventional iTregs in safety profiles and therapeutic efficacies. MAT-iTregs significantly prolonged survival, reduced tissue injury, and attenuated pathogenic effector T cell responses in xenogeneic GvHD mice. Notably, MAT-iTregs maintained suppressive function, durable persistence, and a favorable safety profile in mice models, with no evidence of converting to effector T cells and minimal tissue toxicity. Together, these findings support MAT-iTregs as a clinically translatable cell therapy to promote transplant tolerance and improve outcomes in GvHD.
    Keywords:  graft-versus-host disease; induced regulatory T cells; interleukin-10; membrane-anchored TGF-β1
    DOI:  https://doi.org/10.1016/j.ajt.2026.08.003
  62. Cells. 2026 Aug 05. pii: 1422. [Epub ahead of print]15(15):
    Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy.
    Jianing Zhang, Zimei Tang, Yiran Wang, Jiaying Wan, Yajing Zhou, Jiexiao Li, Jie Ming.
      Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of "metabolic siege" on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites-such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids-function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the "metabolism-epigenetics-immunity" axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.
    Keywords:  T cell exhaustion; epigenetic remodeling; immunotherapy; metabolic reprogramming; oncometabolites; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15151422
  63. Front Oncol. 2026 ;16 1869239
    Integrating cryoablation with immunotherapy in non-small cell lung cancer: mechanisms, clinical evidence, and translational barriers.
    Chulan Yang, Xinan Long, Yangyang Ma, Lizhi Niu.
      Despite major advances in targeted therapy and immune checkpoint blockade, advanced NSCLC still has poor long-term outcomes. Only a minority of patients achieve durable benefit, and many eventually experiencing disease progression. Local ablation techniques, particularly cryoablation, directly destroy tumors and remodel the local immune microenvironment by inducing immunogenic cell death and releasing tumor antigens and damage-associated molecular patterns (DAMPs). These processes may contribute to systemic antitumor immunity and are associated with a more inflamed tumor immune microenvironment. This review summarizes the biological mechanisms underlying the potential synergy between cryoablation and immunotherapy, particularly immune checkpoint inhibitors. Cryoablation has been proposed to act as an in situ vaccination strategy by preserving native tumor antigens and enhancing antigen presentation and T-cell priming. These effects may in turn trigger systemic antitumor immune responses beyond the treated site. The article summarizes preclinical and clinical evidence supporting this combined approach. Available studies suggest that cryoablation combined with immunotherapy may improve tumor control and survival outcomes in selected NSCLC settings. However, current clinical evidence remains heterogeneous and is still limited in scale. Finally, we discuss key challenges, including treatment sequencing, biomarker development, technical standardization, and long-term safety, and outline future directions for prospective and biomarker-informed clinical studies. This review highlights the potential role of cryoablation as an adjunct to immunotherapy in selected NSCLC settings, while emphasizing the need for further prospective validation.
    Keywords:  NSCLC; combination therapy; cryoablation; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1869239
  64. Nat Rev Urol. 2026 Aug 11.
    Unconventional T cells in urological cancers: catch them if you can.
    Amber D Bowler, Sylvain Nguyen, Sonia Domingos-Pereira, Ilaria Lucca, Laurent Derré.
      Unconventional T cells - including γδ T cells, mucosal-associated invariant T cells, natural killer T cells, double-positive (CD4⁺CD8⁺) and double-negative (CD4- CD8-) T lymphocytes - are an underexplored component of immune surveillance in urological cancers. Unlike conventional αβ T cells, these populations recognize mainly non-peptidic antigens independently of classic major histocompatibility complex restriction, enabling rapid responses to cellular stress, microbial cues and metabolic dysregulation within tissues and the tumour microenvironment. Emerging evidence suggests that each subset exhibits context-dependent behaviour across prostate cancer, bladder cancer and renal cell carcinoma, ranging from cytotoxic to immunoregulatory. Together, these unconventional T cell subsets offer a foundation for novel diagnostic and therapeutic strategies. Combination approaches currently in clinical trials that integrate checkpoint blockade, adoptive cell transfer or Bacillus Calmette-Guérin-based immunotherapy could be guided by emerging insights into how these cells recognize or are shaped by tumour cells. Research in mechanistic and translational studies involving unconventional T cells is gaining momentum and could ultimately redefine immune targeting in urological cancers.
    DOI:  https://doi.org/10.1038/s41585-026-01178-z
  65. Nat Med. 2026 Aug 10.
    Decade-long persistence of CD19 CAR T cells in B cell lymphomas.
    Luca Paruzzo, Emeline R Chong, Elise A Chong, Zhixuan Zheng, Puneeth Guruprasad, Daniel J Landsburg, Sunita D Nasta, Federico Stella, Ranjani Ramasubramanian, Vitor B de Souza, Mohannad H Alkhatib, Matthew Ho, Antonio Imparato, Gregory M Chen, Don L Siegel, Gabriela Plesa, Anlan Dai, Shane Mackey, Priyamvada Das, Peter Michener, Julie Jadlowsky, Frederic D Bushman, Vrutti Patel, Alberto Carturan, Ellen B Napier, Vanessa E Gonzalez, Danuta Jarocha, Rong Xu, Bruce L Levine, Patrizia Porazzi, Noelle Frey, David L Porter, Jakub Svoboda, Joseph A Fraietta, Carl H June, Stephen J Schuster, Marco Ruella.
      Chimeric antigen receptor (CAR) T cell therapy induces durable remissions in lymphoid malignancies, yet the extent and biology of long-term CAR T cell persistence in B cell lymphoma remain unclear. Here we report the persistence and characteristics of 4-1BB-costimulated anti-CD19 CAR T cells (CART19) up to 10 years after infusion in 38 patients with non-Hodgkin lymphoma. Beyond year five, the CAR19 transgene was detectable in five of eight long-term responders (7.0-10.1 years), with three patients maintaining B cell aplasia, which is consistent with sustained functional activity. In one patient with a progression-free survival of 10.1 years, CART19 cells comprised 1.2% of circulating T cells 9.3 years after infusion. Long-term persisting CART19 cells exhibited a predominant double-negative (CD4-CD8-), effector-memory-like phenotype associated with increased aerobic metabolism and T cell activation programs. Longitudinal profiling revealed a progressive transition from CD8+ to double-negative CAR T cells over time. Persisting CART19 shared transcriptional features with long-term CAR T cells described in acute and chronic leukemias. T cell receptor sequencing demonstrated oligoclonal persistence at 9.3 years, with a dominant clone (70% of CART19 cells) already detectable at low frequency (<0.1%) at day 14. Lentiviral integration-site analysis identified a predominant integration within PACS1 without evidence of known drivers of CAR T cell expansion. These findings demonstrate that CART19 cells can persist for more than 10 years in lymphoma and identify phenotypic, transcriptional and clonal features associated with exceptionally long-term persistence. ClinicalTrials.gov registration: NCT02030834.
    DOI:  https://doi.org/10.1038/s41591-026-04578-1
  66. Int J Mol Sci. 2026 Jul 28. pii: 6755. [Epub ahead of print]27(15):
    Artificial Intelligence and Genomic Data Analysis: New Frontiers in Precision Medicine.
    Alexandra-Maria Blaga, Răzvan-Octavian Mihuț, Andreea-Ramona Treteanu, Octavian Andronic, Ștefan Sebastian Busnatu, Simona Dima, Viorica-Elena Rădoi.
      The rapid expansion of next-generation sequencing technologies has generated unprecedented volumes of genomic data; however, translating these data into reliable and clinically actionable insights remains a major challenge in precision medicine. Artificial intelligence (AI) has emerged as a key enabling technology across the genomic medicine pipeline, supporting variant detection, variant interpretation, polygenic risk prediction, disease subtyping, biomarker discovery and treatment-response modelling. This review provides a clinically oriented, pipeline-based synthesis of contemporary AI applications in genomic medicine. Major computational paradigms, including machine learning, deep learning, ensemble methods, multimodal AI, explainable AI frameworks and emerging foundation models, are discussed in the context of their contribution to genomic analysis and clinical decision support. Particular emphasis is placed on the factors that determine model robustness and clinical utility, including dataset composition, class imbalance, label noise, calibration, ancestry representation, distributional shift and external validation. Evidence from rare genetic disorders, cardiovascular genetics and precision oncology is examined to illustrate both successful translational applications and persistent barriers to implementation. The review further analyses common sources of failure in real-world genomic AI systems, including overfitting, limited transportability across populations and sequencing environments, inadequate interpretability, and insufficient prospective validation. Ethical and regulatory challenges are discussed in relation to clinical accountability, genomic privacy, algorithmic bias and equitable implementation. Ultimately, the successful clinical translation of genomic AI will depend not only on methodological innovation, but also on rigorous validation, transparent reporting, continuous calibration, robust governance and sustained expert oversight.
    Keywords:  AI; artificial intelligence; cancer; genetic variants; genomic biomarkers; precision medicine; variant interpretation
    DOI:  https://doi.org/10.3390/ijms27156755
  67. Front Immunol. 2026 ;17 1891642
    Psychological distress as a putative host-state determinant of cancer immunotherapy response.
    Agnieszka Bronisz, Klaudia Kiel, Jakub Godlewski.
      Cancer immunotherapy has transformed oncology, yet durable benefits remain limited to a subset of patients, and those cases are incompletely explained by tumor-intrinsic biomarkers alone. Growing evidence indicates that the host immune state is a critical contextual determinant of therapeutic response and may itself be shaped by psychological distress. In cancer patients, such distress-related states have been associated with altered neuroendocrine activity and related cortisol regulation, inflammation, reduced natural killer cell function, and broader immune dysregulation. In parallel, preclinical studies show that glucocorticoid and adrenergic signaling can impair antitumor immunity by promoting T-cell dysfunction, metabolic exhaustion, and increased inhibitory signaling, as well as suppressing antigen presentation. Emerging clinical studies in patients receiving immune checkpoint inhibitors further suggest that emotional distress before immunotherapy initiation is associated with poorer progression-free survival, response, and overall survival outcomes in several cancer settings, including non-small-cell lung cancer, gastroesophageal cancer, gastric cancer, and recurrent high-grade glioma. As these patient data remain largely observational, current evidence supports psychological distress as a putative host-state modifier or correlate, rather than as a proven causal determinant, of immunotherapy response. These observations support a psycho-neuro-immune framework in which psychological distress may identify or contribute to a host state that is less permissive for effective immunotherapy. Here, we review evidence linking host immune competence to immunotherapy efficacy, summarize clinical and molecular data connecting distress to immune dysregulation in cancer, and incorporate emerging evidence that brain-body signaling may shape tumor immunity through neural, endocrine, and immune pathways. We propose that psychological distress should be considered not merely as a parallel quality-of-life variable, but as a biologically relevant and clinically verifiable host-state factor with implications for biomarker development and future host-modulation immunotherapy trials.
    Keywords:  cancer immunotherapy; cortisol; host immune state; immune checkpoint inhibitors; neuroimmune signaling; psycho-neuro-immunology; psychological distress
    DOI:  https://doi.org/10.3389/fimmu.2026.1891642
  68. Saudi Pharm J. 2026 Aug 11. pii: 52. [Epub ahead of print]34(4):
    Gut microbiota modulation of systemic immunity and cancer immunotherapy: mechanisms, evidence, and therapeutic implications.
    Bader S Alotaibi.
      The gut microbiota plays a critical role in regulating systemic immune responses and has emerged as a key determinant of therapeutic efficacy and toxicity in cancer immunotherapy. Accumulating evidence indicates that specific microbial taxa and microbiota-derived metabolites modulate antitumor immunity by shaping immune cell maturation, cytokine signaling, and the tumor microenvironment. In particular, gut microbial metabolites such as short-chain fatty acids, bile acids, and inosine influence immune checkpoint inhibitor responses by regulating T-cell activation, dendritic cell function, and immune homeostasis beyond the intestinal compartment. Preclinical and clinical studies have demonstrated that alterations in gut microbiota composition are associated with variability in immunotherapy outcomes, including treatment resistance and immune-related adverse events. Importantly, microbiota-targeted interventions such as dietary modulation, probiotics, prebiotics, antibiotics, and fecal microbiota transplantation have shown promise in enhancing immunotherapy efficacy and reducing toxicity. This review synthesizes current mechanistic insights and clinical evidence linking the gut microbiota to systemic immunity and cancer immunotherapy outcomes, highlighting microbiome modulation as a potential therapeutic adjuvant to optimize immunotherapy response and support precision oncology.
    Keywords:  Cancer immunotherapy; Fecal microbiota transplantation; Gut microbiota; Immune checkpoint inhibitors; Microbiota-derived metabolites; Probiotics; Systemic immunity; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s44446-026-00107-w
  69. Front Med (Lausanne). 2026 ;13 1903811
    Medicine 4.0: the era of revolutionary access.
    Chris Macdonald.
      The evolution of modern healthcare is transitioning from a reactive, disease-centered paradigm (Medicine 2.0) toward a proactive, personalised model focused on maximising healthspan (Medicine 3.0). While this shift represents a vital optimisation of medical philosophy, it remains critically incomplete. This Perspective proposes a new paradigm (Medicine 4.0) which adds a foundational third dimension to the lifespan-healthspan model: radical access to both medical services and scientific ideas. The author analyses how commercial incentives, regulatory frameworks, and market forces frequently distort the production of scientific evidence, marginalise transformative, low-cost treatments, and delay paradigm shifts. Furthermore, the author examines the dual-edged nature of emerging digital health technologies, warning that monetisation through paywalls and engagement-driven ad models risks ossifying existing public health inequalities rather than democratising care. By realigning institutional incentives and dismantling structural obstructions to inquiry, Medicine 4.0 advocates for a return to the foundational Baconian principle that scientific knowledge must serve humanity. Ultimately, the author argues that medical progress must be evaluated not merely by its technological surface area, but by its total societal volume.
    Keywords:  Medicine 3.0; Medicine 4.0; digital health; healthcare access; healthspan; lifespan; personalised medicine; preventive medicine
    DOI:  https://doi.org/10.3389/fmed.2026.1903811
  70. Biotechnol Rep (Amst). 2026 Sep;51 e00974
    Validation of an automated total and viable cell counting for GMP-compliant production of human bone marrow stromal cells.
    Scarlett Desclaux, Narong Chitchongyingcharoen, Chanatat Threeratanah, Chavalwit Soonthronsuk, Sorawut Thamyongkit, Chagriya Kitiyakara, Natnaree Siriwon.
      Bone marrow stromal cells (BMSCs) are classified as Advanced Therapy Medicinal Products (ATMPs) in the subcategory of Cell Therapy Medicinal Products (CTMPs), and the production of these cells for clinical use under good manufacturing practice (GMP) standards is regulated by the European Medicines Agency (EMA). To meet GMP standards for CTMPs, the accuracy and precision of cell-counting methods are essential for monitoring in-process quality and controlling clinical dosing. To achieve this purpose, we validated an automated cell-counting method for evaluating cell concentration and viability, enabling large-scale analysis and reducing analyst-associated variability. Automated cell counting was performed using the LUNA™ automated cell counter, and we validated the parameters against the hemocytometer using the ICH Q2R1 framework. The results showed that automated cell counting yielded acceptable accuracy (90-110%) and RSD (<10%). This demonstrates that LUNA™ automated cell counters may provide an efficient alternative for measuring BMSC cell concentration and viability.
    Keywords:  Automated cell counter; BMSCs; GMP manufacturing; Total cell concentration, viability
    DOI:  https://doi.org/10.1016/j.btre.2026.e00974
  71. Sci Rep. 2026 08 08. pii: 24539. [Epub ahead of print]16(1):
    mRNA-based immunotherapy improves the efficacy of adoptively transferred TCR transgenic T cells in a murine solid tumour model.
    Janna Krueger, Janne J Ruotsalainen, Johannes Lutz, Regina Heidenreich.
      Adoptive T cell therapy (ACT) has shown remarkable clinical success in treating haematological malignancies; however, its efficacy against solid tumours remains limited. This is largely due to poor persistence and functionality of transferred T cells, restricted tumour infiltration, and the presence of an immunosuppressive tumour microenvironment. Here, using the MC38-OVA murine tumour model, we tested whether combining Transgenic T cell receptor (TCRtg) T cell therapy with an adjunctive mRNA-based immunotherapy could address these challenges and drive effective and long-lasting anti-tumour response. Tumour-bearing mice were treated with different numbers of in vivo-activated, ovalbumin (OVA)-specific TCRtg CD8+ T cells harvested from OT-I mice, either alone or in combination with lipid nanoparticle (LNP)-encapsulated mRNA encoding OVA. Tumour progression was monitored, and analyses were performed to assess survival, T cell expansion, phenotype, infiltration, and effector function. The combination therapy of a low dose of TCRtg T cells and mRNA immunotherapy led to robust and durable anti-tumour responses, significantly improving survival compared to monotherapies. Notably, transferred TCRtg T cells expanded only following mRNA immunotherapy, and circulating TCRtg T cells exhibited a memory precursor and effector memory phenotype. These cells infiltrated tumours effectively and displayed more potent cytotoxic activity, resulting in regression of large tumours-even without prior lymphodepletion. Overall, our findings demonstrate that mRNA immunotherapy can substantially enhance the efficacy of TCRtg T cell therapy in a solid tumour model. This combinatorial approach holds promise for overcoming key limitations of ACT by boosting T cell expansion, persistence, infiltration, and functional capacity within the tumour microenvironment.
    Keywords:  Adoptive T cell therapy—ACT; Cancer immunotherapy; Cancer vaccine; Immunotherapy; Transgenic T cell receptor (TCR); mRNA
    DOI:  https://doi.org/10.1038/s41598-026-65120-4
  72. Biotechnol Bioeng. 2026 Aug 12.
    Circular Logic: Engineering Next-Generation Circular RNA Therapeutics for Precision Oncology.
    Amr Ali Mohamed Abdelgawwad El-Sehrawy, Hamzeh J Al-Ameer, Jasur Rizaev, Ihsan K Jasim, Waleed Badrideen Mahmood, Laxmidhar Maharana, Divya Singhal, Neeraj Bainsal.
      The topology of RNA therapeutics is emerging as a critical design dimension in precision oncology. Unlike linear mRNA, circular RNA (circRNA) lacks free ends, conferring exceptional resistance to exonuclease degradation and enabling sustained protein expression for days to weeks. Beyond their use as engineered therapeutics, endogenous circRNAs exhibit cancer-associated expression patterns and persistence in biofluids, supporting complementary roles in tumor biology and as candidate biomarkers for diagnosis and longitudinal disease monitoring. This review argues that circular topology should be viewed as an active pharmacologic variable, not merely a stability enhancement. We dissect recent advances in cap-independent translation initiation, including IRES elements and m6A-driven mechanisms, rolling-circle translation for multi-epitope vaccine design, and programmable stability circuits that integrate tumor-microenvironment cues such as miRNA signatures. Delivery innovations are equally transformative: antibody-guided lipid nanoparticles and engineered extracellular vesicles enable increasingly selective RNA delivery, while local depot formulations and organ-selective systemic routes expand therapeutic reach. Safety considerations are re-evaluated as double-edged tools-innate immunogenicity can serve as a self-adjuvant for cancer vaccines, whereas back-splice-junction neoantigens offer both vaccine opportunities and tolerance risks. Recent advances in scarless circularization, topology-sensitive purification, dsRNA depletion, and lyophilized formulations have begun to address key manufacturing bottlenecks, although clinical-scale recovery and process scalability remain insufficiently characterized. Key applications include circRNA cancer vaccines, transient CAR-T/NK cell engineering, tumor-suppressor replacement, and circRNA-encoded bispecific T-cell engagers. The field now requires real-time pharmacokinetic tracking, reproducible and scalable manufacturing, validated liquid-biopsy assays, and indication-specific regulatory pathways to translate circRNA from bench to bedside.
    Keywords:  RNA‐based cancer immunotherapy; cap‐independent translation; circular RNA therapeutics; non‐viral RNA delivery; precision oncology
    DOI:  https://doi.org/10.1002/bit.70344
  73. Front Artif Intell. 2026 ;9 1870819
    Continuous assurance for AI-driven clinical decision support systems.
    Rami A Al-Horani, Amanuel F Tadesse.
      Healthcare systems are rapidly embedding adaptive and generative AI into core clinical processes. The integration of Artificial Intelligence into Clinical Decision Support Systems (AI-CDSS) highlights a fundamental transformation within healthcare delivery. This transformation enables advanced predictive analytics, multimodal data integration, and real-time augmentation of clinical decisions. However, AI introduces systemic, ethical, operational, and governance risks that challenge traditional healthcare audit and assurance frameworks. In fact, assurance methodologies designed for static software are becoming insufficient for patient safety and regulatory compliance. This review discusses the evolving landscape of AI-CDSS audit, highlighting its transition from a technically focused lifecycle validation to an integrated paradigm centered on socio-technical resilience. Early audit approaches adapted conventional medical device and software validation models to machine learning-enabled clinical tools. While these models established baseline safety oversight, they were not designed to address adaptive algorithms functioning in complex, evolving clinical environments. Modern governance frameworks emphasize continuous performance monitoring, lifecycle surveillance, and structured human oversight. However, a persistent implementation gap remains. Many audit models poorly capture the interactions among algorithmic behavior, clinical workflows, organizational culture, and shifting patient populations. In fact, three major paradigm shifts are reforming the AI-CDSS audit. First, the audit scope is expanding from model-centric evaluation to ecosystem-level assurance that incorporates workflow integration, human-machine collaboration quality, and organizational learning capacity. Second, the field is moving from post-hoc explainability toward reasoning traceability and synergistic clinical sense-making. Third, audit philosophy is shifting from static compliance verification toward resilience-oriented monitoring that focuses on adaptive capacity, graceful degradation, and safe performance evolution. Thus, we propose the STRAICS framework (Socio-Technical Resilience Assurance for Intelligent Clinical Systems), which integrates technical robustness, human-machine interaction safeguards, adaptive governance, and transparency-by-design infrastructure. These components are vital for building trustworthy, effective, and impartial clinical AI ecosystems that can safely manage the increasing complexity of healthcare.
    Keywords:  STRAICS framework; collaborative decision making; continuous assurance; healthcare artificial intelligence; socio-technical resilience
    DOI:  https://doi.org/10.3389/frai.2026.1870819
  74. J Transl Autoimmun. 2026 Dec;13 100391
    Resetting immunometabolic set points in autoimmune disease.
    Xiao Yu, Yidan Zhang, Anquan Shang.
      Autoimmune diseases often persist despite effective suppression of overt inflammation, and many patients experience relapse after treatment tapering or withdrawal. This clinical pattern raises the possibility that disease activity is influenced not only by ongoing immune stimulation, but also by relatively stable biological states that preserve inflammatory potential. In this Review, we propose immunometabolic set points as an integrative framework for examining how immune-cell metabolic programs, tissue metabolic niches, metabolite signaling, and immune or metabolic memory may interact in chronic autoimmune disease. Rather than representing a single pathway or biomarker, an immunometabolic set point is proposed to describe a potentially reversible multicompartment state shaped by immune and tissue interactions. Experimental studies support important roles for cellular metabolism, local nutrient and oxygen conditions, mitochondrial stress, stromal activation, and metabolites such as lactate, succinate, and itaconate in regulating immune function. However, their integration into a unified disease-maintaining state has not been directly established. We therefore distinguish evidence-supported mechanisms from broader conceptual inferences concerning relapse-prone remission and therapeutic reset. We further discuss how longitudinal single-cell profiling, spatial omics, metabolomics, and metabolic flux analysis may be used to test the framework and determine whether treatment produces transient inflammatory suppression or more durable biological reconfiguration.
    Keywords:  Autoimmune disease; Immune tolerance; Immunometabolic set point; Immunometabolism; Metabolic memory; Therapeutic reset
    DOI:  https://doi.org/10.1016/j.jtauto.2026.100391
  75. Front Psychol. 2026 ;17 1892596
    Organizational transitions in awareness: a framework of access, coordination, and regulation.
    Alison King, Darryl Gray.
      Consciousness research often uses overlapping terms such as consciousness, awareness, conscious access, subjective experience, reportability, selfhood, and metacognition. This conceptual compression can make it difficult to distinguish different awareness-related processes or to identify which capacities are preserved, disrupted, or restored across altered states. This paper proposes an organizational framework for distinguishing awareness processes in terms of constrained access, representational coordination, adaptive regulation, and recursive self-modeling. The framework distinguishes three related but partially separable organizational conditions: biological regulation, integrated experiential awareness, and recursive self-modeling. Here, partially separable means that these organizational conditions may overlap and interact while nevertheless exhibiting different patterns of degradation, persistence, or recovery under perturbation. Biological regulation refers to adaptive control and responsiveness that need not involve stable experiential organization. Integrated experiential awareness refers to first-order experiential organization in which sensory, interoceptive, affective, and contextual information is coordinated and stabilized across time. Recursive self-modeling refers to the capacity of a system to represent aspects of its own internal, evaluative, or behavioral states across time. The central hypothesis is that these conditions may show ordered vulnerability across perturbation and recovery. Recursive self-modeling should often be more vulnerable than integrated first-order experiential organization under conditions such as sleep onset, anesthesia, dissociation, depersonalization, neurological disruption, and other altered states, and should often re-emerge later during recovery. This prediction does not require sharp thresholds or fixed natural boundaries. Instead, the proposed conditions are treated as graded transition zones within a multidimensional organizational landscape. The framework is positioned as an organizational crosswalk rather than a replacement for existing theories. Its aim is to clarify relationships between biological regulation, experiential organization, metacognitive accessibility, and recursive self-related processing while generating testable predictions for consciousness research.
    Keywords:  anesthesia; awareness processes; biological regulation; consciousness; integrated experiential awareness; metacognition; ordered vulnerability; recursive self-modeling
    DOI:  https://doi.org/10.3389/fpsyg.2026.1892596
  76. Immunity. 2026 Aug 11. pii: S1074-7613(26)00312-2. [Epub ahead of print]59(8): 2061-2063
    Peripheral vision: Treg cell induction in the gut.
    Taylor A Graham, Peter A Savage.
      Some regulatory T (Treg) cells differentiate at peripheral sites in response to antigens derived from innocuous sources. In this issue of Immunity, Chi et al. examine an extensive array of T cell receptors with specificity for self, microbial, or dietary antigens to define the rules governing peripheral Treg cell differentiation.
    DOI:  https://doi.org/10.1016/j.immuni.2026.07.013
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