bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–08–23
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Irradiated CD19 chimeric antigen receptor YTS cells retain antitumor activity and offer a scalable alternative to autologous CAR-T therapy.
  2. The role of chimeric antigen receptor (CAR) T cell therapy in breast cancer.
  3. Cytokine circuitries as determinants of response, resistance, and toxicity across cancer immunotherapy platforms.
  4. Delivery platforms for in vivo CAR-T engineering.
  5. The spatial revolution in immuno-oncology: artificial intelligence decoding NK cell niches to predict therapeutic response.
  6. In vivo CAR T cells on the highway: a roadmap for the next decade.
  7. Rewiring immunity with in vivo CAR T cell engineering.
  8. Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection.
  9. From pathogen defence to precision health infrastructure: mRNA vaccines beyond infectious disease in preventive health, chronic disease management, and population wellbeing.
  10. Global trends in CAR-T cell therapy for multiple myeloma: A bibliometric analysis, 2013-2025.
  11. Model-Informed Decision Making from Drug Discovery to Reimbursement: A Roadmap for Clinical Pharmacology in Value-Based Healthcare.
  12. Quantum-Augmented Federated AI for Adaptive Pharmacogenomic Precision Oncology: A Perspective.
  13. Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.
  14. Harnessing macrophage signaling pathways and scalable engineering for next-generation immunotherapies.
  15. Long-term outcomes of anti-CD19 CAR T cell therapy in refractory myasthenia gravis: A case series.
  16. CAR-T Cell Therapy-Associated Coagulopathy: From Immunothrombotic Storm Mechanisms to Precision Management Strategies.
  17. Ensuring the quality of in silico evidence: application to medical devices.
  18. R WE ready for reimbursement? A round-up of developments in real-world evidence relating to health technology assessment: part 28.
  19. The Role of the T Cell Receptor Sequence in Shaping T Cell Functional Fate.
  20. Standardized Xenograft Models for Preclinical Cancer Research.
  21. A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia.
  22. In Situ Generation of Claudin18.2-Specific CAR-T Cells via Lipid Nanoparticle-Mediated mRNA Delivery.
  23. CAR T cell-derived TNF is an early determinant of cytokine release syndrome severity.
  24. From digital twins to clinically trustworthy twins: a clinical-claim-based validation framework for personalized digital health.
  25. Emerging trends in nanomedicine: The role of RNAi-based therapies and onpattro's clinical journey.
  26. Chimeric antigen receptor (CAR) therapy in infectious diseases: emerging applications with a focus on invasive fungal infections.
  27. Extracellular vesicles and acetylation: reciprocal regulation in disease progression.
  28. CAR-FIT: CAR-T fitness index for therapy - integrating comorbidity and geriatric assessments to guide safe and equitable delivery of CAR-T in patients with borderline physiological reserve.
  29. T-cell receptor repertoires against HLA class I-restricted minor histocompatibility antigens are highly diverse with a small subset of public clonotypes.
  30. Artificial intelligence agents and agentic artificial intelligence applied to precision medicine.
  31. Management of systemic lupus erythematosus and antiphospholipid syndrome during CAR-T therapy: insights from two clinical cases.
  32. From general-purpose models to purpose-built artificial intelligence systems for health economic modeling.
  33. Calibration of CAR signaling promotes asymmetric cell division to direct CAR-T cell fate and antitumor potency.
  34. Overcoming Resistance to Immune Checkpoint Blockade: Mechanistic Insights and Emerging Therapeutic Directions.
  35. Bispecific antibodies: current advances and future perspectives.
  36. A Comprehensive Review of T-Cell Lymphoma Following CAR T-Cell Immunotherapy.
  37. Analysis of Human Thymopoiesis Reveals Rapid Postnatal Remodeling of Thymocytes Within the First 3 Months of Life.
  38. Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review).
  39. Patient experience data as a methodological and strategic innovation in clinical trial design.
  40. Reprogramming tumor-associated macrophages and interferon-gamma signaling to overcome therapeutic resistance in cancer.
  41. mRNA therapeutics for restoring immune tolerance in autoimmune diseases.
  42. BAFF-R CAR T-cell therapy for relapsed or refractory B-cell lymphomas.
  43. Proposing a Coverage With Evidence Development Framework for Accelerated Approval at the U.S. Food and Drug Administration.
  44. CAR T-cell therapy in cancer treatment: Challenges and nursing perspectives.
  45. Seamless Phase I-II Cancer Clinical Trials Using Kernel-Based Covariate Similarity.
  46. Gene therapy: The current trajectory of clinical and commercial translation.
  47. A survey of transformer and LLM-based architectures, workflows, and systems in drug discovery.
  48. CAR-T Cell Therapy for Glioblastoma: Obstacles and Advances.
  49. Inhibitory receptor states, immune homeostasis and the benefit-risk boundary of cancer checkpoint blockade.
  50. The Neuroimmune Duality of CD4⁺ T Cells: Drivers of Damage and Repair in the Brain.
  51. Emerging therapeutic opportunities targeting nonclassical MHC-I molecules.
  1. Haematologica. 2026 Aug 13.
    Irradiated CD19 chimeric antigen receptor YTS cells retain antitumor activity and offer a scalable alternative to autologous CAR-T therapy.
    Hanan Jaber, Anas Abu Khalaf, Lola Weiss, Itay Cohen, Natali Bannoura, Tamara Osaili, Ortal Maximov, Abigael Eva Chaouat, Mark Kournos, Adi Tabib, Dror Mevorach, Yarden Engel, Michael Berger, Ofer Mandelboim, Shlomo Elias.
      Chimeric antigen receptor (CAR) T cell therapies have revolutionized treatment of hematologic malignancies such as lymphoma and multiple myeloma. However, their success is limited by high manufacturing costs, reliance on autologous T cells, variable product quality, and life-threatening toxicities like cytokine release syndrome. In contrast, natural killer (NK) cells offer a safer, more flexible alternative, but their clinical translation remains constrained by complex expansion protocols and high production costs. Here, we present a transformative approach using the human NK cell line YTS, which is amenable to large-scale culture, genetic manipulation, and cryopreservation. By introducing a CD19-specific CAR into YTS cells, we generate potent effector cells capable of selectively eliminating CD19-expressing targets. We demonstrate that CAR signaling in YTS cells requires intracellular activation and, in certain tumor settings, is enhanced by co-stimulation via the 2B4-CD48 pathway. Importantly, irradiation of YTS-CAR cells prevents proliferation without compromising their cytotoxic function even after freezing and thawing. In preclinical models, injections of irradiated YTS-CAR cells significantly reduced CD19+ tumor burden, underscoring their therapeutic promise. This work positions engineered YTS cells as a novel, scalable, and cost-effective "off-the-shelf" immunotherapy platform suitable for treating refractory leukemias and lymphomas. Future studies will be required to assess safety and to explore applicability to autoimmune diseases and solid tumors.
    DOI:  https://doi.org/10.3324/haematol.2025.300165
  2. Int Immunopharmacol. 2026 Aug 18. pii: S1567-5769(26)01126-4. [Epub ahead of print]188 117280
    The role of chimeric antigen receptor (CAR) T cell therapy in breast cancer.
    Ahmad Farajzadeh, Mahmoud Mahmoudi, Soroush Yazdani, Amir Mohammad Barati, Ramiar Kamal Kheder, OmeFarveh Rostami, Afsane Fadaee, Amene Raouf-Rahmati, Seyed-Alireza Esmaeili.
      Breast cancer is one of the most common malignancies worldwide and remains a leading cause of cancer-related mortality. Over the past decades, advances in multimodal treatment have significantly improved patient survival. However, disease recurrence, metastatic progression, and therapeutic resistance continue to limit long-term outcomes, underscoring the need for more effective therapies. Among emerging immunotherapeutic approaches, chimeric antigen receptor T (CAR-T) cell therapy has attracted considerable attention. CAR-T therapy has achieved remarkable success in hematologic malignancies, prompting its investigation in breast cancer. However, translating this success to solid tumors remains challenging because of fundamental biological differences between hematologic and solid malignancies. Major barriers include antigen heterogeneity, limited tumor trafficking and infiltration, an immunosuppressive tumor microenvironment, and therapy-related toxicities. Numerous preclinical and clinical studies are currently evaluating CAR-T cell therapy in solid tumors, including breast cancer. These efforts incorporate next-generation CAR designs and novel engineering strategies with the goal of reproducing the clinical success achieved in hematologic malignancies. Although the available clinical evidence is still largely limited to early-phase trials, current findings suggest that CAR-T therapy in breast cancer is feasible and generally well tolerated. Most reported adverse events have been low-grade inflammatory toxicities, whereas severe neurotoxicity and dose-limiting toxicities have been infrequent. Despite this favorable safety profile, clinical responses remain modest, with stable disease representing the most common outcome and durable objective responses being uncommon. These findings underscore the need to overcome the major biological barriers that continue to limit CAR-T cell therapy in solid tumors. This review summarizes recent advances in CAR-T cell engineering, discusses the major target antigens investigated to date, provides a comprehensive overview of the available clinical evidence, and examines the key biological and clinical challenges that must be addressed to improve future therapeutic outcomes.
    Keywords:  Breast neoplasms; CAR-T cell therapy; Clinical trials as topic; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2026.117280
  3. Cytokine Growth Factor Rev. 2026 Aug 12. pii: S1359-6101(26)00059-6. [Epub ahead of print]91 110-124
    Cytokine circuitries as determinants of response, resistance, and toxicity across cancer immunotherapy platforms.
    Arpita Mukherjee.
      Cancer immunotherapy has substantially improved the management of solid tumors and hematologic malignancies; however, durable clinical benefit remains limited by primary and acquired therapeutic resistance, immune-related toxicities, and considerable interpatient heterogeneity. Although cytokines, chemokines, and growth factors have been extensively investigated as predictive and prognostic biomarkers, their coordinated functions within dynamic immune networks remain insufficiently integrated into current translational and clinical frameworks. The purpose of this review is to critically evaluate emerging evidence supporting cytokine network dynamics and to introduce adaptive cytokine circuitries as a conceptual framework for understanding how interconnected cytokine signaling regulates therapeutic response, resistance, and toxicity across immune checkpoint blockade, chimeric antigen receptor T-cell therapy, T-cell receptor-engineered therapies, bispecific antibodies, and emerging cellular immunotherapies. Current evidence indicates that cytokine interactions operate through spatially and temporally organized signaling networks that influence T-cell functional states, myeloid cell reprogramming, immune escape, and tissue-specific inflammatory responses, while highlighting important biological uncertainties and the need for prospective clinical validation. The review further examines the translational potential of longitudinal immune monitoring, multiplex cytokine profiling, spatial and single-cell multi-omic technologies, computational network reconstruction, and biomarker-guided patient stratification for precision immunotherapy. Collectively, the available evidence supports a transition from static cytokine measurements toward dynamic cytokine network analysis while underscoring the scientific and clinical challenges that must be addressed before cytokine circuitry-informed strategies can be implemented in precision immuno-oncology.
    Keywords:  Cancer immunotherapy; Cytokine circuitries; Immune-related adverse events; Precision immuno-oncology; Therapeutic resistance
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.07.007
  4. Front Immunol. 2026 ;17 1841160
    Delivery platforms for in vivo CAR-T engineering.
    He Wang, Guangmei Qiao, Ming Ma, Hailong Zhao, Lin Luo, Ting Liu.
      Ex vivo CAR-T changed cancer care, but its made-to-order manufacturing keeps too many patients waiting. In vivo CAR-T takes a different path: deliver the genetic blueprint to a patient's own immune cells and let the body build the therapy. In this review, we compare the leading delivery platforms-retargeted lentiviral vectors, engineered AAVs, LNPs (mRNA/circRNA), polymeric nanoparticles, and bioinspired systems-through the lenses of specificity, expression durability, redosing, manufacturability, immunogenicity, safety, and clinical maturity. Early human observations in hematologic malignancies and autoimmune disease show what's possible; solid-tumor progress is still largely preclinical. Key translational challenges include: off-target transduction and murky biodistribution, liver-skewed exposure for non-viral systems, integration risk for durable vectors, repeat-dose immunity, CMC consistency, and regulatory fit. We outline a practical roadmap-quantitative biodistribution and potency, cargo-tuned persistence, receptor-aware targeting, robust CMC, and indication-specific risk-benefit-to support reproducible and clinically interpretable therapeutic development.
    Keywords:  in situ reprogramming; in vivo CAR-T engineering; mRNA-LNP; next-generation cellular immunotherapy; targeted delivery vectors
    DOI:  https://doi.org/10.3389/fimmu.2026.1841160
  5. Front Immunol. 2026 ;17 1915941
    The spatial revolution in immuno-oncology: artificial intelligence decoding NK cell niches to predict therapeutic response.
    Yun-Qiu Gao, Tong Liu, Yang Yang.
      Natural killer (NK) cells are important effector cells of the innate immune system and have been investigated as a therapeutic platform for cancer immunotherapy. Although NK cell-based therapies have shown clinical activity in hematological malignancies, their application in solid tumors remains limited by restricted tumor infiltration, functional suppression, and the complexity of the tumor microenvironment (TME). Recent advances in spatial transcriptomics and artificial intelligence (AI) have provided new approaches for characterizing NK cell distribution, functional states, and cellular interactions within the TME. Critically, the spatial distribution and structural organization of NK cells within tumor niches - including their proximity to tumor cells, stromal barriers, and immune effector partners - are fundamental determinants of their cytotoxic function. A deeper understanding of how spatial context shapes therapeutic response is therefore central to advancing NK cell immunotherapy. This review summarizes how AI-assisted analysis of spatial and multi-omics data may contribute to the discovery and validation of biomarkers associated with NK cell therapy response. It also discusses the potential applications of AI in optimizing chimeric antigen receptor (CAR)-NK cell engineering, combination therapy strategies, and individualized dosing regimens. By synthesizing studies published in recent years, this review highlights the emerging shift from response prediction toward treatment optimization, while emphasizing the current limitations of available evidence, including model interpretability, data heterogeneity, causal inference, and clinical validation. Finally, we discuss how four-dimensional (4D) dynamic monitoring and explainable AI may support the future development of more precise and personalized NK cell immunotherapy strategies.
    Keywords:  artificial intelligence; biomarkers; natural killer cells; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1915941
  6. Expert Opin Biol Ther. 2026 Aug 21.
    In vivo CAR T cells on the highway: a roadmap for the next decade.
    Markus Barden, Dennis C Harrer, Hinrich Abken.
       INTRODUCTION: Chimeric antigen receptor (CAR) T cell therapy has shown efficacy in the treatment of hematological malignancies. However, the application to a broader patient population is still limited by the complex logistics in coordinating the lymphodepleting chemotherapy and the labor-, time-, and cost-intensive ex vivo manufacturing of patients' CAR T cells in specialized centers. By combining recent advances in lipid nanotechnology, RNA chemistry, and viral particle targeting, engineering CAR T cells in the patient's blood stream is becoming an emerging option that may overcome current limitations. Advanced pre-clinical and early clinical studies support this approach by demonstrating successful engineering of CAR T cells in vivo and producing some anti-tumor responses in clinical trials.
    AREAS COVERED: We review delivery strategies using viral and non-viral vectors, summarize the translation into clinical application, and outline strategies for optimization. We further discuss current challenges with respect to targeting specificity, genomic safety, pharmacokinetics, host immune responses, and regulatory oversight.
    EXPERT OPINION: Although still in its infancy, in vivo genetic engineering shows promise for CAR T cell therapy in a wide range of cancer patients. It also has the potential to reprogram patients' immunity in autoimmunity, chronic infections, and regenerative medicine.
    Keywords:  Chimeric antigen receptor; LNP; T cell; genetic engineering; in vivo gene transfer; nanoparticle
    DOI:  https://doi.org/10.1080/14712598.2026.2722287
  7. Nat Cancer. 2026 Aug 21.
    Rewiring immunity with in vivo CAR T cell engineering.
    Clare Y Slaney, Rachel Xu, Shiyi Wu, Kevin Sek, Colin W Pouton, Michael Dickinson, Michael H Kershaw, Phillip K Darcy.
      Ex vivo engineered chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of certain hematologic malignancies, yet manufacturing complexities and limited patient accessibility constrain its impact. In vivo CAR T cell engineering seeks to overcome these limitations by generating CAR T cells directly within an individual. This Perspective examines the rapidly evolving field of in vivo CAR T cell generation in oncology, outlines principles of lymphocyte targeting, discusses pharmacology and biodistribution and assesses emerging safety issues. We conclude with a translational outlook, highlighting both the opportunities and the outstanding questions that will define the path to clinical implementation.
    DOI:  https://doi.org/10.1038/s43018-026-01216-0
  8. Biochim Biophys Acta Rev Cancer. 2026 Aug 20. pii: S0304-419X(26)00162-9. [Epub ahead of print] 189690
    Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection.
    Lu Ding, Lianfeng Zhao, Mengting Zhang, Tianyu Chen, Zhigang Guo.
      While autologous chimeric antigen receptor (CAR)-T cell therapies have revolutionized the treatment of hematological malignancies, their widespread clinical application remains constrained by lengthy manufacturing cycles, prohibitive costs, and variable patient-derived cell quality. Consequently, "off-the-shelf" universal allogeneic CAR-T cells have emerged as a highly anticipated alternative. However, the clinical translation of these allogeneic therapies faces formidable immunological bottlenecks, principally driven by bidirectional immune rejection: graft-versus-host disease (GVHD) and host-versus-graft rejection (HVGR). To overcome these barriers, multi-tiered immune evasion and engineering strategies are rapidly evolving. This review systematically delineates the mechanisms underlying bidirectional immune rejection and comprehensively summarizes state-of-the-art mitigation strategies. Specifically, we explore how GVHD can be abrogated through gene editing (e.g., TCR knockout), expression blockade, and pharmacological interventions. Conversely, we examine how HVGR is being effectively suppressed via passive immune cloaking, active immune defense mechanisms, and the synergistic remodeling of the host immune microenvironment. Furthermore, we highlight the development of alternative, inherently hypoimmunogenic cell sources as a fundamental approach to circumventing these immunological barriers. Ultimately, this review aims to provide a comprehensive framework and forward-looking reference for translating universal CAR-T cell therapies from conceptual design to broad clinical reality.
    Keywords:  Chimeric antigen receptor T cells (CAR-T); Gene editing; Graft-versus-host disease (GVHD); Host-versus-graft reaction(HVG); Off-the-shelf therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189690
  9. Front Bioeng Biotechnol. 2026 ;14 1869761
    From pathogen defence to precision health infrastructure: mRNA vaccines beyond infectious disease in preventive health, chronic disease management, and population wellbeing.
    Okechukwu Paul-Chima Ugwu, Chinyere Nneoma Ugwu, Godson Emeka Anyanwu, Mariam Basajja.
      Messenger RNA (mRNA) vaccine technology is often portrayed as a pandemic-era innovation for infectious disease control, but this perspective no longer reflects its expanding clinical and societal significance. Although global attention intensified during the SARS-CoV-2 pandemic, mRNA platforms are founded on more than three decades of pre-pandemic research in cancer immunotherapy and experimental vaccinology. Emerging evidence demonstrates that programmable RNA technologies can extend beyond pathogen prevention into oncology, immune modulation, protein replacement, cardiovascular risk reduction, and population-level preventive medicine. Nevertheless, existing literature remains fragmented across disciplines and lacks a unifying framework explaining how a single platform can simultaneously support prevention, therapy, and health-system resilience. This narrative review addresses this gap by synthesising literature from PubMed, Scopus, and Web of Science, emphasising studies published between 2018 and 2025 while retaining seminal pre-2018 mechanistic contributions. We integrate mechanistic, translational, and policy evidence to propose that mRNA vaccines should be reconceptualised as adaptive health infrastructure rather than single-purpose biologics. We introduce the Adaptive Preventive Therapeutics Continuum (APTC), a framework positioning mRNA intervention along a spectrum from anticipatory prevention to chronic disease management and precision restoration of physiological function. The central innovation of mRNA technology lies not only in rapid manufacturing but also in its programmable temporality the capacity to generate transient, titratable, and updateable biological responses tailored to disease stage and population need, thereby supporting resilient and adaptable healthcare systems.
    Keywords:  autoimmune disease; cancer immunotherapy; chronic disease; lipid nanoparticles; mRNA vaccines; pharmacovigilance; precision medicine; preventive health
    DOI:  https://doi.org/10.3389/fbioe.2026.1869761
  10. Hum Vaccin Immunother. 2026 Dec;22(1): 2711554
    Global trends in CAR-T cell therapy for multiple myeloma: A bibliometric analysis, 2013-2025.
    Tiantian Zhang, Shenyu Wang, Xin Li, Xiaohong Li, Yamei Wu.
      CAR-T cell therapy has dramatically changed the treatment paradigm for relapsed/refractory multiple myeloma (R/R MM). Nevertheless, there is a notable paucity of comprehensive bibliometric analyses within this specialized domain. On January 26, 2026, publications on CAR-T cell therapy for MM (2013-2025) were retrieved from the Web of Science Core Collection using: TS = (CAR-T OR "chimeric antigen receptor T*" OR "chimeric antigen receptor modified T" OR "chimeric antigen receptor engineered T" OR "chimeric antigen receptor transduced T" OR "chimeric antigen receptor redirected T") AND TS = ("multiple myeloma*" OR "plasma cell myeloma*" OR "Kahler Disease"). English articles and reviews were included. Bibliometric and visual analyses used CiteSpace 6.2.R1 and VOSviewer 1.6.17. A total of 1,661 eligible documents (including 874 articles and 787 reviews) were included. The annual publication volume showed a continuous upward trend. The United States, Harvard University, Frontiers in Immunology, and Hermann Einsele were the leading contributors by country, institution, journal, and author, respectively. Research focuses on BCMA-CAR-T cell therapy efficacy and safety, comparisons with standard regimens, toxicity management, and combinatorial strategies with bispecific antibodies. Citation burst analysis highlighted emerging directions, including GPRC5D-CAR-T cell therapy and allogeneic "off-the-shelf" CAR-T cell products. The field of research concerning CAR-T cell therapy for multiple myeloma is experiencing rapid advancement. This study systematically summarizes the global research trends, research hotspots and emerging directions in this field, which provides valuable reference for researchers in this field.
    Keywords:  BCMA; CAR-T cells; bibliometrics; emerging topics; multiple myeloma; research hotspots
    DOI:  https://doi.org/10.1080/21645515.2026.2711554
  11. J Clin Pharmacol. 2026 Aug;66(8): e70270
    Model-Informed Decision Making from Drug Discovery to Reimbursement: A Roadmap for Clinical Pharmacology in Value-Based Healthcare.
    Rajesh Krishna, Ananth Kadambi, Patrick Smith, Piet H van der Graaf, Fran Brown.
      The transition to value-based healthcare demands more efficient, evidence-driven approaches to drug discovery, development and medical use. Clinical pharmacology is uniquely positioned to support this shift through model-informed drug development (MIDD) decision-making, integrating quantitative methods across the product lifecycle. This commentary outlines a roadmap for embedding MIDD from early drug discovery through regulatory evaluation and ultimately into reimbursement and real-world use. We highlight how pharmacokinetic/pharmacodynamic modeling, mechanistic modeling, disease progression models, patient-relevant endpoints, and real-world data will inform dose selection, optimize trial design, and reduce uncertainty in benefit-risk and cost-effectiveness assessments. Emphasis is placed on cross-stakeholder alignment, including regulators, payers, clinicians, and industry, to ensure that model-informed evidence translates into demonstrable patient and economic value. Key challenges, such as data integration, model transparency, and acceptance by decision-makers, are discussed alongside practical solutions. By advancing a lifecycle-based, quantitatively informed framework, clinical pharmacology can play a central role in delivering therapies that are not only safe and effective but also aligned with the principles of value-based healthcare.
    Keywords:  clinical pharmacology; model‐informed drug development; payer value; totality of evidence
    DOI:  https://doi.org/10.1002/jcph.70270
  12. ACS Pharmacol Transl Sci. 2026 Aug 14. 9(8): 1985-1993
    Quantum-Augmented Federated AI for Adaptive Pharmacogenomic Precision Oncology: A Perspective.
    Zahid Rafiq, Nahum Puebla Osorio.
      Precision oncology has evolved from single-gene biomarker testing toward multimodal molecular and clinical profiling; however, most therapeutic decisions remain based on static baseline assessments that inadequately capture tumor evolution, treatment response, and emerging resistance. In this perspective, we propose a forward-looking framework that integrates federated learning, pharmacogenomic digital twins, and hybrid quantum-classical optimization to support the development of adaptive, privacy-preserving precision oncology systems. The framework enables collaborative model training across institutions without sharing raw patient data, thereby addressing major barriers associated with data fragmentation and privacy regulations. Patient-specific digital twins serve as continuously evolving computational representations that integrate longitudinal multiomics, imaging, pathology, and clinical information to simulate disease trajectories, estimate therapeutic response, and anticipate resistance patterns. Federated learning allows these models to benefit from geographically distributed patient cohorts while maintaining data sovereignty and institutional privacy. In contrast to near-term deployable components such as federated learning and digital twin modeling, quantum computing is presented as a future-oriented computational strategy that may assist selected combinatorial optimization tasks, including treatment selection, dose optimization, and scheduling, through hybrid quantum-classical workflows. Rather than assuming immediate clinical utility or quantum advantage, the framework emphasizes realistic translational pathways that acknowledge current limitations in quantum hardware, scalability, validation, and regulatory readiness. We further discuss technical feasibility, challenges associated with heterogeneous clinical data, privacy considerations, validation requirements, and regulatory pathways for adaptive AI-enabled clinical decision-support systems. By providing a formal conceptual architecture and translational roadmap, this perspective outlines how federated artificial intelligence, continuously learning digital twins, and future quantum-assisted optimization may collectively contribute to the next generation of adaptive precision oncology.
    Keywords:  OMICS; digital twin; federated and quantum computing; multimodal AI; pharmacogenomics
    DOI:  https://doi.org/10.1021/acsptsci.6c00261
  13. Cancer Gene Ther. 2026 Aug 21.
    Investigating the role of costimulatory domains in enhancing CAR-T cell persistence in TNBC.
    Hany E Marei, Giacomo Pozzoli, Carlo Cenciarelli.
      This work summarizes how costimulatory domains can mediate the persistence, function, and therapeutic potential of CAR-T cells in triple-negative breast cancer (TNBC), a highly aggressive malignancy with limited treatment options and an immunosuppressive tumor microenvironment. Although CAR-T cell therapy has produced remarkable results in hematologic malignancies, its translation to TNBC remains limited by poor T cell persistence, metabolic dysfunction, and rapid exhaustion. Current evidence identifies canonical costimulatory domains (CD28 and 4-1BB) as having differential effects on intracellular signaling, metabolic programming, and T cell differentiation; CD28-based CAR-T cells promote rapid activation and glycolytic metabolism but are commonly associated with terminal differentiation and decreased durability, whereas 4-1BB signaling supports mitochondrial fitness, oxidative phosphorylation, and the development of memory-like T cells that support longer-lasting persistence. The functional differences in CAR-T cells are context-dependent and influenced by antigen density, hypoxia, and other immunosuppressive signals within the TNBC tumor microenvironment. Newer costimulatory domains, such as HVEM and TNFRSF9, have added an additional layer of complexity to T cell signaling by modulating activating and inhibitory pathways, and their incorporation into CAR designs offers new ways to optimally regulate T cell responses; however, their functions are not fully defined in TNBC models. Additionally, dual costimulation strategies and combination therapies (metabolic reprogramming of T cells, epigenetic modulation, and immune checkpoint blockade) have shown promise in preclinical studies, but their translational value remains to be validated. An important message arising from this review is that while persistence may be improved through enhanced costimulatory signaling, the ideal performance of CAR T therapy occurs with the establishment of an ideal balance of stimulating signals that promote the sustained function of effector T cells while inhibiting the exhaustion of T cells and avoiding the deleterious effects of tonic activation. Furthermore, it is critical to evaluate data from TNBC models compared to other solid tumors to inform rational CAR T design strategies in TNBC.
    DOI:  https://doi.org/10.1038/s41417-026-01073-0
  14. Signal Transduct Target Ther. 2026 Aug 18. pii: 331. [Epub ahead of print]11(1):
    Harnessing macrophage signaling pathways and scalable engineering for next-generation immunotherapies.
    Daniela Paasch, Kathrin Haake, Chloe Kan, Cristiana Ulpiano, Eirini Nikolouli, Mi-Sun Jang, Mark-Christian Klassen, Michael Epstein, Ryohichi Sugimura, Nico Lachmann.
      Macrophages have emerged as promising candidates for cell-based immunotherapies due to their intrinsic plasticity, tissue-infiltrating capabilities, and central roles in orchestrating immune responses. Their phenotypic and functional diversity within tissues and the tumor microenvironment has driven interest in harnessing these cells for therapeutic purposes. Integrating recent knowledge in signaling cascades balancing the activity of macrophages in combination with genetic engineering have enabled the development of macrophages with improved functions, including the introduction of synthetic receptors such as chimeric antigen receptors (CARs). These superior macrophages orchestrate innate immune activity with antigen-specific targeting, offering distinct advantages over conventional CAR-T and CAR-NK cell therapies, especially in solid malignancies. Emerging preclinical and early clinical data support the feasibility, safety, and therapeutic potential of macrophage-based strategies. However, successful clinical translation requires overcoming key challenges in standardization, scalable manufacturing and regulatory compliance of cell products. This review integrates current knowledge in the diversity of macrophage signaling which feeds into engineering techniques, therapeutic applications, and manufacturing innovations. Leveraging concepts of macrophage tissue plasticity highlights the potential of macrophages as next-generation cell therapeutics with broad potential in oncology and beyond, bridging fundamental immunology with translational medicine. Continued interdisciplinary research will accelerate clinical adoption and expand indications across diseases.
    DOI:  https://doi.org/10.1038/s41392-026-02907-x
  15. Cell Rep Med. 2026 Aug 21. pii: S2666-3791(26)00417-9. [Epub ahead of print] 103000
    Long-term outcomes of anti-CD19 CAR T cell therapy in refractory myasthenia gravis: A case series.
    Tobias Hegelmaier, Jeremias Motte, Denise Walther, Eugen Feist, Alexander Duscha, Christiane Desel, Vaia Pappa, Martin Böttcher, Marvin Voigt, Melissa Sgodzai, Marwa Al-Dubai, Roland Schroers, Dominic Borie, Georg Schett, Dimitrios Mougiakakos, Ralf Gold, Aiden Haghikia.
      Anti-CD19 CAR T cell therapy represents an emerging therapeutic approach for generalized, treatment-refractory myasthenia gravis (MG), a predominantly B-cell-mediated autoimmune disease for which durable treatment-free remission remains an unmet clinical goal. Despite recent advances, current targeted therapies generally require lifelong repeated administration and rarely induce durable treatment-free remission. We report on three patients with severe, treatment-resistant MG, including one patient with concomitant rheumatoid arthritis, treated with autologous, fully human anti-CD19 CAR T cells. All three patients achieve rapid, sustained clinical MG remission for at least 19 months, allowing discontinuation of MG-specific immunotherapies and substantial improvement in clinical and functional outcomes despite persistent detectable anti-AChR autoantibody titers. B cell depletion is profound, and treatment-related adverse events remain transient and manageable during long-term follow-up. These data support anti-CD19 CAR T cell therapy as a durable, effective intervention for refractory MG and warrant further evaluation in prospective controlled clinical trials.
    Keywords:  CAR T cell therapy; autoimmunity; immune reset; immunotherapy; living drug; long-term remission; neuroimmunological disease; seropositive refractory myasthenia gravis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103000
  16. Crit Rev Oncol Hematol. 2026 Aug 20. pii: S1040-8428(26)00440-3. [Epub ahead of print] 105553
    CAR-T Cell Therapy-Associated Coagulopathy: From Immunothrombotic Storm Mechanisms to Precision Management Strategies.
    Buyi Su, Xingbing Wang.
      Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the management of relapsed or refractory hematologic malignancies, yet its benefit is constrained by immune-mediated vascular toxicities. CAR-T-associated coagulopathy (CARAC) is an under-recognized, potentially fatal syndrome driven by endothelial activation, cytokine amplification and disordered fibrinolysis. In this review, we synthesize current evidence on CARAC pathobiology, emphasizing its dynamic transition from early procoagulant endothelial conversion to secondary hyperfibrinolysis and consumptive coagulopathy. We delineate disease-specific phenotypes, including hemorrhage-prone B-cell acute lymphoblastic leukemia, thrombotic large B-cell lymphoma and assay-confounded multiple myeloma, and highlight key diagnostic pitfalls such as tocilizumab-associated fibrinogen decline. To support standardization, we propose a phase-adapted conceptual framework integrating laboratory kinetics, clinical events and functional coagulation assessment. Finally, we outline precision management strategies spanning risk-adapted anticoagulation, hemostatic rescue and targeted treatment of delayed inflammatory and endothelial complications.
    Keywords:  Biphasic fibrinolysis; CAR-T cell therapy; Coagulopathy; Endothelial activation; Tocilizumab; Toxicity grading
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105553
  17. Brief Bioinform. 2026 Jul 03. pii: bbag442. [Epub ahead of print]27(4):
    Ensuring the quality of in silico evidence: application to medical devices.
    Marc Horner, Ani Amar, Alejandro F Frangi, Martha De Cunha Maluf-Burgman, Thierry Marchal, Francesco Pappalardo.
      The use of in silico methods-computational modelling and simulation-to support the development, evaluation, and regulatory approval of medical devices is expanding rapidly. These approaches offer clear benefits in accelerating innovation, reducing development burden, and strengthening safety assessment, yet their regulatory acceptance remains inconsistent across jurisdictions. This variability reflects differences in model maturity, documentation practices, and the absence of globally harmonised criteria for assessing credibility. Building on established standards and regulatory guidance, this position paper outlines a risk-informed framework for the credible generation, assessment, and regulatory utilisation of in silico evidence that could be implemented across the medical device lifecycle. The framework emphasises clear definition of a question of interest and context of use, proportional credibility requirements based on model risk, and rigorous application of verification, validation, and uncertainty quantification. Emerging challenges posed by data-driven and hybrid models, including artificial intelligence, highlighting additional governance and data integrity considerations are also addressed. Importantly, the generation of in silico evidence increasingly relies on bioinformatics and computational biomedicine workflows, including the integration of heterogeneous biomedical data sources (e.g. medical imaging, real-world data, and population-level datasets), preprocessing and feature extraction pipelines, and hybrid mechanistic-data-driven modelling approaches. In this perspective, the authors argue that the credibility of in silico evidence is not determined solely at the level of the executable model, but across the full computational pipeline, encompassing data provenance, preprocessing, model implementation, and reproducible analysis workflows.
    Keywords:  bionformatics; computational modelling and simulation (CM&S); data pipelines; hybrid models; in silico evidence; model credibility; risk-informed framework; validation and uncertainty quantification (VVUQ); verification
    DOI:  https://doi.org/10.1093/bib/bbag442
  18. J Comp Eff Res. 2026 Aug 20. e260167
    R WE ready for reimbursement? A round-up of developments in real-world evidence relating to health technology assessment: part 28.
    Paul Arora, Kirk Geale, Sreeram V Ramagopalan.
      In this update, we consider the role of real-world evidence in the European Union's new Joint Clinical Assessment (JCA) process and also review a systematic review and meta-analysis of the concordance between target trial emulations and their benchmarking randomized controlled trials.
    Keywords:  EU Health Technology Assessment Regulation; European Medicines Agency; Joint Clinical Assessment; PICO; health technology assessment; randomized controlled trial; real-world data; real-world evidence; target trial emulation
    DOI:  https://doi.org/10.57264/cer-2026-0167
  19. Immunol Rev. 2026 Aug;341(1): e70157
    The Role of the T Cell Receptor Sequence in Shaping T Cell Functional Fate.
    Sreekar Mantena, Soumya Raychaudhuri.
      The T cell receptor (TCR) has long been studied through the lens of antigen recognition, with decades of work characterizing how the TCR sequence specifies the peptide-MHC ligands a T cell can engage. Yet a growing body of evidence indicates that the TCR sequence carries another dimension of functional information: it biases the transcriptional fate a T cell is likely to adopt. In this review, we synthesize the evidence that TCR sequence features shape T cell differentiation during both thymic development and peripheral responses. We provide an overview of the landscape of T cell fates and the TCR structure, describe advancements in technologies to profile T cell phenotype and TCR sequence, and outline computational strategies for modeling the relationship between them. We specifically examine four reproducible axes of covariation between TCR sequence and T cell fate, including innate-like lineages, regulatory T cells, CD4 versus CD8 commitment, and peripheral memory formation. Understanding the probabilistic fate biases encoded by the TCR may advance our ability to interpret repertoires in health and disease and engineer next-generation cellular therapies.
    DOI:  https://doi.org/10.1111/imr.70157
  20. J Vis Exp. 2026 Aug 18.
    Standardized Xenograft Models for Preclinical Cancer Research.
    Dmitriy Ovcharenko.
      Xenograft models are the principal in vivo platform of preclinical oncology and the most established experimental link between cell culture and clinical investigation. From the carcinogen-exposed rabbit models of the early twentieth century through the current generation of humanized patient-derived xenograft (PDX) systems, these platforms have evolved in response to the demands of translational cancer research. This review critically examines the biological principles, methodological standards, and translational applications of the principal xenograft platforms in current use. Cell line-derived xenograft (CDX) models remain the most widely used and most cost-effective modality for preclinical efficacy testing, offering the reproducibility, scalability, and accessibility that have sustained their role across oncology drug development pipelines for decades. PDX models have emerged as the preferred platform for co-clinical trial design, predictive biomarker discovery, and personalized oncology applications, preserving the genomic landscape, intratumor heterogeneity, and histological architecture of the donor tumor across serial passages. The engraftment biology of PDX systems, including immunodeficient host strain selection, implantation site, tumor source, and passage biology, is reviewed, together with humanized and autologous humanized configurations that extend the platform to immune checkpoint inhibitors, bispecific T-cell engagers, and chimeric antigen receptor T (CAR-T) cell therapy evaluation. This review addresses preclinical-to-clinical translation as a function of immunological divergence, incomplete tumor microenvironment recapitulation, and standardization. Formal frameworks, including the PDX Model Minimal Information (PDX-MI) standard and the Minimal Information for Standardization of Humanized Mice (MISHUM), are examined alongside global biobank infrastructure and emerging AI-driven translational modeling approaches.
    DOI:  https://doi.org/10.3791/71892
  21. Sci Transl Med. 2026 Aug 19. 18(863): eaei0875
    A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia.
    Base Edited-CAR T cell group
      Chimeric antigen receptor (CAR) T cell therapy for acute myeloid leukemia (AML) is constrained by antigen heterogeneity and shared expression with healthy compartments, and there are often challenges in obtaining autologous T cells from heavily pretreated patients. To address these challenges, we developed universal donor-derived, base-edited, anti-CD33 CAR T cells (BE-CAR33) that used precise multiplexed cytidine deamination to simultaneously disrupt the TRAC, CD52, and CD7 loci to prevent graft-versus-host disease and evade immunotherapy effects. An open-label, nonrandomized, single-center phase 1 study (ISRCTN14430213) evaluated the safety, feasibility, and activity of BE-CAR33 cell therapy ahead of allogeneic stem cell transplantation (allo-SCT) for patients with AML. Eligible participants were aged less than 16 years with relapsed/refractory AML. Five patients were screened, and three were enrolled; one additional adult received BE-CAR33 through compassionate access. Participants received fludarabine, cyclophosphamide, and alemtuzumab followed by 1.2 to 1.8 × 106 BE-CAR33 cells per kilogram. Treatment-emergent adverse events included cytokine release syndrome (grade ≤2), neurotoxicity (grade 3), cytopenias (grade 4), and transient rashes. Two patients demonstrated reduced minimal residual disease and proceeded to allo-SCT. Serial flow cytometry, chimerism quantification, and vector copy number analyses tracked BE-CAR33 T cells until elimination during transplant. Differentially expressed genes included editing signatures and switched from manufacturing-related toward postexpansion effector and exhaustion profiles. Although primary end points were not met, this first-in-human study demonstrated the feasibility of an "off-the-shelf" base-edited CAR T cell approach and informs future multiantigen strategies against AML.
    DOI:  https://doi.org/10.1126/scitranslmed.aei0875
  22. J Vis Exp. 2026 Aug 14.
    In Situ Generation of Claudin18.2-Specific CAR-T Cells via Lipid Nanoparticle-Mediated mRNA Delivery.
    Henghui Li, Jingyao Li, Ying Wang, Liang Chen.
      Chimeric antigen receptor (CAR) T-cell therapy has achieved remarkable clinical success in hematological malignancies; however, its broader application is limited by high manufacturing costs and insufficient efficacy against solid tumors. To overcome these challenges, an in situ CAR-T cell generation strategy was developed based on lipid nanoparticle (LNP)-mediated delivery of CAR mRNA targeting Claudin18.2, enabling the transient production of CAR-T cells directly within tumor tissue. Following LNP transfection, activated T cells exhibited efficient surface expression of CARs. These transient CAR-T cells demonstrated potent cytotoxic activity against Claudin18.2-positive gastric carcinoma cell lines, including NUGC4 and NCI-N87, and produced significant antitumor efficacy in tumor-bearing mouse models. This protocol describes detailed procedures for in vitro transcription of CAR mRNA, LNP formulation, T-cell activation and transfection, CAR expression analysis, and in vitro and in vivo functional evaluation of CAR-T-mediated cytotoxicity. Taken together, this strategy provides a cost-effective and versatile platform for generating transient CAR-T cells and offers a promising approach for treating solid tumors.
    DOI:  https://doi.org/10.3791/71482
  23. Sci Immunol. 2026 Aug 21. 11(122): eaea6276
    CAR T cell-derived TNF is an early determinant of cytokine release syndrome severity.
    Pieter L Lindenbergh, Theodoros Giavridis, Ophélie Vivier, Michael A Lopez, Anton Dobrin, Matthias Mack, José L Cohen, Maria Themeli, Michel Sadelain.
      Cytokine release syndrome (CRS) is a common and potentially severe toxicity of chimeric antigen receptor (CAR) T cell therapy, characterized by activation of the host myeloid compartment and systemic inflammation. Although downstream effectors such as interleukin-6 (IL-6) and IL-1β are well-characterized, the upstream signals that initiate CRS remain incompletely understood. By selectively disrupting tumor necrosis factor (TNF) signaling in a mouse model of CRS, we show that CAR T cell-derived TNF promotes the accumulation of pro-inflammatory monocyte-derived macrophages at the tumor site and the induction of host-derived cytokines including IL-6 and IL-1β. We further show that TNF is a determinant of CRS severity in humanized xenochimeras, governing the overall disease course including eventual lethality. Our findings thus identify TNF as an upstream regulator of CRS acting at least in part via the host macrophage compartment.
    DOI:  https://doi.org/10.1126/sciimmunol.aea6276
  24. Front Digit Health. 2026 ;8 1908794
    From digital twins to clinically trustworthy twins: a clinical-claim-based validation framework for personalized digital health.
    Alexandre Vallée.
      Digital twins are increasingly presented as a computational foundation for personalized and preventive medicine, because they promise to integrate multimodal data into dynamic representations of patients, organs, diseases, or care pathways. Yet the translational maturity of medical digital twins remains limited. Many systems labelled as digital twins are still digital models, digital shadows, descriptive simulations, or prediction tools whose clinical claims exceed the evidence provided for calibration, uncertainty, transportability, causal validity, or real-world utility. This Perspective argues that the next bottleneck for digital twins in health is not model complexity but clinical trustworthiness. The main contribution of this Perspective is a claim-to-evidence typology that links the evidentiary burden of a digital twin to the clinical claim it makes, rather than to its computational architecture alone. This approach connects individual-level multimodal modelling with epidemiology, prediction science, causal inference, and implementation science. This article outlines a staged framework that distinguishes descriptive, predictive, counterfactual, interventional, and population-health clinical claims made by systems labelled or proposed as digital twins, each associated with a distinct evidentiary threshold. This article further proposes that validation should integrate verification, calibration, external and temporal validation, uncertainty quantification, fairness assessment, target trial emulation where causal claims are made, and post-deployment monitoring. Without such methodological discipline, digital twins may remain sophisticated but clinically fragile simulations. Conversely, population-calibrated and prospectively evaluated digital twins could become a robust infrastructure for personalized prevention, adaptive treatment, and learning health systems.
    Keywords:  artificial intelligence; calibration; causal inference; digital health; digital twin; epidemiology; implementation science; personalized medicine
    DOI:  https://doi.org/10.3389/fdgth.2026.1908794
  25. Iran J Basic Med Sci. 2026 ;29(6): 812-822
    Emerging trends in nanomedicine: The role of RNAi-based therapies and onpattro's clinical journey.
    Dilpreet Singh, Satvir Singh, Nitin Tandon, Akshay Thakur, Neena Bedi.
      Nanomedicine has transformed therapeutic strategies by enabling precise delivery of nucleic acid-based drugs, including small interfering RNA (siRNA), messenger RNA (mRNA), and antisense oligonucleotides. A landmark achievement is Onpattro (patisiran), the first FDA-approved RNAi therapy, which employs lipid nanoparticles (LNPs) to silence transthyretin in hereditary amyloidosis. Its approval validates RNAi as a viable therapeutic modality and underscores the central role of nanocarriers in clinical translation. Despite this success, barriers such as nanoparticle stability, targeted delivery, immunogenicity, and manufacturing scalability remain. Recent advances in mRNA vaccines, CRISPR-based gene editing, and stimuli-responsive nanoparticles are addressing these challenges, supported by growing clinical case studies and real-world data. This review highlights Onpattro's clinical development, compares delivery platforms, discusses translational challenges, and examines emerging technologies that will guide the next generation of RNAi nanomedicines in personalized therapy.
    Keywords:  Amyloid neuropathies; Drug delivery systems; Familial; Lipid nanoparticles; Nanomedicine; RNA interference; Small interfering RNA
    DOI:  https://doi.org/10.22038/ijbms.2026.89795.19366
  26. Clin Microbiol Infect. 2026 Aug 17. pii: S1198-743X(26)00466-0. [Epub ahead of print]
    Chimeric antigen receptor (CAR) therapy in infectious diseases: emerging applications with a focus on invasive fungal infections.
    Carme Bracke, Ignacio Grafia, Pedro Puerta-Alcalde.
       BACKGROUND: Infections remain a major cause of morbidity and mortality among immunocompromised patients, particularly in the context of invasive fungal infections (IFIs), where outcomes are strongly dependent on host immune status. Despite advances in antifungal therapy, mortality remains high, highlighting the need for novel immunotherapeutic strategies.
    OBJECTIVES: This review aims to summarize current evidence on chimeric antigen receptor (CAR)-based therapies for infectious diseases, with a particular focus on IFIs, and to discuss their potential role, limitations, and future perspectives.
    SOURCES: A narrative review of the literature was conducted using PubMed, focusing on preclinical and clinical studies evaluating CAR-based approaches in fungal, viral, and selected bacterial infections. Relevant references were identified from database searches and cross-referencing of key articles.
    CONTENT: CAR-engineered immune cells, particularly CAR T cells, represent a promising strategy to restore pathogen-specific immunity in immunocompromised hosts. In IFIs, targeting conserved fungal cell wall components such as β-glucans and mannans has shown encouraging preclinical results, with different CAR constructs demonstrating enhanced antifungal activity and immune activation, particularly against Aspergillus and Candida species. Alternative platforms, including CAR-NK cells and CAR macrophages, may offer advantages such as reduced toxicity and off-the-shelf availability, and have shown preliminary clinical feasibility in a patient with IFI. While CAR-based approaches have also demonstrated activity against viral and selected bacterial pathogens, their clinical application remains largely exploratory. Several challenges limit translation into clinical practice, including complex manufacturing, delayed availability, safety concerns, antigen heterogeneity, and limited clinical evidence.
    IMPLICATIONS: CAR-based immunotherapy represents a novel and potentially transformative approach for the management of severe infections in immunocompromised patients, particularly those with refractory or multidrug-resistant disease. Advances in manufacturing, target selection, and combination strategies will be essential to overcome current limitations. Further clinical studies are needed to define their safety, efficacy, and positioning within existing therapeutic frameworks.
    Keywords:  CAR-T; adoptive therapy; chimeric antigen receptor; immunotherapy; invasive fungal disease; invasive fungal infection; viral infection
    DOI:  https://doi.org/10.1016/j.cmi.2026.08.019
  27. Front Immunol. 2026 ;17 1890445
    Extracellular vesicles and acetylation: reciprocal regulation in disease progression.
    Yang Liu, Sinan Wu, Yaqian Wang, Xiali Zhu, Le Kang.
      Extracellular vesicles (EVs) are membrane-bound particles secreted by diverse cell types and mediate intercellular communication through the transfer of proteins, RNAs, lipids, metabolites and other biomolecules. EVs participate in multiple physiological and pathological processes, including immune regulation, tumor progression, metastasis, neurodegenerative disorders and cardiovascular disease. Acetylation is a dynamic post-translational and epigenetic modification that regulates protein function, chromatin accessibility, transcription, metabolism and immune responses. Emerging evidence indicates a bidirectional regulatory relationship between EVs and acetylation. Acetylation can regulate EV biogenesis, cargo loading, secretion and EV-associated protein trafficking, whereas EVs can reshape intracellular acetylation states in recipient cells by transferring non-coding RNAs, proteins, metabolites and acetylated proteins. In this review, we summarize the mechanisms by which acetylation controls EV generation and cargo composition, and how EVs, in turn, modulate acetyl-CoA metabolism, acetylation writers and erasers, and acetylated protein signaling in recipient cells. Given the relevance of this axis to cancer immunity, we also discuss its implications for antigen presentation, macrophage polarization, CD8+ T-cell dysfunction, regulatory T cells, natural killer cells and immune checkpoint regulation. Furthermore, we evaluate the biomarker potential of EV-associated acetylation signatures, the therapeutic relevance of histone deacetylase inhibitors and EV-based interventions, and the current methodological and translational limitations of the field. This review provides a conceptual framework for understanding the EV-acetylation axis in disease progression and highlights future directions for immunological, biomarker and therapeutic development.
    Keywords:  acetylation; exosomes; extracellular vesicles; histone acetylation; histone deacetylase inhibitors
    DOI:  https://doi.org/10.3389/fimmu.2026.1890445
  28. Transplant Cell Ther. 2026 Aug 15. pii: S2666-6367(26)00669-X. [Epub ahead of print]
    CAR-FIT: CAR-T fitness index for therapy - integrating comorbidity and geriatric assessments to guide safe and equitable delivery of CAR-T in patients with borderline physiological reserve.
    Kye Ling Wong, Lawrence Cheng Kiat Ng, Nicole-Ann Lim, Francesca Lim, Shin Yeu Ong, Tertius Tuy, Chieh Hwee Ang, Michelle Limei Poon, Esther Chan, Victor Ling, Wee Lee Chan, Edwin Thong, Rachel Ng, Hiu Kwan To, Chandramouli Nagarajan, William Hwang, Aloysius Ho, Yunxin Chen.
       BACKGROUND: Appropriate patient selection for chimeric antigen receptor T-cell (CAR-T) therapy is essential to minimise preventable adverse outcomes and optimize resource allocation.
    OBJECTIVE: We propose a CAR-T fitness index (CAR-FIT) that integrates frailty and comorbidity assessments derived from a real-world cohort to enable objective stratification of patients.
    STUDY DESIGN: Eighty patients with relapsed diffuse large B cell lymphoma treated with CAR-T therapy between 2020-2025 were retrospectively reviewed. Outcomes included overall survival (OS), progression free survival (PFS) and severe treatment-related complications, defined as Grade ≥3 cytokine release syndrome (CRS), immune-effector cell-associated neurotoxicity syndrome (ICANS) or immune effector cell-associated haematotoxicity (ICAHT). Patients' fitness and comorbidities were assessed using eastern cooperative oncology group (ECOG), Karnofsky, Cumulative Illness Rating Scale (CIRS), Severe4 and Cellular Therapy Comorbidity Index (CTCI) scores and categorized to either "fit", "borderline" or "unfit".
    RESULTS: Using individual comorbidities scores, 30% (n=24) had CIRS ≥7, 8.8% (n=7) had Severe4, and 5% (n=4) had CTCI >3. With CAR-FIT, patients were fit (51.2%, n=41), borderline-fit (28.8%, n=23) and unfit (20%, n=16). There was a significant difference in 1-year OS among the fit, borderline and unfit groups (96.7%, 95% CI 90.5-100; 66.7%, 95% CI 47.3-94.1; 45.8%, 95% CI 22.2-94.8 respectively; p=0.03). A corresponding difference in 1-year PFS was also noted (fit: 78.1%, 95% CI 65.7-92.9; borderline-fit: 52.9%, 95% CI 35.1-79.6; unfit: 43.8%, 95% CI 22.1-86.8; p<0.01).
    CONCLUSION: Combining CIRS, Severe4, and CTCI scores correlated with good outcome stratification. When integrated with frailty assessment, this approach can refine patient selection to allow safer access to potentially eligible candidates.
    Keywords:  Chimeric antigen receptor T-cell therapy; Hematological malignancies; Patient selection; Risk stratification; comorbiditiy assessment; resource allocation; treatment eligibility
    DOI:  https://doi.org/10.1016/j.jtct.2026.08.028
  29. J Immunother Cancer. 2026 Aug 20. pii: e015350. [Epub ahead of print]14(8):
    T-cell receptor repertoires against HLA class I-restricted minor histocompatibility antigens are highly diverse with a small subset of public clonotypes.
    Kyra J Fuchs, Marian van de Meent, Michel G D Kester, Renate S Hagedoorn, Indu Khatri, Peter van Balen, Mirjam H M Heemskerk, Erik B van den Akker, J H Frederik Falkenburg, Marieke Griffioen.
       BACKGROUND: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a curative treatment for hematological diseases. After HLA-matched alloHSCT, donor T cells may recognize minor histocompatibility antigens (MiHAs), which are polymorphic HLA-binding peptides on patient cells that are absent from donor cells due to genetic differences. Donor T cells can induce beneficial anti-tumor effects if MiHAs are targeted on malignant hematopoietic cells in the patient, while graft-versus-host disease (GvHD) may develop if MiHAs are targeted on patients' healthy non-hematopoietic tissues.
    METHODS: We previously isolated T-cell clones from patients responding to donor lymphocyte infusions (DLIs) after HLA-matched alloHSCT, and identified HLA class I-restricted MiHAs. To investigate MiHA-specific T-cell responses in patients, we here sequenced the T-cell receptors (TCRs) of MiHA-specific T-cell clones and identified 394 distinct TCRs against 122 MiHAs. We used the collection of identified TCRs to measure frequencies of matched MiHA-specific TCRs in 39 patients responding to DLI with antitumor responses accompanied with no (n=9), limited (n=8) or severe (n=22) GvHD.
    RESULTS: The data showed higher MiHA-specific TCR frequencies in patients with severe GvHD, which were mainly driven by clonal expansion. Moreover, within the diverse MiHA-specific TCR repertoires in these patients, we identified five public TCRs against four MiHAs with identical CDR3 regions and several TCRs targeting MiHAs with similar, but not identical, CDR3 regions.
    CONCLUSION: Patients with severe GvHD have high MiHA-TCR frequencies mainly driven by clonal expansion, and that MiHA-specific TCR repertoires in patients responding to DLI after alloHSCT are highly diverse with a few public clonotypes.
    Keywords:  Graft versus host disease - GVHD; Graft versus leukemia; Hematologic Malignancies; T cell; T cell Receptor - TCR
    DOI:  https://doi.org/10.1136/jitc-2026-015350
  30. Drug Discov Today. 2026 Aug 19. pii: S1359-6446(26)00186-8. [Epub ahead of print] 104781
    Artificial intelligence agents and agentic artificial intelligence applied to precision medicine.
    Fabricio F Costa.
      Precision medicine seeks to individualise care by integrating multimodal biomedical data, yet most deployed clinical artificial intelligence (AI) remains assistive, providing predictions without managing workflows or adapting autonomously. Agentic AI, built on large language models (LLMs), has emerged as a paradigm characterised by autonomy, goal-directed reasoning, memory, planning and tool use. This review synthesises evidence on agentic AI and LLMs applied to precision medicine, encompassing drug discovery, genomics, oncology, rare disease diagnostics and clinical pharmacology. This review also examines architectural components, recent validation milestones and emerging challenges, including hallucination, sociodemographic bias and evolving regulatory frameworks across the FDA, the EU AI Act and the WHO.
    Keywords:  agentic AI; clinical decision support; drug discovery; genomic foundation models; large language models; multiagent systems; precision medicine
    DOI:  https://doi.org/10.1016/j.drudis.2026.104781
  31. Immunooncol Technol. 2026 Sep;31 101609
    Management of systemic lupus erythematosus and antiphospholipid syndrome during CAR-T therapy: insights from two clinical cases.
    C Normand, S Almaz, R Stadelmann, M Goodyer, B Navarro, A I Martin Quesada, A Mulvey, P Szturz, B Gentner, L Trueb, C Arber, E Ghisoni, M Le Moine.
       Background: Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are autoimmune disorders marked by the presence of pathogenic autoantibodies predominantly produced by B cells. Both conditions are chronic, incurable, and require lifelong treatment. Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising treatment for refractory hematological malignancies, with anti-CD19 CAR-T therapy demonstrating high efficacy in relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The profound depletion of B cells induced by anti-CD19 CAR-T therapy suggests that this treatment may influence the clinical course of patients with DLBCL and concomitant SLE or APS.
    Materials and methods: We report two clinical cases of patients diagnosed with both DLBCL and concomitant SLE and APS who underwent anti-CD19 CAR-T therapy at our institution. We describe the lymphoproliferative disease course as well as the serological evolution and longitudinal cytokine profiles measured before and after CAR-T therapy.
    Results: In both cases, CAR-T therapy resulted in complete and long-lasting metabolic remission of the lymphoproliferative disorder. Concurrently, autoantibody titers stabilized, permitting stepwise de-escalation of the immunomodulatory treatment.
    Conclusion: These cases demonstrate that CAR-T therapy for DLBCL is feasible and appears safe in patients with concomitant autoimmune disease but requires close monitoring and interdisciplinary management. These findings support further preclinical and clinical investigation of CAR-T therapy as a potential therapeutic approach in patients with DLBCL and concomitant SLE and APS.
    Keywords:  CAR-T therapy; antiphospholipid syndrome; case report; cytokines; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.iotech.2026.101609
  32. Expert Rev Pharmacoecon Outcomes Res. 2026 Aug 17. 1-10
    From general-purpose models to purpose-built artificial intelligence systems for health economic modeling.
    Attila Imre, Bertalan Nemeth, Ákos Józwiak, Balázs Nagy, László Balkányi, Ahmad Fasseeh, Zoltán Kaló, Antal Zemplényi.
       INTRODUCTION: Health economic models (HEMs) provide a solid foundation for reimbursement policy decisions that shape patient access to new treatments and the allocation of scarce healthcare resources. Model development is labor-intensive and time-consuming, often requiring months of expert work. Recent advances in large language models (LLMs) prompted interest in whether artificial intelligence can support or partially automate this process, but the evidence base remains scattered and has not been mapped against the modeling workflow.
    AREAS COVERED: This review examines current applications of LLMs to health economic modeling. Five proof-of-concept studies are included and mapped to an eight-stage workflow adapted from the ISPOR-SMDM Modeling Good Research Practices framework and discussed in terms of reproducibility, validation, adaptability, and technology readiness. Published work addressed model parameterization, model implementation, reporting and quality assessment, and local adaptation, while research question design, model conceptualization, uncertainty analysis, and model validation remained unaddressed.
    EXPERT COMMENTARY: The evidence supports cautious optimism. Near-term gains are augmenting human modelers on decomposed, verifiable sub-tasks rather than pursuing autonomous end-to-end modeling, which remains distant given current reliability levels and the iterative, collaborative nature of model development.
    Keywords:  Artificial intelligence; cost-effectiveness analysis; generative AI; health economic modeling; health technology assessment; large language models
    DOI:  https://doi.org/10.1080/14737167.2026.2717289
  33. Cell Rep. 2026 Aug 14. pii: S2211-1247(26)00926-5. [Epub ahead of print]45(8): 117848
    Calibration of CAR signaling promotes asymmetric cell division to direct CAR-T cell fate and antitumor potency.
    Xiaolin Shen, Xiaobao Xu, Jie Jiang, Shize Zhang, Jiangqing Chen, Ruoqi Chen, Ying Gu, Chun Zhou, Gang Xiao, He Huang, Morgan Huse, Michel Sadelain, Jiawei Zhang, Jie Sun.
      Asymmetric cell division (ACD) is an evolutionarily conserved mechanism that diversifies T cell fate, yet how engineered receptor signaling regulates ACD in chimeric antigen receptor (CAR)-T cells remains unknown. Here, we show that antigen engagement induces ACD in CAR-T cells through polarized inheritance of the CAR immune synapse (CARIS), supporting the generation of progeny with divergent functional trajectories. CARhigh progeny acquires a short-lived effector-like state, whereas CARlow progeny retains memory-like features, with enhanced persistence and superior antitumor efficacy. We identify CAR signaling strength as a tunable determinant of this fate bifurcation: selective mutation of CD3ζ immunoreceptor tyrosine-based activation motifs (1XX CAR) enhances ACD. Mechanistically, 1XX signaling promotes pre-mitotic MTOC-CARIS coupling through the PLCγ1-diacylglycerol (DAG) polarity axis, enabling asymmetric CARIS inheritance. Adoptive transfer studies further support a link between signaling-driven asymmetry, fate-determination, and therapeutic efficacy. Together, our findings reveal CAR signaling as a regulator of fate diversification through synapse-coupled asymmetric division.
    Keywords:  ACD; CAR immune synapse; CAR signaling calibration; CARIS; CP: cell biology; CP: immunology; DAG signaling; MTOC; asymmetric cell division; microtubule-organizing center
    DOI:  https://doi.org/10.1016/j.celrep.2026.117848
  34. Iran J Immunol. 2026 08 22. 23(3): 1
    Overcoming Resistance to Immune Checkpoint Blockade: Mechanistic Insights and Emerging Therapeutic Directions.
    Yuyu Xu, Huiling Shen.
      Immune checkpoint inhibitors have revolutionized cancer therapy by delivering long-lasting responses in a subset of patients across many cancer types. Yet, their effectiveness is often limited by high rates of primary and acquired resistance. This resistance is driven by complex interactions among tumor-intrinsic alterations, immunosuppressive factors within the tumor microenvironment, and host-related determinants. This review critically examines the biological mechanisms underlying resistance to immune checkpoint inhibitors, including defects in antigen presentation, dysregulated interferon signaling, activation of oncogenic pathways, compensatory upregulation of alternative immune checkpoints, and microbiome-associated immune modulation. In addition to defining these challenges, this review also highlights emerging opportunities for overcoming these obstacles. Emerging opportunities to circumvent resistance include biomarker-guided patient stratification, rational combination therapies that engage complementary immune pathways, modulation of the tumor microenvironment, and integration of multi-omics approaches to identify predictive resistance signatures. The central conclusion of this review is that effective clinical translation will necessitate a paradigm shift from discrete pathway inhibition toward integrated precision immuno-oncology strategies that combine molecular profiling, immune-contexture analysis, and mechanism-based combination therapies. Such integrated approaches may improve patient selection, overcome resistance, and expand the proportion of patients who achieve durable responses to immune checkpoint blockade.
    Keywords:  Cancer; Immune checkpoints; Immunotherapy; Monoclonal antibodies
    DOI:  https://doi.org/10.22034/iji.2026.111387.3205
  35. Int Immunol. 2026 Aug 18. pii: dxag044. [Epub ahead of print]
    Bispecific antibodies: current advances and future perspectives.
    Toshiya Hino, Yusuke Ito, Yuki Kagoya.
      Bispecific antibodies (BsAbs) are emerging immunotherapeutics that simultaneously engage two distinct targets. This property provides unique mechanisms of action that are not achieved by conventional monoclonal antibodies, including cell-cell bridging, modulation of multiple signaling pathways, and recruitment of diverse immune effector cells. Among these approaches, T cell-engaging BsAbs are the most established modality. By simultaneously targeting a tumor-associated antigen and CD3 on T cells, they promote tumor-T cell bridging, immune synapse formation, and MHC-independent T cell activation, and have shown marked clinical efficacy in several hematologic malignancies. More recently, their application has been extended to solid tumors, supported by encouraging data from clinical trials. Despite these advances, the efficacy and safety of BsAbs face several limitations, including short half-lives, tumor antigen escape, off-tumor toxicity, and insufficient T cell activation due to the lack of costimulatory signals. To address these obstacles, BsAb structures have been modified in various ways, including Fc fusion, multispecific targeting, and armored designs that enhance T cell function. These approaches aim to improve pharmacokinetics, specificity, and antitumor efficacy. In addition to these efforts, novel delivery platforms have been developed to further enhance the therapeutic potential of BsAbs. Engineered extracellular vesicles and nanoparticle-based systems may improve pharmacokinetics and tumor delivery, while enabling the integration of additional functional molecules beyond conventional BsAb formats. In this review, we summarize the basic principles of BsAbs, highlight key clinical developments, and discuss emerging strategies and remaining challenges in the development of next-generation BsAbs.
    Keywords:  antigen escape; bispecific antibody; extracellular vesicle; immunotherapy; nanoparticle
    DOI:  https://doi.org/10.1093/intimm/dxag044
  36. Blood Adv. 2026 Aug 20. pii: bloodadvances.2026021166. [Epub ahead of print]
    A Comprehensive Review of T-Cell Lymphoma Following CAR T-Cell Immunotherapy.
    Wangpan Shi, Huan-You Wang.
      While chimeric antigen receptor (CAR) T-cell therapy provides potential cure for patients with non-Hodgkin B-cell lymphomas/leukemias and plasma cell myelomas, rare reports of development of T-cell lymphomas(TCLs) in these patients have raised serious safety concerns with regard to whether CAR T-cell therapy could directly contribute to the development of TCLs in a specific patient or in those with certain types of underlying hematologic malignancy. This review aims to comprehensively evaluate the clinicodemographic features, types of TCLs, immunophenotypic characteristics, mutational profiles, and CAR-T transgene expression status within the lymphoma cells, as well as explore the underlying mechanisms of lymphomagenesis. A special focus is placed on the interplay between the pre-existing clonal hematopoiesis, immune dysregulation, and reported genomic alterations that may predispose to and/or drive T-cell lymphomagenesis. Among the total 18 reported cases, they developed in all types of underlying hematologic malignancies, and they occurred in all types of widely used commercial CAR T-cell products. The majority of the TCLs showed aberrant T-cell phenotypes according to CD4 and/or CD8 expression. The infused CAR-T transgene from lymphoma cells was detected in 63%(10/16) cases, and 73%(8/11) cases showed integration of the CAR transgene into a known tumor suppressor gene or oncogene. At the molecular genomic level, mutations involved in epigenetic regulators (TET2 and DNMT3A) and JAK-STAT signaling pathway especially JAK3 mutation, were often detected. The potential mechanisms of T-cell lymphomagenesis were complex and multifactorial including but not limited to pre-existing clonal hematopoiesis of indeterminate potential genes, malignant transformation of CAR T-cells, and lymphodepletion chemotherapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2026021166
  37. Eur J Immunol. 2026 Aug;56(8): e70257
    Analysis of Human Thymopoiesis Reveals Rapid Postnatal Remodeling of Thymocytes Within the First 3 Months of Life.
    Camille Kergaravat, Jean-Marc Doisne, Clarisse Godard, Agata Cieslak, Mourad Amrane, David Vermijlen, Vahid Asnafi, Kamel Benlagha, James P Di Santo, Emmanuel Clave, Antoine Toubert.
      The thymus generates a diverse and self-tolerant T-cell repertoire. Its development and output undergo profound changes from fetal to early postnatal life, yet the dynamics of this transition remain incompletely understood. Here, we performed a comprehensive analysis of human thymopoiesis across the perinatal (birth to <10 days), early postnatal (10 days-3 months), and homeostasis (>3 months) periods using high-dimensional flow cytometry and signal joint T-cell receptor excision circle (sjTREC) quantification. Within the perinatal phase, the thymus exhibits the highest intrathymic production, with elevated frequencies of CD4+ T cells and unconventional T cell (UTC), including regulatory T cells (Tregs). After 10 days of age, the frequency of double-positive (DP) thymocytes increases and is associated with dynamic thymocyte phenotypic shifts that suggest enhanced progenitor commitment and proliferation, accompanied by reduced T-cell receptor (TCR) signaling strength. Early postnatal UTCs (birth to 3 months) display a distinct phenotype compared with those generated after 3 months. We notably identified a postnatal wave of effector Vδ2+ γδ T cells emerging between 10 days and 3 months of age. These findings suggest a transition in human thymopoiesis from an early effector-prone unconventional output to predominantly conventional T-cell production after 3 months, highlighting a critical window in immune system establishment.
    Keywords:  perinatal immunity; postnatal immune development; thymopoiesis; unconventional T cells
    DOI:  https://doi.org/10.1002/eji.70257
  38. Int J Oncol. 2026 Oct;pii: 119. [Epub ahead of print]69(4):
    Post‑translational modification‑governed immune states in cancer immunity: Biomarker implications for checkpoint competence, tumor visibility and immunotherapy resistance (Review).
    Jinghao Pan, Boyang Li, Ruonan Lin, Chenlu Fang, Lucy Yue Lau, Zehao Hong, Yi Chen.
      Immune escape and therapeutic resistance remain major obstacles to durable benefit from cancer immunotherapy, yet transcript‑based or abundance‑based biomarkers often fail to capture the regulatory states that determine effective immune control. Post‑translational modifications (PTMs) form a dynamic protein‑state layer that rapidly reshapes protein stability, trafficking, complex assembly, and signaling persistence under tumor‑intrinsic and therapy‑imposed stress. In the present review, a biomarker‑oriented framework is proposed in which PTM biology is interpreted through three recurrent immune constraints: Checkpoint competence, tumor visibility and stress‑conditioned immune‑state programming. Within this framework, programmed death‑ligand 1 is viewed as a protein‑state biomarker problem rather than a static expression marker; tumor visibility is defined by durable antigen‑presentation competence and interferon‑linked reinforcement; and stress‑driven immune dysfunction is interpreted through metabolite‑sensitive PTM rewiring and chromatin‑coupled suppressive stabilization. Rather than cataloguing PTMs comprehensively in cancer immunity, the present review focuses on five core exemplar PTM axes, glycosylation, palmitoylation, ubiquitin editing, phosphorylation and lactylation, because they repeatedly map to rate‑limiting immune constraints, are supported by mechanistic evidence, and represent candidate assay‑compatible or intervention‑relevant state variables at differing levels of translational maturity. It is further outlined how integrated proteogenomic, immuno‑peptidomic, and spatial datasets can be used to discover candidate PTM‑state biomarkers, validate mechanism‑proximal readouts in prespecified pretreatment and on‑treatment settings, and prioritize single or co‑dominant state constraints for patient stratification, pharmacodynamic monitoring, and rational combination design. By organizing PTM biology around measurable state variables rather than modification class alone, the present review provides a phase‑aware translational framework for candidate biomarker discovery, fit‑for‑purpose validation, constraint‑guided stratification, and therapeutic prioritization in cancer immunotherapy.
    Keywords:  biomarkers; cancer immunity; immunotherapy resistance; post‑translational modifications; programmed death‑ligand 1; tumor visibility
    DOI:  https://doi.org/10.3892/ijo.2026.5932
  39. Drug Discov Today. 2026 Aug 18. pii: S1359-6446(26)00180-7. [Epub ahead of print] 104775
    Patient experience data as a methodological and strategic innovation in clinical trial design.
    Alice Vanneste, Axelle Jankelevitch, Linda Lukeba, Peter Sinnaeve, Isabelle Huys, Tom Adriaenssens.
      Patient experience data (PED) are increasingly recognised as a methodological and strategic innovation in drug development, yet their implementation in clinical trial design remains inconsistent. Drawing on a structured literature review and multistakeholder interviews, this analysis examines how PED inform endpoint decision-making. Although clinical development is shifting towards more patient-informed measures, challenges persist due to limited standardisation, validation, methodological gaps and operational constraints. Opportunities include early patient involvement, validated disease-specific measures, consensus-based core outcome sets and clearer regulatory guidance, enabling meaningful and structured PED implementation that strengthens evidence generation, reduces development risk and improves trial efficiency and real-world relevance.
    Keywords:  clinical trial design; endpoint science; literature review; patient experience data; patient input; patient-reported outcomes; semi-structured interviews
    DOI:  https://doi.org/10.1016/j.drudis.2026.104775
  40. Pathol Res Pract. 2026 Aug 10. pii: S0344-0338(26)00311-0. [Epub ahead of print]287 156658
    Reprogramming tumor-associated macrophages and interferon-gamma signaling to overcome therapeutic resistance in cancer.
    HongMei Li, Xiaoqiang Dai.
      Therapeutic resistance remains a major obstacle in cancer treatment and limits the durability of immunotherapy, chemotherapy, and targeted therapy. Tumor-associated macrophages (TAMs) contribute to resistance through spatially and functionally heterogeneous programs shaped by hypoxia, vascular niches, metabolic stress, tumor-derived signals, and therapy-induced inflammation. Chronic IFN-γ exposure can also promote adaptive resistance through checkpoint induction, altered antigen presentation, suppressive feedback signaling, metabolic rewiring, and epigenetic remodeling. This review examines how TAM heterogeneity and IFN-γ signaling intersect to support therapy evasion, with emphasis on macrophage niches, phagocytosis resistance, lactate-associated epigenetic regulation, and clinically relevant feedback loops. We also discuss why several TAM-directed strategies, including CSF1R inhibition, have shown stronger activity in preclinical models than in clinical trials. Finally, we evaluate emerging approaches such as macrophage reprogramming, CD47/SIRPα blockade, CAR-macrophage engineering, and biomarker-guided combination therapy. A clearer understanding of TAM states, spatial context, and IFN-γ dynamics may improve patient stratification and support more rational translational strategies to overcome therapeutic resistance.
    Keywords:  Interferon-γ; Macrophage Reprogramming; Therapeutic Resistance; Tumor-Associated Macrophages
    DOI:  https://doi.org/10.1016/j.prp.2026.156658
  41. Drug Discov Today. 2026 Aug 19. pii: S1359-6446(26)00181-9. [Epub ahead of print] 104776
    mRNA therapeutics for restoring immune tolerance in autoimmune diseases.
    Moncef Zouali.
      Autoimmune diseases arise from breakdown of immune tolerance and are commonly treated with broad immunosuppression that limits efficacy and increases toxicity. For drug discovery, mRNA therapeutics offer a programmable, modular platform to develop antigen-specific and mechanism-driven autoimmune therapies. mRNA-based approaches enable transient, controllable expression of self-antigens, immunoregulatory proteins and transcription factors to induce tolerance, reshape local immune microenvironments and enhance regulatory immune pathways. Preclinical studies across models of multiple sclerosis, type 1 diabetes, lupus, inflammatory bowel disease and rheumatoid arthritis demonstrate proof-of-concept and translational potential. Collectively, these findings position mRNA therapeutics for selective immune modulation while preserving immunity.
    Keywords:  antigen-presenting cells; immune tolerance; immunosuppressive microenvironment; nanovectors; regulatory immune cells
    DOI:  https://doi.org/10.1016/j.drudis.2026.104776
  42. Lancet. 2026 Aug 20. pii: S0140-6736(26)01329-2. [Epub ahead of print]
    BAFF-R CAR T-cell therapy for relapsed or refractory B-cell lymphomas.
    PMB-CT01 Study Group
      
    DOI:  https://doi.org/10.1016/S0140-6736(26)01329-2
  43. Pharmacoepidemiol Drug Saf. 2026 Sep;35(9): e70464
    Proposing a Coverage With Evidence Development Framework for Accelerated Approval at the U.S. Food and Drug Administration.
    Dhanush Bearelly, Purav Desai, David T Zhu, Rajesh Balkrishnan.
      
    DOI:  https://doi.org/10.1002/pds.70464
  44. J Educ Health Promot. 2026 ;15 325
    CAR T-cell therapy in cancer treatment: Challenges and nursing perspectives.
    Bhartendra Sharma, Sukhbir Kaur, Vikas Sharma.
      
    DOI:  https://doi.org/10.4103/jehp.jehp_1714_25
  45. Pharm Stat. 2026 Sep-Oct;25(5):25(5): e70107
    Seamless Phase I-II Cancer Clinical Trials Using Kernel-Based Covariate Similarity.
    Kana Makino, Natsumi Makigusa, Masahiro Kojima.
      In response to the U.S. Food and Drug Administration's (FDA) Project Optimus, a paradigm shift is underway in the design of early-phase oncology trials. To accelerate drug development, seamless Phase I/II designs have gained increasing attention, along with growing interest in the efficient reuse of Phase I data. We propose a nonparametric information-borrowing method that adaptively discounts Phase I observations according to the similarity of covariate distributions between Phase I and Phase II. Similarity is quantified using a kernel-based maximum mean discrepancy (MMD) and transformed into a dose-specific weight incorporated into a power-prior framework for Phase II efficacy evaluation, such as for the objective response rate (ORR). Considering the small sample sizes typical of early-phase oncology studies, we analytically derive a confidence interval for the weight, enabling assessment of borrowing precision without resampling procedures. Simulation studies under four toxicity scenarios and five baseline-covariate settings showed that the proposed method improved the probability that the lower bound of the 95% credible interval for ORR exceeded a prespecified threshold at efficacious doses, while avoiding false threshold crossings at weakly efficacious doses. A case study based on a metastatic pancreatic ductal adenocarcinoma trial illustrates the resulting borrowing weights and posterior estimates.
    Keywords:  Bayesian optimal interval design; maximum mean discrepancy; project optimus
    DOI:  https://doi.org/10.1002/pst.70107
  46. Prog Biophys Mol Biol. 2026 Aug 15. pii: S0079-6107(26)00056-8. [Epub ahead of print]202 101945
    Gene therapy: The current trajectory of clinical and commercial translation.
    Justin R Gibson, Renee N Cottle.
      The rapid pace of innovation in gene therapy has ushered in a new era of transformative medicine, as demonstrated by landmark clinical success in the rapid development and administration of the first personalized n-of-1 treatment for carbamoyl-phosphate synthetase 1 deficiency. While the therapeutic efficacy and safety profiles of these cutting-edge modalities have steadily improved, the primary barriers to their broad clinical translation are becoming increasingly clear. The most significant challenges are no longer confined to the on-target potency of the therapeutic itself; rather, they are rooted in the complexities of commercial formulation and the limitations of a traditional regulatory framework. The scientific progress in drug efficacy, while continuous and necessary, is now outpaced by the significant logistical and procedural hurdles of scaling production, ensuring product consistency, and navigating a regulatory landscape that was not designed for the unique characteristics of these one-time, patient-specific therapies. This review will explore how production bottlenecks, matters of market demand and regulatory compliance, as well as the perpetuation of traditional systemic incentives now stand as the predominant forces impeding the translatability of advanced gene therapies from bench to bedside and delve into the prevailing institutional strategies for providing its access to patients.
    Keywords:  And controls; Bioprocessing; Cell and gene therapy; Chemistry; Clinical translation; Manufacturing; Manufacturing scalability; Payment models; Regulatory science
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.08.002
  47. J Comput Aided Mol Des. 2026 Aug 18. pii: 205. [Epub ahead of print]40(1):
    A survey of transformer and LLM-based architectures, workflows, and systems in drug discovery.
    Stefanos Tsimenidis, Eleni Vrochidou, George A Papakostas.
      Drug discovery has greatly benefited from the recent progress in Artificial Intelligence (AI). Numerous tasks within pharmaceutical research and development are being formulated as classification, regression, generation, or sequence-to-sequence problems, and tackled via AI systems that can learn from data, making the process of discovery and screening faster and more efficient. Two of the greatest breakthroughs in AI have arguably been the advent of transformers and Large Language Models (LLMs). With their parallel processing capabilities, their ability to detect dependencies and interactions in sequence data, and the vast knowledge stored in their millions or billions of parameters, transformers and LLMs are successful, highly popular additions to the computational drug discovery arsenal. This work provides an extensive overview of transformer-based architectures and workflows utilized in drug discovery. The conducted analysis focuses on the types of transformers and LLMs currently in use, as well as the systems and workflows that integrate them. Research findings indicate the transformer architecture's exceptional flexibility and adaptability, which support its implementation across diverse configurations and systems. This versatility positions it as a transformative model with the promising potential to revolutionize drug discovery and drive significant scientific breakthroughs.
    Keywords:  Artificial intelligence; Drug discovery; Large language models; Transformer architecture
    DOI:  https://doi.org/10.1007/s10822-026-00911-5
  48. Crit Rev Oncol Hematol. 2026 Aug 21. pii: S1040-8428(26)00443-9. [Epub ahead of print] 105556
    CAR-T Cell Therapy for Glioblastoma: Obstacles and Advances.
    Lin Chen, Zhenwei Zou.
      Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.
    Keywords:  : glioblastoma; CAR-T cell therapy; antigen heterogeneity; biomaterials; blood–brain barrier; chimeric antigen receptor T cells; focused ultrasound; real-time imaging; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105556
  49. Front Immunol. 2026 ;17 1762484
    Inhibitory receptor states, immune homeostasis and the benefit-risk boundary of cancer checkpoint blockade.
    Xiaodong Wang, Wei Gao, Qianqian Wang, Songjiang He, Songli Cui, Bingchen Duan, Gouping Ding, Yiping Huang, Bingwen Zou.
      Immune checkpoint blockade has transformed cancer treatment, but its clinical success depends on releasing antitumor immunity without collapsing peripheral tolerance. Biomarkers such as PD-L1 expression, mismatch-repair deficiency and tumor mutational burden capture only selected aspects of this balance and provide limited guidance on immune-related adverse events (irAEs). This Review examines inhibitory receptor states as dynamic readouts of the therapeutic window in cancer immunotherapy. Rather than treating PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, VISTA and NKG2A as isolated abundance markers, we discuss how their signaling intersects with CD3, CD28 and cytokine-driven activation, immune-cell differentiation, tissue localization and homeostatic restraint. We further consider how checkpoint blockade converts these circuits into either tumor control or organ-specific immune injury. Evidence from tissue pathology, blood immunomonitoring, single-cell and spatial multi-omics, routine laboratory markers, imaging and emerging host-immune surrogates is integrated into a longitudinal, regimen-specific framework. We argue that clinically useful models should jointly estimate response and toxicity risk, distinguishing reinvigoratable antitumor states from fixed dysfunction and autoreactive vulnerability. Such an approach could support patient selection, regimen tailoring, early toxicity surveillance and more precise use of combination immunotherapy.
    Keywords:  benefit–risk stratification; immune checkpoint blockade; immune homeostasis; immune-related adverse events; inhibitory receptors
    DOI:  https://doi.org/10.3389/fimmu.2026.1762484
  50. Mol Neurobiol. 2026 Aug 18. pii: 843. [Epub ahead of print]63(1):
    The Neuroimmune Duality of CD4⁺ T Cells: Drivers of Damage and Repair in the Brain.
    Nishant Kumar, Prince Ahad Mir, Gyamcho Tshering Bhutia, Jasreen Uppal, Anureet Kaur, Gurkiran Kaur, Sukesh Kumar Gupta.
      CD4⁺ T cells are central regulators of neuroimmune responses, and their dysregulation is increasingly recognized as a pathogenic driver across multiple neurological disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke (IS), traumatic brain injury (TBI), central nervous system (CNS) infections, and stress-induced vestibular dysfunction. This review outlines the differentiation and functional specialization of CD4⁺ T cell subsets T helper 1 (Th1), Th17, Th2, Th9, regulatory T cells (Tregs), and T follicular helper (Tfh) cells and evaluates their distinct roles in CNS injury and repair. In MS, autoreactive Th17 cells promote demyelination through C-C chemokine receptor type 6 (CCR6)-C-C motif ligand 20 (CCL20)-mediated CNS trafficking and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent microglial activation. In contrast, neurodegenerative conditions involve antigen-specific CD4⁺ T cell responses to disease-associated neoantigens, including amyloid-beta (Aβ) and tau in AD, and α-synuclein in PD, often preceding clinical manifestation. Disease-specific differences in antigen identity, glial crosstalk, and temporal infiltration patterns are described for each condition. Age-related CD4⁺ T cell dysfunction, encompassing thymic involution, imbalance between naïve and memory T cell populations, diminished plasticity, and metabolic alterations in senescent lymphocytes, is discussed as a contributor to chronic neuroinflammation in aging. Current and emerging therapeutic strategies are evaluated, including disease-modifying therapies, immune checkpoint modulation, cytokine blockade, Treg-based adoptive transfer, antigen-specific tolerance via nanoparticle systems, metabolic interventions, and chimeric antigen receptor (CAR)-Treg and gene-based approaches. Collectively, these insights indicate the importance of CD4⁺ T cell dynamics in shaping targeted immunotherapeutic strategies for neurological diseases.
    Keywords:  CD4⁺ T cells; Immunomodulation; Immunotherapy; Neurodegeneration; Neuroinflammation; Regulatory T cells
    DOI:  https://doi.org/10.1007/s12035-026-06138-7
  51. Trends Mol Med. 2026 Aug 17. pii: S1471-4914(26)00182-6. [Epub ahead of print]
    Emerging therapeutic opportunities targeting nonclassical MHC-I molecules.
    Yan-Ruide Li, Yuning Chen, Lili Yang.
      Nonclassical major histocompatibility complex class I (MHC-I) molecules, including human leukocyte antigen E (HLA-E), HLA-F, HLA-G, MHC-I-related protein 1 (MR1), and the CD1 family, constitute a conserved antigen-presenting system that regulates immune surveillance, tissue homeostasis, and tolerance through specialized interactions with innate and unconventional T cells. Although these molecules have long been implicated in cancer, infection, autoimmunity, and transplantation, their distinct immunobiology and therapeutic potential have largely been considered in isolation. Recent advances in structural immunology, single-cell and spatial profiling, engineered immune cell technologies, and early clinical studies have established nonclassical MHC-I pathways as tractable targets for immunotherapy. In this review, we synthesize the biology, disease-associated functions, and therapeutic targeting of these molecules, integrating immune checkpoint blockade, antibody-based therapeutics, and MR1- and CD1-restricted cellular immunotherapies into a unified framework. We further highlight shared immunological principles, emerging clinical translation, and opportunities for universal, off-the-shelf immune interventions.
    Keywords:  CD1 antigen-presenting molecules; HLA-F; HLA-G; human leukocyte antigen (HLA)-E; immunotherapy; major histocompatibility complex class I-related protein 1 (MR1)
    DOI:  https://doi.org/10.1016/j.molmed.2026.07.012
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