bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–07–05
sixty-one papers selected by
Luca Bolliger, lxBio
  1. Why CAR T cell therapy fails in renal cell carcinoma.
  2. A breath of fresh AIR in novel CAR T cell design.
  3. Advances and prospects in cell therapy for cancer: explorations from T cells to stem cells.
  4. A guide to CAR T cell therapies: development, current status and future prospects.
  5. Application and challenges of chimeric antigen receptor T cell therapy in the treatment of acute myeloid leukemia (Review).
  6. Neurological complications of current and emerging CAR-T cell therapies.
  7. T cell engagers in autoimmune diseases.
  8. Research advances and application prospects of CAR-T therapy in the treatment of age-related diseases.
  9. Fusion protein-mediated costimulation in engineered T cells: from intrinsic signaling to tumor microenvironment rewiring.
  10. Advances and challenges in CAR-T cell therapy for breast cancer: from molecular design to clinical application.
  11. Standardized Flow Cytometry Assay Using Dried Recombinant Antibody Panels for CAR T Cell Characterization.
  12. Resistance mechanisms and overcoming strategies for CAR T-cell therapy in B-cell hematologic malignancies.
  13. Outsmarting Antigen Escape: Next-Generation CAR T Cell Engineering Strategies for Durable Remissions in Hematologic Malignancies.
  14. CAR-T cell therapy and oncolytic viruses: A synergic approach for advanced GI cancers.
  15. Infections and CAR-T cells for the treatment of lymphoid malignancies: a narrative review.
  16. Comparing National Health Technology Assessment approaches and the new European Joint Clinical Assessment framework: The case of onco-hematological medicines.
  17. A federated digital twin reveals cytomegalovirus reactivation impairs CAR-T cell therapy via IL-15-mediated cytokine competition in B-Cell lymphoma.
  18. Development of chimeric antigen receptors targeting the γδ T cell receptor.
  19. Current landscape of academic and point of care CAR-T cell therapy in low-middle income countries.
  20. Expedited regulatory approval pathways for novel oncology drugs.
  21. FDA Gene Therapy Approvals (1998-2025): Current Status, Regulatory Evolution, and Future Directions.
  22. The Last Mile in CAR-T Cell Therapy.
  23. Universal CD7-targeted CAR T-cell therapy in T-ALL: a promising bridge to transplant, but not without caveats-a critical reappraisal.
  24. Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.
  25. CAR T-Cell Therapy for Cancer: Updates and Challenges for Response Assessment.
  26. Artificial Intelligence in drug discovery and development: current landscape, challenges, and future perspectives.
  27. Fertility and pregnancy outcomes after CAR T-cell therapy: insights from a systematic review.
  28. Editorial: Exploring unconventional T cells and CAR-T-cells in cancer immunotherapy.
  29. Decoupling CAR-T Expansion, Conversion, and Decay Timing: Physiologically Aligned Semi-Mechanistic Modeling With Smooth Gating and a Cauchy Likelihood Residual Model.
  30. Immune effector cell-associated hematotoxicity following CAR-T cell therapies: insights from a large national database.
  31. Direct Injection of Stem Cells and Differentiated Cells: European Experience and Dubai Perspective.
  32. Guided immunotherapy for residual solid tumor: integrating platelets and CAR T cells to reduce post-surgical recurrence.
  33. GPNMB-directed CAR-T cell therapies for solid tumors.
  34. High-Precision Intrinsic Interactome Elucidation of Chimeric Antigen Receptors via Photocatalytic Micromapping (μMap-CAR).
  35. [Artificial Intelligence in the Pharmaceutical Industry: Governance, Quality, and Regulatory Challenges].
  36. Immune Reconstitution After Hematopoietic Stem Cell Transplantation: Cellular Dynamics, Clinical Determinants, and Emerging Therapeutic Strategies.
  37. Engineering immune cell therapies for inflammatory bowel disease: from stem cells to CAR T cells.
  38. Proteomics in Acute Myeloid Leukemia: Current Applications in Precision Medicine and Targeted Immunotherapy.
  39. Epitope mapping of humoral immunogenicity of orvacabtagene autoleucel shows an IgM response with minimal impact on CAR T cellular kinetics.
  40. Interoperability-Driven Digital Twins in Healthcare: A Conceptual and Technical Analysis of FHIR, openEHR, and OMOP.
  41. Large language model-guided CAR-T in silico platform for cytokine optimization in liver cancer with low antigen density.
  42. Editorial-Immune reset in sight: CAR-T cell therapy in autoimmune disease.
  43. Genomic information contributing to the understanding of rheumatic diseases.
  44. Navigating AI and machine learning in cancer research: an end-to-end translational framework.
  45. Future of xenotransplantation in Korea.
  46. Clinical artificial intelligence (AI) in Japan: Regulatory pathways, domain-specific evidence, and its data infrastructure from an international perspective.
  47. Perfusion development and its potential for cell therapy manufacturing with adherent cells.
  48. Real-World Evidence in Asian Health Technology Assessment: Evolving Roles, Practices, and Future Directions (2015-2024).
  49. The Price of Speed: Estimating the Impact of List Prices on Time to Availability of New Medicines in 18 European Countries.
  50. The evolving biology of T cell memory: A dynamic continuum of function and persistence.
  51. CD7 chimeric antigen receptor T cells in patients with relapsed or refractory CD7-positive acute myeloid leukemia.
  52. Rare disease genomics and justice: overview of a workshop at the Fondation Brocher, 22-24 January 2025.
  53. Impact of Disease Biology and Bridging Strategy on Outcomes After CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma.
  54. Minor histocompatibility antigen TCR-T.
  55. Allogeneic Hematopoietic Cell Transplant Following Standard of Care Brexucabtagene Autoleucel (Brexu-cel) in Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA).
  56. Identification of human DP8α regulatory T cell sub-populations reactive to health-associated anti-inflammatory gut commensals.
  57. Role of oral microbiome in cancer immunotherapy.
  58. Fecal microbiota transplantation: from empirical remedy to precision medicine.
  59. Early Feasibility Studies in Europe: A Multisite Qualitative Study of Operational Challenges and Site Selection Determinants at 6 University Hospitals.
  60. AI Privacy and Security in Healthcare: A Systematic Literature Review.
  61. Doubly robust augmented weighting estimators for the analysis of externally controlled single-arm trials and unanchored indirect treatment comparisons.
  1. Front Immunol. 2026 ;17 1828738
    Why CAR T cell therapy fails in renal cell carcinoma.
    Hua-Jun Zhang, Lv-Zhou Han, Xiang Zhang, Yang-Lu Ge.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of hematologic malignancies, yet its clinical efficacy in solid tumors remains limited. Renal cell carcinoma (RCC) presents a striking paradox: despite its established responsiveness to immune modulation and the expression of targetable tumor antigens, CAR-T therapies have failed to produce durable clinical benefit. This failure has often been attributed to antigen heterogeneity or lack of tumor specificity; however, accumulating clinical and experimental evidence suggests that antigen recognition alone does not determine therapeutic success in RCC. In this review, we discuss evidence that CAR-T failure in RCC may reflect consistent biological constraints suggesting a systemic mismatch between engineered T cells and the renal tumor ecosystem. Across clinical studies targeting multiple RCC-associated antigens, CAR-T cells demonstrate limited tumor trafficking, rapid functional decline, and poor intratumoral persistence, with little evidence of antigen-driven escape. We examine three interrelated barriers underlying this failure: immune exclusion driven by abnormal vasculature, hypoxia, and suppressive myeloid populations; profound metabolic competition and bioenergetic stress imposed by the uniquely rewired RCC microenvironment; and the insufficiency of antigen targeting in the absence of environmental support for sustained T cell function. We further discuss how these insights necessitate a shift from generic CAR-T platforms toward RCC-adapted cellular therapies. Strategies that enhance tumor homing, improve metabolic fitness, tolerate hypoxia, and actively remodel the myeloid-dominated microenvironment may be essential for achieving durable efficacy. Finally, we outline implications for clinical trial design, patient selection, and biologically rational combination strategies. Reframing CAR-T therapy as a systems-level intervention, rather than a target-restricted cytotoxic approach, may be critical for unlocking its potential in renal cell carcinoma.
    Keywords:  CAR-T cell therapy; hypoxia; metabolic reprogramming; myeloid cell suppression; renal cell carcinoma; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1828738
  2. Sci Immunol. 2026 Jul 03. 11(121): eaej9802
    A breath of fresh AIR in novel CAR T cell design.
    Bin-Bin Schell, Laura Solt.
      Insertion of a compact motif into CARs enables activation-induced receptor shedding, thereby enhancing CAR T cell potency.
    DOI:  https://doi.org/10.1126/sciimmunol.aej9802
  3. Signal Transduct Target Ther. 2026 Jul 01. pii: 255. [Epub ahead of print]11(1):
    Advances and prospects in cell therapy for cancer: explorations from T cells to stem cells.
    Guisha Zi, Lei Zhang, Ling Zhou, Xiansheng Liu, Lingling Wang, Runxuan Zhou, Pengdou Zheng, Jia Wei, Xiaoping Chen, Shuang Wei.
      The increasing global burden of cancer necessitates innovative therapeutic strategies. Cell therapy represents a major breakthrough in oncology, evolving rapidly from the successful application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies to a multiplatform landscape characterized by the concurrent development of diverse strategies. Current research focuses on T cell receptor-engineered T (TCR-T) cells, tumor-infiltrating lymphocytes (TILs), gamma delta (γδ) T cells, CAR-natural killer (CAR-NK) cells, CAR-macrophages (CAR-Ms), and various strategies based on dendritic cells (DCs), B cells, and stem cells. The translational paradigm is expanding from the relatively mature field of hematologic malignancies to the more prevalent and mechanistically complex domain of solid tumors. In recent years, this field has exhibited a clear trend toward expansion from autologous therapies to allogeneic "off-the-shelf" platforms. Approaches such as CAR-NK and CAR-natural killer T (CAR-NKT) cell therapies exhibit significant clinical potential because of their low immunogenicity and reduced risk of graft-versus-host disease (GvHD). Concurrently, in vivo engineering technologies that directly deliver CAR genes in situ are emerging as promising approaches to lower costs and simplify manufacturing by bypassing complex ex vivo procedures. This review systematically outlines recent advances in these strategies, focusing on their mechanisms of action, target antigens, and clinical translation. Despite progress, formidable challenges remain, including tumor heterogeneity, the immunosuppressive tumor microenvironment (TME), and therapy-related toxicity. To address these challenges, future research will focus on novel target discovery, enhanced toxicity management, and scalable manufacturing processes. The integration of multidisciplinary technologies, such as multiomics analysis, artificial intelligence, and synthetic biology, will advance cell therapies toward safer, more effective, and widely accessible applications.
    DOI:  https://doi.org/10.1038/s41392-026-02780-8
  4. Nat Rev Immunol. 2026 Jul 02.
    A guide to CAR T cell therapies: development, current status and future prospects.
    Hind Rafei, Ranjan Upadhyay, Padmanee Sharma.
      Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foundational discoveries in T cell biology and synthetic immunoengineering, CAR T cell therapy has transformed the treatment of B cell malignancies, resulting in durable remissions in patients with B cell leukaemias, lymphomas and multiple myeloma. Next-generation CAR designs are now expanding the reach of this approach into autoimmune disease and solid tumours. Innovations in gene editing, allogeneic manufacturing and in vivo delivery are improving the scalability, safety and accessibility of CAR T cell therapies, although challenges persist in overcoming antigen heterogeneity and tumour microenvironmental barriers and in promoting the long-term persistence of CAR T cells. In this Review, we summarize the key discoveries that laid the foundations for CAR T cell therapies and provide a broad overview of the current principles of CAR design, their clinical development and emerging strategies aimed at enhancing efficacy, broadening indications and achieving durable immune control across disease types.
    DOI:  https://doi.org/10.1038/s41577-026-01322-1
  5. Oncol Lett. 2026 Aug;32(2): 361
    Application and challenges of chimeric antigen receptor T cell therapy in the treatment of acute myeloid leukemia (Review).
    Jingjing Zhang, Feilin Wang, Dandan Sui, Ziyi Huang, Yijian Chen.
      Chimeric antigen receptor (CAR) T cell therapy is a rapidly evolving form of targeted immunotherapy that merges the antigen-recognition specificity of monoclonal antibodies with the potent cytotoxic function of T cells. While it has achieved remarkable clinical success in B cell hematologic malignancies, its application to acute myeloid leukemia (AML) remains limited by several key obstacles. These include the absence of AML-specific antigens, antigen escape, an immunosuppressive tumor microenvironment and pronounced intratumoral heterogeneity. Together, these challenges substantially hinder the efficacy and safety of CAR-T cell therapy in AML. The present review provides a comprehensive overview of current advancements in CAR-T cell therapy for AML, with particular emphasis on strategies to overcome existing barriers such as improved target antigen selection, CAR structural optimization and modulation of the tumor microenvironment. These insights aim to inform the development of next-generation CAR-T therapies with enhanced precision, persistence and therapeutic benefit in AML.
    Keywords:  acute myeloid leukemia; chimeric antigen receptor T cells; targeted therapy
    DOI:  https://doi.org/10.3892/ol.2026.15716
  6. Neurotherapeutics. 2026 Jun 30. pii: S1878-7479(26)00121-2. [Epub ahead of print]23(6): e00951
    Neurological complications of current and emerging CAR-T cell therapies.
    Anna G Hauswirth, Jorg Dietrich.
      Harnessing an individual patient's immune system to enhance anti-tumor responses has been a long-standing goal in oncology. Multiple immune modulating or immune enhancing therapies have been FDA approved or are under development, utilizing varying strategies to engage the patient's own immune system. One such therapy is chimeric antigen receptor T-cell therapy (CAR-T), in which T-cells are genetically engineered to target specific antigens present on tumor cells. Multiple CAR-T products are currently approved for clinical use, with impressive and durable responses seen in hematologic cancers. With their efficacy for treating cancer comes the risk of complications, including a high frequency of neurologic complications. Based on the success seen with cellular therapies in hematologic cancers, these technologies are being tested for both the use in solid malignancies, including central nervous system tumors, and for their application in non-neoplastic conditions such as autoimmune diseases. As new CAR-T therapies are designed and introduced into clinical practice, it will be important to assess their risks of neurologic toxicity and to develop therapies to either prevent or treat these complications. Here, we provide an overview of the acute and potentially long-term neurologic complications encountered with these novel and powerful cellular therapies, focusing on emerging CAR-T technologies, their associated neurotoxicities and potential interventions to limit such neurologic complications.
    Keywords:  CAR-T cells; ICANS; Neurologic complications; Neurotoxicity; TIAN
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00951
  7. Nat Rev Immunol. 2026 Jun 30.
    T cell engagers in autoimmune diseases.
    Ricardo Grieshaber-Bouyer, Lei Wu, Georg Schett, Patrick A Baeuerle.
      T cell engagers (TCEs) are antibody-based, bispecific or multi-specific constructs that can reprogramme T cells to eliminate target cells expressing a defined surface antigen. Originally developed for cancer therapy, TCEs are now being investigated for the treatment of autoimmune diseases, with promising initial results. The interest in using TCEs for autoimmune diseases is rapidly growing given their comparable potency with cellular therapies, combined with the advantages of biologics, including ease of manufacturing, off-the-shelf availability, better safety and more convenient delivery. Here we review the history of TCEs, focus on distinct aspects of the mechanism of action of TCEs and explain design principles. We also discuss key challenges for future TCE development in autoimmunity, including enhanced safety, high convenience and complete target cell elimination. Finally, we provide an overview of the preclinical and clinical development landscape and give an outlook on next-generation TCEs that are optimized to treat a wide variety of autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-026-01318-x
  8. Front Immunol. 2026 ;17 1835582
    Research advances and application prospects of CAR-T therapy in the treatment of age-related diseases.
    Xiaoge An, Tingting Wu, Rong Gou, Yudong Fang.
      Cellular senescence constitutes the core biological basis of body aging. It not only directly drives the occurrence and progression of multiple age-related diseases, but also establishes and maintains a chronic inflammatory microenvironment through the senescence-associated secretory phenotype (SASP), thereby continuously exacerbating tissue functional decline. In recent years, CAR-T cell therapy, as the first revolutionary therapy in cancer immunotherapy, has opened up new ways to intervene in age-related diseases with its excellent target elimination capabilities. This article first studies the molecular mechanisms of cellular senescence and its pathological effects. Then a systematic overview of the design principles, development trajectory and current applications of CAR-T technology is given, focusing on the latest experimental and clinical advances in aging-related cancers, neurodegenerative diseases and cardiovascular diseases. We also dive into key current challenges, including immune-senescence, target reliability, and treatment safety. Finally, we will explore the future optimization direction of CAR-T therapy and its translational potential through various strategies such as engineered immune cells and combination therapy, hoping to provide valuable insights into research and clinical practice in this field.
    Keywords:  CAR-T therapy; age-related diseases; cellular senescence; immune senescence; immunotherapy; kidney diseases
    DOI:  https://doi.org/10.3389/fimmu.2026.1835582
  9. Front Immunol. 2026 ;17 1819470
    Fusion protein-mediated costimulation in engineered T cells: from intrinsic signaling to tumor microenvironment rewiring.
    Ryma Toumi, Simonne J Guenette, Shannon K Oda.
      Adoptive T cell therapies have markedly improved outcomes in hematologic malignancies but their efficacy in solid tumors can be diminished by a hostile tumor microenvironment that impedes sustained therapeutic responses. Beyond challenges such as limited trafficking and antigen heterogeneity, engineered T cells face suppressive myeloid and stromal populations, inhibitory checkpoint ligand interactions, and metabolically hostile niches that collectively diminish effector function and persistence. To overcome these barriers, a new generation of fusion protein-based costimulatory strategies has emerged that couple ligand-guided sensing of the tumor microenvironment with modular control of T cell activation and fate. This review examines how conventional and non-canonical costimulatory modules, when incorporated into chimeric antigen receptor (CAR) and T cell receptor (TCR) architectures, modulate T cell differentiation and function within the tumor site. It further analyzes how membrane-anchored and secreted fusion proteins enable engineered T cells to activate dendritic cells, reprogram myeloid cells, and convert poorly inflamed tumors into treatment-responsive environments. Together, these advances establish a design framework in which fusion protein-based receptors and ligands enhance T cell function and remodel the tumor microenvironment, thereby expanding the therapeutic potential of adoptive T cell therapy for solid tumors.
    Keywords:  T cell engineering; costimulatory signaling; fusion protein; myeloid cell reprogramming; switch receptor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1819470
  10. Cancer Causes Control. 2026 Jun 30. pii: 114. [Epub ahead of print]37(7):
    Advances and challenges in CAR-T cell therapy for breast cancer: from molecular design to clinical application.
    Honghao Yu, Wenzhi Feng, Di Lan, Qianyi Liu, Xia He, Siyu Zhang, Chunyu Tong, Bocui Song.
      Globally, breast cancer remains a leading cause of morbidity in women. Conventional therapies, including surgical intervention, radiation, and chemical treatments, though effective, frequently result in significant adverse effects and toxicity. CAR-T cell therapy represents a novel immunotherapeutic strategy, wherein T cells are genetically modified to precisely target and eradicate malignant cells. The article provides a detailed introduction to the structure and function of CAR-T cells, particularly the improvements in anti-tumor efficacy across different generations of CAR-T cells. Furthermore, the article explores the primary targets of CAR-T cell therapy in the clinical treatment of breast cancer, such as HER2, EGFR, and MUC1, and analyzes the potential and limitations of these targets in therapy. In conclusion, the review outlines significant hurdles in CAR-T cell therapy for breast cancer, such as tumor diversity, the inhibitory tumor milieu, unintended targeting, and cytokine storm, offering strategic solutions to mitigate these obstacles.
    Keywords:  Breast cancer; CAR-T cell therapy; Chimeric antigen receptor-T cells; Clinical targets; Immunotherapy
    DOI:  https://doi.org/10.1007/s10552-026-02200-w
  11. J Vis Exp. 2026 Jun 09.
    Standardized Flow Cytometry Assay Using Dried Recombinant Antibody Panels for CAR T Cell Characterization.
    Annika Ridzal, Anja Brauchle, Desiré Missing, Michael Hudecek, Marsilius Mues, Maik Luu, Concetta Quintarelli, Stephan Wilmes.
      Flow cytometry is commonly used to assess critical quality attributes of Chimeric Antigen Receptor T (CAR T) cells, including viability, phenotype, and transduction efficiency. Conventional liquid reagent workflows require multiple preparation steps, which can introduce variability and differences in operator-dependent handling. Preformulated dried recombinant antibody panels provide an alternative format that combines recombinant antibody technology with a ready-to-use configuration. Recombinant antibodies offer defined specificity and reduced lot-to-lot variability, while the dried format reduces preparation steps and simplifies reagent handling. Here, we present a step-by-step workflow for CAR T cell analysis using dried recombinant antibody panels. The protocol includes sample staining, data acquisition, and analysis, and is accompanied by a schematic overview of the workflow. Representative staining results are shown to illustrate panel application, and differences in hands-on time compared to a conventional liquid reagent workflow are highlighted. The examples provided demonstrate how these panels can be used to streamline the multiparametric characterization of CAR T cells. Overall, this work provides a practical framework for implementing dried recombinant antibody panels in flow cytometry-based CAR T cell analysis.
    DOI:  https://doi.org/10.3791/70343
  12. Front Immunol. 2026 ;17 1861111
    Resistance mechanisms and overcoming strategies for CAR T-cell therapy in B-cell hematologic malignancies.
    Pupu Li, Xia Xue, Zisen Zhang.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed/refractory (R/R) B-cell malignancies, including B-cell non-Hodgkin lymphoma (B-NHL), B-cell acute lymphoblastic leukemia (B-ALL), and related diseases. However, treatment failure caused by primary or secondary resistance remains a major clinical challenge, thereby limiting long-term efficacy and patient survival. Recent studies have systematically clarified the multidimensional mechanisms underlying resistance to CAR T-cell therapy, which can be broadly classified into tumor-intrinsic factors, CAR T-cell dysfunction, and an immunosuppressive tumor microenvironment (TME). At the same time, innovative strategies to overcome these barriers have rapidly emerged, including multitarget CAR design, metabolic and epigenetic modulation, and microenvironment remodeling. This review summarizes the latest advances in the mechanisms of resistance to CAR T-cell therapy and corresponding therapeutic strategies in B-cell malignancies, and further discusses future perspectives to provide a theoretical basis for optimizing CAR T-cell therapy.
    Keywords:  B-cell malignancies; CAR T-cell therapy; hematologic cancers; immunotherapy; overcoming strategies; resistance mechanisms
    DOI:  https://doi.org/10.3389/fimmu.2026.1861111
  13. Eur J Haematol. 2026 Jul 01.
    Outsmarting Antigen Escape: Next-Generation CAR T Cell Engineering Strategies for Durable Remissions in Hematologic Malignancies.
    Amr Ali Mohamed Abdelgawwad El-Sehrawy, Islam Alfreahat, Nurillo Bobokulov, Quvonch Tursunov, Gulnora Shakhmurova, Rajashree Panigrahi, Rswl Mahmoud Hashem, Neeraj Bainsal.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, producing unprecedented clinical responses in relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma, and multiple myeloma. Despite these advances, durable remission remains limited by disease relapse, with antigen escape emerging as one of the principal mechanisms of therapeutic resistance. This review comprehensively summarizes the biologic mechanisms underlying antigen escape and highlights emerging engineering strategies designed to overcome immune evasion and improve long-term CAR T-cell efficacy. We discuss both irreversible and reversible resistance pathways, including genetic alterations, alternative splicing, lineage plasticity, trogocytosis, epigenetic repression, and tumor microenvironment-mediated antigen modulation. Particular emphasis is placed on clinically relevant examples such as CD19 loss in B-ALL and BCMA dysregulation in multiple myeloma. The review further examines next-generation approaches developed to prevent antigen-negative relapse, including dual- and multi-target CAR constructs, logic-gated systems, pharmacologic enhancement of antigen density, epitope spreading, and TCR-mimic CAR platforms targeting intracellular antigens. In addition, we evaluate the major translational and biologic challenges associated with these advanced strategies, including structural complexity, manufacturing barriers, toxicity control, tumor heterogeneity, and limited long-term clinical validation. Finally, we discuss future perspectives involving single-cell and multi-omic technologies, computational modeling, and universal modular CAR systems that may enable the development of safer, more adaptable, and precision-guided cellular immunotherapies for hematologic malignancies.
    Keywords:  CAR T‐cell therapy; antigen escape; dual‐target CAR; hematologic malignancies; single‐cell multi‐omics; trogocytosis; tumor microenvironment
    DOI:  https://doi.org/10.1111/ejh.70252
  14. Biomed Pharmacother. 2026 Jul 01. pii: S0753-3322(26)00733-X. [Epub ahead of print]201 119697
    CAR-T cell therapy and oncolytic viruses: A synergic approach for advanced GI cancers.
    Seyed Kiarash Aghayan, Amin Azizan, Hadi Esmaeili Gouvarchin Ghaleh, Ebrahim Salimi-Sabour, Reza Mirnejad, Soheil Vazifedust, Mohamadali Abyazi, Vahid Nazarpour.
      Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, largely due to high recurrence rates, and limited responsiveness to existing systemic therapies. Although immunotherapy has transformed the management of several malignancies, its clinical impact in GI cancers has been comparatively modest. Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in hematological malignancies but faces substantial barriers in solid tumors, including poor trafficking, limited infiltration, antigen heterogeneity, and profound tumor microenvironment-mediated immune suppression. This review aims to critically evaluate the rationale, mechanisms, and emerging evidence supporting the combination of oncolytic viruses (OVs) with CAR-T cell therapy as a novel immunotherapeutic strategy for gastrointestinal malignancies. Accumulating evidence demonstrates that OVs can enhance CAR-T cell efficacy by improving tumor antigen availability, promoting immune cell trafficking and infiltration, reversing local immunosuppression, and supporting CAR-T cell activation and persistence. Diverse OV platforms-including cytokine-armed viruses, antigen-delivering vectors, and multifunctional immunomodulatory constructs-have shown synergistic antitumor effects with CAR-T cells in preclinical GI cancer models, often resulting in durable tumor regression and immunological memory. The integration of oncolytic virotherapy with CAR-T cell therapy represents a promising avenue to overcome key limitations of adoptive cell therapy in GI cancers. While clinical translation remains in its infancy, this combinatorial strategy offers a compelling framework for the development of more effective and durable immunotherapies for solid tumors.
    Keywords:  Adoptive Cell Therapy; Chimeric antigen receptor (CAR) T-cell therapy; Gastrointestinal Cancer; Oncolytic Virus; Tumor Microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2026.119697
  15. Front Med (Lausanne). 2026 ;13 1830105
    Infections and CAR-T cells for the treatment of lymphoid malignancies: a narrative review.
    Carolina Secreto, Filippo Fasano, Davide Stella, Mattia Novo, Barbara Botto, Marco Cerrano, Roberto Freilone, Alessandro Busca.
      The use of chimeric antigen receptor-T (CAR-T) cells have revolutionized the therapeutic paradigm of patients with lymphoid malignancies. However, infectious complications represent a frequent CAR-T cell-related adverse event, potentially being a major hurdle for the successful outcome of the patients. The infection incidence follows a biphasic pattern, with "early" infections rising during the first 30 days after CAR-T cells infusion, and "late" infections from day 30 onward. Overall, bacterial infections prevail in the early phase after therapy, with a switch to viral or opportunistic infections in the long-term period, while invasive fungal infections are rare events after CAR-T therapy. Risk factors associated with infectious complications include host-related factors such as the underlying malignancy and previous treatments, and treatment-related factors [CAR-T cell product, cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHT), hypogammaglobulinemia]. Careful attention to signs and symptoms of infections is mandatory for an optimal management of patients undergoing CAR-T therapy, and strategies to mitigate infectious risk are clinically relevant: indeed, over half of non-relapse mortality in these patients is attributed to infections. In the present review we attempt to summarize the current knowledge on infectious complications occurring in patients receiving CAR-T cell therapy for lymphoid malignancies in order to provide the readers tools for better management and prevention strategies.
    Keywords:  antimicrobial prophylaxis; chimeric antigen receptor-T cell (CAR-T cell) therapy; infections; lymphoid malignancies; risk factors
    DOI:  https://doi.org/10.3389/fmed.2026.1830105
  16. Eur J Clin Pharmacol. 2026 Jun 29. pii: 191. [Epub ahead of print]82(7):
    Comparing National Health Technology Assessment approaches and the new European Joint Clinical Assessment framework: The case of onco-hematological medicines.
    Benedetta Starinieri, Eleonora Allocati, Chiara Gerardi, Roberta Joppi, Rita Banzi.
       PURPOSE: To analyze national-level evaluations conducted by selected Health Technology Assessment (HTA) bodies and compare them with the methodological framework outlined in the European HTA Regulation for Joint Clinical Assessment (JCA), in order to assess whether JCA would improve alignment among national practices.
    METHODS: We used onco-hematological medicines as a case model. From the European Medicine Agency (EMA) website, we identified onco-hematological medicines licensed from January 2023 to April 2025 and the pivotal trials supporting their marketing authorization (MA). We retrieved the reports of seven national HTA agencies and examined the rationale and evidence underlying the agencies' evaluation and their final recommendations. To estimate how the JCA opinion would have changed compared to those taken by the national HTA authorities, we developed a set of possible Population, Intervention, Comparators, and Outcomes (PICOs) and applied JCA criteria to selected medicines.
    RESULTS: We assessed ten trials supporting the MA of eight medicines. All except momelotinib were approved based on one single pivotal trial. Six were single-arm studies. By June 2025, 22 national HTA reports were available for six medicines, incorporating pivotal trial data and indirect treatment comparisons for five medicines. Overall, recommendations from HTA agencies varied. The PICO scoping process generated at least four PICOs per medicine, reflecting high heterogeneity across countries. The limited evidence at the time of MA was insufficient to address all the PICOs.
    CONCLUSION: Although JCA strengthens procedural harmonization, the current HTA fragmentation may persist due to the proliferation of PICOs and divergent interpretations of evidence.
    Keywords:  European HTA Regulation; Health technology assessment; Indirect comparisons; Joint Clinical Assessment; Onco-hematology
    DOI:  https://doi.org/10.1007/s00228-026-04123-6
  17. Front Immunol. 2026 ;17 1844927
    A federated digital twin reveals cytomegalovirus reactivation impairs CAR-T cell therapy via IL-15-mediated cytokine competition in B-Cell lymphoma.
    Padmasri Sridharan, Mini Ghosh.
       Background: Cytomegalovirus (CMV) reactivation occurs in 30-40% of seropositive patients receiving chimeric antigen receptor T-cell (CAR-T) therapy for B-cell lymphoma and is strongly associated with treatment failure. However, the causal immunological mechanism driving this failure whether through direct viral cytopathic effects, T-cell exhaustion, or resource competition remains undefined. Furthermore, existing predictive models lack the mechanistic insight needed to guide intervention. We developed a privacy-preserving, mechanistic digital twin to test the "cytokine sink" hypothesis, wherein CMV-specific CD8+ T cells compete with CAR-T cells for the limiting homeostatic cytokine IL-15 .
    Methods: We constructed a system of ordinary differential equations formalizing this competition for IL-15 . The model was trained using a Hierarchical Bayesian Federated Averaging algorithm on multi-institutional data from 414 patients across five academic cancer centres (Sites A-E). without centralizing raw patient data. An independent sixth centre (Site F, n=89 ) served exclusively as the prospective validation site and contributed no data to the training process. In silico counterfactual analyses and simulations of antiviral prophylaxis were performed.
    Results: The digital twin predicted clinically significant CMV reactivation defined as CMV viral load ≥10,000 IU/mL by Day 28 post-infusion (primary outcome; threshold selected based on ECIL-7 guidance for threshold-triggered pre-emptive antiviral therapy in T-cell-depleted immunotherapy) with an AUROC of 0.91 (95% CI:0.88-0.94) , significantly outperforming existing clinical risk scores. Two pre-specified secondary thresholds were also analysed: (i) any detectable reactivation (≥1,000 IU/mL ) and (ii) severe reactivation (≥50,000 IU/mL ). Under the structural assumptions of the fitted mechanistic model, the data are quantitatively consistent with IL-15 resource competition as a mechanism linking CMV reactivation to CAR-T impairment. Mechanistically, the model revealed that CMV reactivation was associated with reduced peak CAR-T expansion by 41.8% (p<0.001) in counterfactual analysis. Global sensitivity analysis identified the pre-infusion frequency of CMV-specific T-cell precursors (ξ) and the resource competition coefficient (α) as the primary drivers of this effect, explaining 38% and 29% of output variance, respectively. In silico simulation of a risk-adapted, digital-twin-guided antiviral prophylaxis strategy reduced projected six-month progression by 32% while reducing aggregate drug exposure by 36% . In the prospective validation cohort, the model-predicted kinetic impairment independently predicted progression-free survival (hazard ratio [HR] 3.4, 95% CI:1.5-7.8, p=0.004) . Formal model competition analysis against three alternative mechanistic hypotheses (Results Section 3.3) further supports the cytokine sink hypothesis over exhaustion-based or mediation-only alternatives.
    Conclusion: Under the structural assumptions of the fitted mechanistic model, the data are quantitatively consistent with IL-15 resource competition as a mechanism linking CMV reactivation to CAR-T impairment. Formal model competition analysis against three alternative mechanistic hypotheses further supports the cytokine sink hypothesis; randomised interventional evidence is required for definitive causal proof. We further demonstrate that a privacy-preserving, mechanistic digital twin can serve as a clinically actionable tool for early risk stratification and personalized intervention, while providing a scalable blueprint for collaborative systems immunology research. Definitive validation of clinical utility requires a randomised controlled trial in which treatment decisions are prospectively guided by the digital twin's predictions.
    Keywords:  B-cell lymphoma; CAR-T cell therapy; cytomegalovirus; digital twin; federated learning; immune resource competition; privacy-preserving machine learning; systems immunology
    DOI:  https://doi.org/10.3389/fimmu.2026.1844927
  18. Mol Ther Oncol. 2026 Sep 17. 34(3): 201260
    Development of chimeric antigen receptors targeting the γδ T cell receptor.
    Lauren C Cutmore, Norris Lam, Christina Amatya, Katherine A Weissler, Stephen M Hewitt, Danielle A Natrakul, James N Kochenderfer.
      T cell malignancies expressing γδ T cell receptors (TCRs) have poor prognoses. No approved treatments specifically target γδ T cell malignancies. To address this deficiency, we aimed to develop chimeric antigen receptors (CARs) targeting the γδ TCR. We generated a panel of CARs with variations in antigen-recognition domains, hinge and transmembrane (HTM) domains, and costimulatory domains. We expressed CARs in human T cells by γ-retroviral transduction. By assessing CAR T cell cytokine release in response to γδ TCR-expressing target cells, we identified two single-chain variable fragments (scFvs) with superior antigen specificity for the γδ TCR. CARs containing one of the two scFvs, which was designated maximal gamma-delta-long (MGDL), exhibited higher transduction efficiency. We compared three MGDL-containing CARs: MGDL-28Z (CD28 HTM and costimulatory domains), MGDL-CD828Z (CD8α HTM domains and CD28 costimulatory domain), and MGDL-CD8BBZ (CD8α HTM domains and 4-1BB costimulatory domain). Levels of antigen-specific cytokine release were higher for T cells expressing MGDL-28Z compared with the other MGDL CARs. We tested T cells expressing the three MGDL-containing CARs in two murine γδ T cell leukemia treatment models. MGDL-28Z-expressing T cells caused the most anti-leukemia activity and longest mouse survival. These findings support testing MGDL-28Z-expressing T cells in a clinical trial.
    Keywords:  CAR; cancer; chimeric antigen receptor; immunotherapy; leukemia; lymphoma; t cell; γδ T cells
    DOI:  https://doi.org/10.1016/j.omton.2026.201260
  19. Clin Hematol Int. 2026 ;8(2): 63-72
    Current landscape of academic and point of care CAR-T cell therapy in low-middle income countries.
    Sofía I Quezada-Ramírez, José E Montelongo-Cepeda, Gabriel A González-López, Rosario Salazar-Riojas, Dalila M Alvarado-Navarro, Andrés Gómez-De León, David Gómez-Almaguer.
      Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a transformative treatment for patients with relapsed or refractory hematologic malignancies, offering new possibilities beyond conventional transplantation. Since their approval in high-income countries, CAR-T products have demonstrated remarkable efficacy; however, their implementation in low- and middle-income countries (LMICs) remains limited due insufficient infrastructure, complex regulatory requirements and high costs. In some countries, like Mexico, these barriers are particularly pronounced, with limited access to clinical-grade vectors, early phase clinical research programs, and lack of government and private sector infrastructure and funding opportunities. Facing these challenges, there is a substantial patient population with B-cell acute lymphoblastic leukemia, multiple myeloma, or diffuse large B-cell lymphoma, who could benefit from CAR-T therapy. Advances in point-of-care manufacturing within academic settings -particularly the use of closed, semi-automated systems- have demonstrated feasibility in LMICs, by reducing costs and simplifying procedures, while maintaining product quality. These approaches may provide a viable alternative to commercial products, with the potential to lower the economic burden and increase accessibility. Regulatory innovation with the establishment of expert multidisciplinary oversight committees, will also be critical to ensure safe implementation. Ultimately, CAR-T therapy in LMICs is both a scientific and public health opportunity, and its integration into healthcare systems will depend on collaborative strategies that address financial, logistical, and policy barriers. By highlighting our experience, this review underscores the importance of developing locally adapted solutions to expand access to advanced cellular therapies in resource-constrained settings.
    Keywords:  CAR-T; cellular therapy; lower-income countries; point-of-care
    DOI:  https://doi.org/10.46989/001c.163505
  20. Med Oncol. 2026 Jul 03. pii: 211. [Epub ahead of print]43(8):
    Expedited regulatory approval pathways for novel oncology drugs.
    Vikesh Kumar Shukla, Akshma Chauhan, Krishnajit Malakar, Manshi Rana.
      Expedited regulatory approval pathways are vital for providing timely patient access to novel therapies in oncology and other serious conditions. The traditional drug development pathway can take significant time, substantial costs (often more than ten years), and has a relatively low success rate. Programs such as the FDA's Accelerated Approval and Breakthrough Therapy, JP-PMDA's Sakigake Designation and Conditional Early Approval, AU-TGA's Priority Review and Provisional Approval, CDSCO's Accelerated Approval Mechanism and Emergency Use Authorization and the EMA's PRIME scheme, utilize mechanisms like rolling review and surrogate endpoints to accelerate development. The primary benefit of these pathways is significantly reducing the time to market for promising drugs, addressing critical unmet medical needs. However, this speed introduces challenges, including reliance on immature data from surrogate endpoints and frequent delays in completing mandatory confirmatory trials. Despite these limitations, expedited pathways have delivered important treatments for rare diseases like cancer, demonstrating their purpose as innovative accelerators. This review critically analyses the benefits, risks, and global variations of these pathways and provides recommendations to enhance their robustness, transparency, and international harmonization. To ensure that patients receive prudent, appropriate, and prompt treatments. This study concludes that a balanced strategy - integrating rigorous pre-market assessment with robust, enforced post-marketing surveillance - is essential to ensure these pathways deliver both rapid and beneficial patient outcomes.
    Keywords:  Oncology drug approval; Patient access; Regulatory agencies (FDA, EMA, PMDA, TGA, CDSCO); Regulatory harmonization; Surrogate endpoints
    DOI:  https://doi.org/10.1007/s12032-026-03313-7
  21. J Clin Pharmacol. 2026 Jul;66(7): e70226
    FDA Gene Therapy Approvals (1998-2025): Current Status, Regulatory Evolution, and Future Directions.
    Charles Oo, Xiaofa Qin, Sherwin Kb Sy.
      FDA approvals of gene therapies began slowly and were concentrated within a few early modalities, but recent years have seen a marked acceleration across RNA-based agents, viral and non-viral in vivo platforms, and ex vivo genetically modified cell therapies. This expansion reflects the maturation of gene therapy into a diverse therapeutic class while revealing scientific, regulatory, and economic challenges that traditional development paradigms cannot fully accommodate. In response, FDA has introduced platform-aligned, risk-based initiatives-including the plausible mechanism framework, CMC flexibility initiative, and advanced manufacturing technologies program-to support individualized, mechanistically targeted, and potentially curative products. Persistent issues such as high upfront costs, manufacturing complexity, and payer constraints underscore the need for sustainable development and access models. Mechanistic and model-informed drug development, increasingly supported by AI/ML-enabled analytics, is becoming central to dose selection, safety evaluation, and durability prediction. These scientific, regulatory, and clinical-pharmacology perspectives define the evolving landscape of FDA gene therapy approvals and outline future directions needed to ensure durable benefit, equitable access, and long-term safety as genetic medicines expand into broader patient populations.
    Keywords:  FDA approvals; advanced manufacturing; biologics license applications (BLAs); drug development strategy; gene therapy; genetic‑medicine platforms; genome editing; regulatory science
    DOI:  https://doi.org/10.1002/jcph.70226
  22. Transplant Cell Ther. 2026 Jul;pii: S2666-6367(26)00479-3. [Epub ahead of print]32(7): 773-774
    The Last Mile in CAR-T Cell Therapy.
    Biju George, Uday Kulkarni.
      
    DOI:  https://doi.org/10.1016/j.jtct.2026.06.012
  23. Front Oncol. 2026 ;16 1856798
    Universal CD7-targeted CAR T-cell therapy in T-ALL: a promising bridge to transplant, but not without caveats-a critical reappraisal.
    Qinghua Ke, Shiqiong Zhou.
      
    Keywords:  T-cell acute lymphoblastic leukemia; T-cell aplasia; allogeneic stem cell transplantation; antigen escape; base editing; therapeutic paradox; universal CAR-T cells
    DOI:  https://doi.org/10.3389/fonc.2026.1856798
  24. Cancer Lett. 2026 Jun 28. pii: S0304-3835(26)00463-5. [Epub ahead of print]657 218699
    Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.
    Chaoyang Zhu, Zhiwu Jiang, Rui Jing, Wei Guo, Yong Lu.
      The design of antigen-binding domains (binders) is emerging as a decisive frontier in chimeric antigen receptor (CAR)-T cell engineering. Rather than serving as passive recognition elements, binders actively shape antigen selectivity, signaling thresholds, exhaustion propensity, persistence, and toxicity. We propose that optimal CAR performance requires a multidimensional design strategy. Success cannot be achieved by maximizing a single variable like affinity. Designers must instead integrate epitope position, binding kinetics, avidity, molecular geometry, and biophysical stability. In this review, we synthesize recent advances showing how these parameters collectively govern immunological synapse formation, antigen-density discrimination, and functional durability. Importantly, we highlight that the consequences of binder design are increasingly evident not only in mechanistic and preclinical studies, but also in real-world clinical translation and commercial trajectories. We further examine how the binder landscape has expanded beyond conventional scFvs to include VHHs, monobodies, DARPins, D-domains, peptides, natural ligands, TCR-mimic binders, and de novo AI-designed proteins. Together, these advances support a shift from empirical binder selection to rational binder orchestration as a foundational principle for next-generation CAR-T immunotherapy.
    Keywords:  Binders; CAR engineering; CAR-T immunotherapy; Clinical translation; Tumor-associated antigens
    DOI:  https://doi.org/10.1016/j.canlet.2026.218699
  25. J Nucl Med. 2026 Jul 01. 67(7): 1021-1031
    CAR T-Cell Therapy for Cancer: Updates and Challenges for Response Assessment.
    Dorine de Jong, Jeremy P McGale, Timothy J Robinson, Matthew J Liao, Jeeban P Das, Ajay Major, Kathleen M Capaccione, Colton Ladbury, Jorge Mansilla-Soto, Hong Ma, Karine A Al Feghali, Andre H Goy, Egesta Lopci, Ran Reshef, Lawrence H Schwartz, Roch Houot, Laurent Dercle.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape for multiple hematologic malignancies, demonstrating a clear curative potential in select cases. Since 2017, 7 CAR T-cell products have indications approved by the Food and Drug Administration, and research is continuously evolving with the intent of enhancing CAR T-cell efficacy while reducing side effects and the risk of relapse. Nuclear medicine has played a crucial role throughout this optimization process, assisting initial staging, treatment response assessment, and adverse-effect monitoring. This review provides an introduction to CAR T-cell therapy and highlights gold-standard nuclear medicine practices and imaging innovations for use in the care of oncology patients. Additionally, it emphasizes the need for continuing innovation in medical imaging as the field progresses.
    Keywords:  CAR T-cell; hematologic malignancies; immunotherapy-related toxicity; nuclear medicine; therapy response assessment
    DOI:  https://doi.org/10.2967/jnumed.123.266605
  26. Crit Rev Oncol Hematol. 2026 Jun 27. pii: S1040-8428(26)00348-3. [Epub ahead of print]226 105461
    Artificial Intelligence in drug discovery and development: current landscape, challenges, and future perspectives.
    Attila A Seyhan, Claudio Carini.
      Artificial intelligence (AI) is transforming drug discovery and development, fields historically constrained by long timelines, high costs, and substantial attrition. Recent advances, particularly in generative modeling, enable an accelerated and increasingly systematic exploration of vast chemical and biological spaces, improving molecular interaction modeling and streamlining the identification and optimization of therapeutic candidates. However, the true utility of this expanded search space remains strictly bounded by the quality of upstream data and the logistical constraints of downstream experimental validation. Emerging platforms, including scaffold-aware and 3D molecular design tools (e.g., AlphaFold, MoleR, and PocketCrafter), single-cell foundation models, and large language models (LLMs), are expanding AI's applicability across the research and development pipeline, spanning target identification, drug discovery, lead optimization, phenotypic screening, and precision biology.AI is also increasingly integrated into preclinical and clinical research workflows, informing adaptive trial design, enabling AI-driven drug repurposing, and supporting the development of safer and more personalized therapies. While the U.S. FDA has approved numerous AI-enabled medical devices and software tools, no fully AI-discovered and AI-designed drug has yet received marketing approval. Nonetheless, several AI-originated candidates have progressed into clinical development, underscoring AI's growing translational impact. Collectively, these advances position AI as a collaborative "lab partner," capable of uncovering non-intuitive molecular designs, accelerating target and lead optimization, and enabling exploration of previously inaccessible chemical and biological space to inform downstream development and clinical decision-making. Despite gains in efficiency, scalability, and cost reduction, the broader impact of AI depends on access to high-quality multimodal data, robust regulatory and ethical frameworks, and careful recognition of methodological limitations. This review critically examines the evolution of AI approaches, highlighting key challenges and opportunities that shape the future of data-driven therapeutic innovation.
    Keywords:  Artificial intelligence; and ethical and regulatory implications; clinical trials; drug repurposing; drug/target identification and development; generative AI
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105461
  27. EULAR Rheumatol Open. 2026 Mar;2(1): 62-68
    Fertility and pregnancy outcomes after CAR T-cell therapy: insights from a systematic review.
    Phillip Kremer, Marie-Therese Holzer, Nikolas Ruffer, Ina Kötter, Martin Krusche, Isabell Haase.
      Chimeric antigen receptor (CAR) T-cell therapy represents an emerging option for refractory autoimmune diseases, but long-term effects are unknown. Based on its remarkable effects in achieving drug-free remission in highly selected patients, a possible role in the early disease course is also discussed. With the increasing use of this treatment in patients of reproductive age, understanding its impact on fertility and pregnancy is crucial to provide counselling. Evidence from oncology provides valuable insights for rheumatology. We found 3 publications reporting 10 pregnancies after CAR T-cell therapy of the mother (n = 7) or the father (n = 3). In 8 of these 10 pregnancies, live births were confirmed, whereas the other 2 had unknown outcomes. One case of intrauterine growth retardation, 1 third-trimester bleeding in a mother with placenta previa, and 1 emergency section occurred. Neonatal outcomes were described in 3 cases: 1 polydactyly, 1 small for gestational age (SGA) neonate, and 1 healthy newborn. B-cell counts were normal in 2 infants and reduced in 1. Besides the reported use of assisted reproduction techniques in 2 pregnancies, no details on the fertility status before or after CAR T-cell therapy could be retrieved. Data on the impact of CAR T-cell therapy on fertility and pregnancy outcomes are scarce. Unlike oncology patients, many rheumatology patients eligible for CAR T-cell therapy are of reproductive age, further highlighting the need for tailored research and guidance. Addressing these gaps will be critical to ensure safe and informed reproductive health management for patients receiving CAR T-cell therapy in rheumatology.
    DOI:  https://doi.org/10.1016/j.ero.2025.11.011
  28. Front Immunol. 2026 ;17 1900363
    Editorial: Exploring unconventional T cells and CAR-T-cells in cancer immunotherapy.
    Laura Patrussi, Chenran Zhang.
      
    Keywords:  CAR T cell; MAIT (mucosal-associated invariant T) cell; gamma delta T (γδ T) cells; iNKT (invariant natural killer T cell); tumor microenvironment - TME; unconventional T cell
    DOI:  https://doi.org/10.3389/fimmu.2026.1900363
  29. J Clin Pharmacol. 2026 Jul;66(7): e70232
    Decoupling CAR-T Expansion, Conversion, and Decay Timing: Physiologically Aligned Semi-Mechanistic Modeling With Smooth Gating and a Cauchy Likelihood Residual Model.
    Yiming Cheng, Yan Li.
      Chimeric antigen receptor (CAR) T-cell therapies exhibit complex cellular kinetics with high variability, frequent observations below the limit of quantification (BLQ), and influential outliers. These features can destabilize parameter estimation under Gaussian assumptions, motivating robust likelihood-based approaches. While Student's t residuals with M3 censoring improve robustness, the lack of a closed-form cumulative distribution function (CDF) complicates implementation across platforms like Monolix. We evaluated the Cauchy distribution as an implementation-friendly, heavy-tailed alternative providing closed-form probability density and CDF expressions. In pharmacokinetic simulations with terminal-phase outliers, Cauchy residuals preserved stable parameter recovery comparable to Student's t while Normal residuals exhibited significant bias. In a real-data integrated CAR-T application using full Bayesian inference, Cauchy and Student's t likelihoods yielded highly concordant posterior inference and subject-level predictions. Furthermore, we extended the semi-mechanistic CAR-T framework by replacing piecewise switching with smooth, S-shaped rate functions and process-specific transition times. Full Bayesian summaries supported asynchronous transitions, revealing earlier memory conversion relative to expansion and delayed decay-related transitions. These results support Cauchy likelihoods for robust cross-platform implementation and demonstrate that smooth, decoupled transition modeling enhances the physiological plausibility of CAR-T kinetics.
    Keywords:  BLQ censoring (M3); CAR‐T; Cauchy likelihood; Student's t; cellular kinetics; robust nonlinear mixed‐effects modeling
    DOI:  https://doi.org/10.1002/jcph.70232
  30. Jpn J Clin Oncol. 2026 Jul 01. pii: hyag103. [Epub ahead of print]
    Immune effector cell-associated hematotoxicity following CAR-T cell therapies: insights from a large national database.
    Connor Frey.
      Immune effector cell-associated hematotoxicity is a recognized but incompletely characterized complication of chimeric antigen receptor T-cell (CAR-T) therapy, defined by prolonged, severe, or recurrent cytopenias following CAR-T infusion, not explained by conditioning chemotherapy or disease progression alone. Despite formal consensus grading criteria from the European Hematology Association and European Bone Marrow Transplantation group, the post-marketing pharmacovigilance profile of ICAHT across all approved CAR-T agents has not been systematically described. The FDA Adverse Event Reporting System (FAERS) was queried through March 2026 using OpenVigil 2.1 for all seven currently FDA-approved CAR-T products. Disproportionality was assessed using the Reporting Odds Ratio (ROR) with 95% confidence intervals, Proportional Reporting Ratio with chi-squared statistic, and Bayesian Reporting Rate Ratio. An adverse drug reaction classification was applied when all three signal detection thresholds were simultaneously met. ICAHT cases were identified in five of seven agents. Axicabtagene ciloleucel had the highest case count (n = 18) and most precisely estimated ROR (1365.54; 95% CI: 778.83-2394.24). All five agents with ICAHT reports met pre-specified signal detection criteria across all three analytical methods, with lower ROR confidence bounds substantially exceeding 1.00 in every case. No ICAHT reports were identified for obecabtagene autoleucel or tisagenlecleucel, with the former having minimal post-marketing data and the latter potentially reflecting genuine mechanistic differences related to its 4-1BB co-stimulatory domain. These findings demonstrate that ICAHT generates exceptionally strong and concordant pharmacovigilance signals across multiple CAR-T products, supporting heightened post-infusion hematologic monitoring with a low threshold for investigating unexplained cytopenias.
    Keywords:  Bayesian analysis; CAR-T; ICAHT; axicabtagene ciloleucel; immune effector cell-associated hematotoxicity
    DOI:  https://doi.org/10.1093/jjco/hyag103
  31. Facial Plast Surg Clin North Am. 2026 Aug;pii: S1064-7406(26)00040-4. [Epub ahead of print]34(3): 495-499
    Direct Injection of Stem Cells and Differentiated Cells: European Experience and Dubai Perspective.
    Jaffer Khan, Zara Yousufzai.
      This article reviews the clinical application of direct injection of stem cells and differentiated cells, comparing established European experience with the rapidly evolving regenerative medicine landscape in Dubai. It highlights the strongest evidence in orthopedic applications, outlines current limitations in standardization and long-term outcomes, and examines emerging technologies such as exosomes and engineered cellular therapies. Differences in regulatory frameworks and clinical adoption are discussed, emphasizing the need for continued evidence-based integration and ethical oversight in the expansion of regenerative medicine.
    Keywords:  Advanced therapy medicinal products; Induced pluripotent stem cells; Mesenchymal stem cell; Stromal vascular fraction
    DOI:  https://doi.org/10.1016/j.fsc.2026.05.005
  32. Biomark Res. 2026 Jul 03.
    Guided immunotherapy for residual solid tumor: integrating platelets and CAR T cells to reduce post-surgical recurrence.
    Farshad Heydari, Hoda Zendehdel, Mahsa Manafi Varkiani, Soheila Fahmi, Mehdi Derakhshani, Samira Anvari, Fatemeh Farhid, Michael R Hamblin, Jalal Naghinezhad.
      Postoperative recurrence remains a major obstacle to durable remission in patients with solid tumors, even after complete macroscopic resection. Growing evidence suggests that surgery creates a transient yet highly permissive biological window characterized by inflammatory signaling, coagulation activation, endothelial disruption, and systemic immune suppression. Together, these processes foster a protective niche that enables microscopic residual disease to evade immune surveillance and initiate metastatic outgrowth. Although modern adjuvant therapies have improved outcomes, their effectiveness is often limited by inadequate tumor-site specificity, systemic toxicity, poor immune cell trafficking, and tumor heterogeneity. Consequently, a critical unmet clinical need persists for biologically precise strategies capable of eliminating residual tumor cells at their point of vulnerability. Platelets, traditionally viewed as mediators of hemostasis, are now recognized as active regulators of tumor progression. By facilitating fibrin deposition, shielding circulating tumor cells from immune attack, and shaping inflammatory networks, platelets inadvertently support the survival of postoperative tumors. Paradoxically, these same wound-targeting properties create a compelling therapeutic opportunity: leveraging platelet-driven homing mechanisms to direct immunotherapy precisely to fibrin-rich surgical beds where recurrence often originates. In this review, we propose a platelet-guided CAR-T platform that leverages endogenous wound biology to create a precision immunotherapeutic delivery system. This strategy integrates platelet membrane cloaking or platelet-CAR-T conjugation with thrombin-responsive biomaterial depots to enhance local effector retention, amplify effector-to-target ratios, and prolong functional persistence. Programmable safety features, including affinity tuning, logic-gated activation, and inducible suicide switches, are used to reduce thrombo-inflammatory risk while preserving therapeutic efficacy. These mechanisms restrict activity to appropriate contexts and allow controlled shutdown in case of adverse events, improving overall safety. When coupled with minimal residual disease-guided patient selection using circulating biomarkers, this approach establishes a clinically actionable framework for perioperative intervention. Emerging preclinical evidence suggests that localized platelet-assisted delivery can reduce circulating tumor cell burden, enhance antigen presentation when combined with immune adjuvants, and suppress recurrence more effectively than systemic therapies. With rigorous safety validation, scalable manufacturing, and biomarker-enriched clinical trials, platelet-guided CAR-T therapy has the potential to transform the postoperative microenvironment from a sanctuary of tumor survival into a targeted domain for durable immune-mediated eradication.Clinical trial numberNot applicable.
    Keywords:  CAR-T cell therapy; Drug delivery systems; Immunotherapy; Minimal residual disease; Platelet-guided drug delivery; Tumor microenvironment; Tumor recurrence
    DOI:  https://doi.org/10.1186/s40364-026-00957-5
  33. Nat Cancer. 2026 Jul 01.
    GPNMB-directed CAR-T cell therapies for solid tumors.
    Christopher W Mount, Marcela V Maus.
      
    DOI:  https://doi.org/10.1038/s43018-026-01201-7
  34. J Am Chem Soc. 2026 Jul 01.
    High-Precision Intrinsic Interactome Elucidation of Chimeric Antigen Receptors via Photocatalytic Micromapping (μMap-CAR).
    Sean W Huth, Chenmengxiao Roderick Pan, Philip Raftopoulos, Ciaran P Seath, Gabrielle H Lovett, Beryl Li, Sushma Yechan Gunja, Vaishali Agarwal, Yuka Amako, Harris Bell-Temin, Helen Pham, Helen Evans, Jennifer X Qiao, Haibo Liu, Brook Barajas, David W C MacMillan.
      Chimeric Antigen Receptor T-cell (CAR-T) therapies represent a powerful modality for treating a variety of hematological cancers. However, limited efficacy in broader disease contexts, particularly solid tumors, underscores the need for improved CAR design to enhance potency, persistence, and safety. Key design features of CARs have been profoundly informed by extensive knowledge of the T-cell receptor (TCR) and its interactome. To advance CAR-T therapies, new functionally relevant proteins are needed to support engineering efforts. Until now, the actual molecular microenvironment surrounding CARs has remained poorly defined, chiefly due to the lack of a characterization method with the required precision and sensitivity. Herein, we introduce μMap-CAR, a high-resolution photocatalytic proximity labeling platform featuring key methodological optimizations that enable direct elucidation of the CAR interactome on live T-cell surfaces. The platform performs robustly in a model CAR-T cell system under both resting and simulated activation conditions. The high sensitivity of μMap-CAR allows interrogation of interactome differences upon CAR endodomain alterations, linking perturbed signaling networks directly to CAR components. We further deliver the first high-resolution intrinsic CAR interactome in primary T-cells, defined by shared interactors across donors, and validate candidates via super-resolution microscopy and CAR-T activation perturbation. This platform constitutes a powerful, broadly applicable tool for CAR interactome profiling while also providing actionable targets for proximity-guided CAR engineering applications.
    DOI:  https://doi.org/10.1021/jacs.6c08969
  35. Ann Pharm Fr. 2026 Jul 02. pii: S0003-4509(26)00107-0. [Epub ahead of print]
    [Artificial Intelligence in the Pharmaceutical Industry: Governance, Quality, and Regulatory Challenges].
    Ouedraogo Jean-Marie.
       OBJECTIVE: Artificial intelligence (AI) is progressively transforming the pharmaceutical industry by impacting manufacturing, quality assurance, regulatory affairs, supply chain management, and governance of industrial systems. The objective of this review is to provide a critical synthesis of the applications, limitations, and regulatory challenges associated with the integration of AI into regulated pharmaceutical environments.
    METHODOLOGY: This narrative review is based on a corpus of more than forty recent academic publications, institutional reports, and regulatory documents covering pharmaceutical manufacturing, Good Manufacturing Practices (GMP), quality assurance, regulatory affairs, supply chain management, data governance, organizational adoption, and sustainability.
    RESULTS: AI contributes to process optimization, predictive maintenance, real-time quality control, document automation, regulatory decision support, and improved supply chain performance. It also promotes the emergence of more connected and adaptive production models within the framework of Pharma 4.0. However, these benefits remain highly dependent on data quality and interoperability, model validation, system explainability, cybersecurity, GMP constraints, governance requirements, and the control of generative AI use in regulated environments.
    CONCLUSION: AI represents a major driver of transformation in the pharmaceutical industry, but its value depends on its integration into robust industrial, organizational, and regulatory frameworks. The development of pharmaceutically credible AI requires systems that are validatable, governable, auditable, and compatible with the trust requirements inherent to healthcare activities.
    Keywords:  Artificial Intelligence; Durabilité; Industrie pharmaceutique; Innovation technologique; Intelligence Artificielle; Pharmaceutical Industry; Sustainability; Technological Innovation
    DOI:  https://doi.org/10.1016/j.pharma.2026.06.011
  36. Immunol Invest. 2026 Jul 01. 1-31
    Immune Reconstitution After Hematopoietic Stem Cell Transplantation: Cellular Dynamics, Clinical Determinants, and Emerging Therapeutic Strategies.
    Eida Elmansorry.
       BACKGROUND: Immune reconstitution following HSCT is a complex process that strongly determines post-transplant outcomes. Delayed or impaired immune recovery increases susceptibility to opportunistic infections, viral reactivation, graft-versus-host disease, relapse, and transplant-related morbidity and mortality.
    OBJECTIVE: This review summarizes current evidence on the kinetics, functional recovery, and clinical significance of innate and adaptive immune reconstitution after HSCT.
    METHODS: A narrative review of recent literature was performed focusing on immune cell reconstitution dynamics and influencing clinical and biological factors.
    RESULTS: Innate immunity (neutrophils, NK cells) recovers early, providing initial defense. Adaptive immunity is delayed, driven by thymic output and peripheral T- and B-cell expansion. Regulatory T cells and γδ T cells support tolerance and graft-versus-leukemia effects. Recovery is influenced by age, conditioning, graft source, GVHD, infections, and microbiome. Numerical recovery may not equal functional immune competence.
    CONCLUSION: Advances in immune profiling, biomarkers, and systems immunology, along with adoptive cellular therapy and microbiome-based interventions, may enable personalized strategies to improve immune reconstitution and long-term outcomes.
    Keywords:  Hematopoietic stem cell transplantation; graft-versus-host disease; immune monitoring; immune reconstitution; natural killer cells; precision immunology
    DOI:  https://doi.org/10.1080/08820139.2026.2696004
  37. Nat Rev Gastroenterol Hepatol. 2026 Jun 30.
    Engineering immune cell therapies for inflammatory bowel disease: from stem cells to CAR T cells.
    Markus F Neurath, Raja Atreya, Jean-Frederic Colombel, Saurabh Mehandru.
      Despite the development of novel small molecules and antibody-based therapies targeting pro-inflammatory immune pathways, the clinical management of inflammatory bowel disease (IBD) remains challenging. In this Perspective, we highlight emerging treatment strategies with a focus on engineered cellular immunotherapies, including stem cell-based approaches, regulatory T cell and type 1 regulatory T cell therapies, as well as chimeric antigen receptor (CAR) T cell platforms (CAR T cells, CAR Treg cells). Early-stage studies using haematopoietic and mesenchymal stem cells have yielded promising clinical results, although the safety and efficacy of such therapies require further careful validation. Moreover, efforts in immune cell engineering are now directed towards the expansion and adoptive transfer of allogeneic IL-10-producing type 1 regulatory T cells and autologous transforming growth factor-β-secreting regulatory T cells, which are currently being evaluated in early-stage clinical trials. Notably, a recent case report demonstrated that CD19-targeted CAR T cell therapy can induce long-term remission of intestinal inflammation in ulcerative colitis, highlighting a potential pathogenic role of mucosal B cells and plasmablasts in ulcerative colitis and underscoring the transformative therapeutic potential of CAR T cell strategies in IBD. Although these approaches offer exciting therapeutic prospects in IBD, rigorous prospective and controlled clinical trials are essential to fully assess their safety and efficacy.
    DOI:  https://doi.org/10.1038/s41575-026-01226-4
  38. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261464315
    Proteomics in Acute Myeloid Leukemia: Current Applications in Precision Medicine and Targeted Immunotherapy.
    Eva De Backer, Florian Van Oers, Zwi Berneman, Sébastien Anguille.
      Acute myeloid leukemia (AML) is a heterogeneous and aggressive malignancy with limited therapeutic options and high relapse rates. Despite advances in genomic profiling, many genetic aberrations remain untargetable, and current risk stratification models often fail to predict treatment responses. Proteomics offers a complementary approach by directly measuring protein abundance, post-translational modifications, and protein-protein interactions, providing mechanistic insights into drug resistance, disease progression, and therapeutic vulnerabilities. In this review, we explore the emerging role of proteomics in AML, focusing on its application in biomarker discovery, prediction of drug responses, and identification of novel therapeutic targets. Special attention is given to antigen discovery for immunotherapy, where surface and immunopeptidomics enable the identification of AML-specific antigens and neoepitopes. These insights are critical for the development of antigen-targeted therapies, including chimeric antigen receptor (CAR) and T cell receptor (TCR)-based immunotherapies. Integrating proteomics into a multiomics framework could provide actionable insights for guiding precision medicine and improving AML outcomes.
    Keywords:  acute myeloid leukemia; immunotherapy; multi-omics; precision medicine; proteomics
    DOI:  https://doi.org/10.1177/15330338261464315
  39. Mol Ther Adv. 2026 Sep 10. 34(3): 201763
    Epitope mapping of humoral immunogenicity of orvacabtagene autoleucel shows an IgM response with minimal impact on CAR T cellular kinetics.
    Xianghong Liu, Hongxiang Hu, Yanshan Dai, Michael Pazos, Jochem Gokemeijer, Ken Ogasawara, Oda Stoevesandt, Volker Stadler, Johanna Mora, Vibha Jawa.
      Orvacabtagene autoleucel (orva-cel) is a fully human B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapy evaluated in a phase 1/2 study in patients with relapsed or refractory multiple myeloma (RRMM). To assess treatment-related immunogenicity, anti-CAR therapeutic domain-specific antibodies (ATAs) were monitored in 157 treated patients. The ATAs were detected in 44.6% of patients over the course of study, with titers and incidence increasing over time. The goal of this study was to further characterize the observed immune response. The ATA status did not affect CAR T cell expansion or patient survival outcomes, though reduced persistence was observed in ATA-positive patients. Comprehensive immune profiling-including isotype analysis and B cell epitope mapping-identified five immunodominant consensus peptide sequences within the CAR domain. These epitopes were targeted by both Immunoglobulin G (IgG) and Immunoglobulin M (IgM) isotypes, with a persistent IgM response detected in most ATA-positive individuals. Despite the presence of ATAs, no adverse impact on cellular expansion was observed, potentially due to lymphodepletion and baseline immune suppression characteristic of B cell malignancies. These data suggest that the limited functional T- and B-cell capacity in RRMM may attenuate the clinical consequences of ATA development. The in vitro immunogenicity risk assessment and epitope mapping identified immunogenic hotspots within the CAR structure, which could have led to the high incidence of immune response observed in the patients. However, the analysis from this study points to a weak clinically non-relevant nature of the response that could be attributed to the patient's immune status and diseased state.
    Keywords:  B cell epitope mapping; CAR T cell; IgM isotype; anti-therapeutic antibodies; cellular kinetics; humoral immunogenicity; multiple myeloma; orvacabtagene autoleucel
    DOI:  https://doi.org/10.1016/j.omta.2026.201763
  40. Stud Health Technol Inform. 2026 Jun 29. 338 668-672
    Interoperability-Driven Digital Twins in Healthcare: A Conceptual and Technical Analysis of FHIR, openEHR, and OMOP.
    Somayeh Abedian, Diego Boscá, Severin Kohler.
      Digital Twins (DTs) are gaining attention as a promising approach for next-generation healthcare systems. However, their real-world adoption remains limited, mainly due to fragmented data environments and a lack of effective interoperability across clinical systems. Although much of the current research focuses on modeling and advanced analytics, the role of interoperability as a structural enabler has received less attention. This paper examines interoperability as a core requirement for healthcare DTs. It considers how three commonly used standards, HL7 FHIR, openEHR, and the OHDSI OMOP Common Data Model, support different needs across the DT lifecycle, including data exchange, semantic representation, and data reuse for analysis. Each of these standards is effective in specific contexts. OMOP, for instance, is widely used for cohort studies, openEHR supports structured longitudinal records, and FHIR is effective for system integration and data exchange. However, developing more complete DT solutions requires coordinating these complementary capabilities. The paper takes a lifecycle-and role-based view, suggesting that DTs are better understood as the result of coordinated data infrastructures rather than standalone systems. This lifecycle framework provides actionable guidance for scalable DT architectures.
    Keywords:  Digital Twins; HL7 FHIR; Healthcare Interoperability Standards; OMOP; openEHR
    DOI:  https://doi.org/10.3233/SHTI260929
  41. J Hematol Oncol. 2026 Jul 01. pii: 49. [Epub ahead of print]19(1):
    Large language model-guided CAR-T in silico platform for cytokine optimization in liver cancer with low antigen density.
    Haochen Nan, Xinyuan Shen, Youcheng Yang, Shubing Wang, Yan-Ruide Li.
      CAR-T cell therapy has shown remarkable success in hematologic malignancies but remains limited in solid tumors such as liver cancer due to antigen heterogeneity, low target antigen density, and an immunosuppressive tumor microenvironment (TME). Cytokine engineering can enhance CAR-T persistence and effector function; however, the optimal cytokine payload may vary depending on tumor type, target antigen expression level, and microenvironmental context, making systematic experimental comparison time-consuming and labor-intensive. Here, we applied a large language model (LLM)-based CAR-T in silico platform to systematically evaluate cytokine engineering strategies, including IL-2, IL-7, IL-12, IL-15, and IL-18, in glypican-3 (GPC3)-targeted CAR-T cells for liver cancer. We used cytokine selection as a biologically grounded benchmark to test whether the platform could recover known CAR-T cell-relevant cytokine biology and support future novel predictions. Computational predictions identified IL-15 as the most effective enhancer, particularly against tumor cells with low GPC3 expression. Guided by these results, we generated cytokine-armored GPC3 CAR-T cells and performed in vitro and in vivo validation. IL-15-engineered CAR-T cells exhibited superior proliferation, persistence, and serial cytotoxicity against GPC3-low liver cancer cells. In human liver cancer xenograft models, IL-15-enhanced CAR-T cells achieved improved tumor control compared with conventional and other cytokine-engineered CAR-T cells. The recovery of IL-15 served as a positive benchmark supporting the validity of the LLM-guided CAR-T in silico workflow. Collectively, this study establishes an LLM-guided framework, schema-constrained for rational cytokine selection in CAR-T engineering and identifies IL-15 as a potent enhancer for targeting antigen-low liver cancers.
    Keywords:  Agent-based modeling; Antigen escape.; CAR-engineered T (CAR-T) cell; Chimeric antigen receptor (CAR); Cytokine engineering; GPC3; IL-15; Large language model (LLM); Liver cancer; Physics of multicellular biology
    DOI:  https://doi.org/10.1186/s13045-026-01822-6
  42. EULAR Rheumatol Open. 2025 Oct;1(3): 103-104
    Editorial-Immune reset in sight: CAR-T cell therapy in autoimmune disease.
    Melanie Hagen, Georg Schett, Andreas Wirsching.
      
    DOI:  https://doi.org/10.1016/j.ero.2025.06.003
  43. EULAR Rheumatol Open. 2025 Oct;1(4): 368-371
    Genomic information contributing to the understanding of rheumatic diseases.
    Kazuhiko Yamamoto.
      Genomic information related to rheumatic diseases is accumulating, but the connection between this information and the understanding of diseases and better medical care is not yet sufficient. This review aims to provide an overview of the current status of genomic information that can contribute to rheumatic diseases.
    DOI:  https://doi.org/10.1016/j.ero.2025.10.007
  44. J Transl Med. 2026 Jun 27. pii: 827. [Epub ahead of print]24(1):
    Navigating AI and machine learning in cancer research: an end-to-end translational framework.
    Shalini Saha, Md Saif Ali, Anand Kumar Tengli, Sankeerthana Renuka Prasad, Pramod Mallikarjunaswamy, Ramkumar Pillappan, Komal Kumar Javarappa.
      Cancer is a complex and heterogeneous disease that is characterized by multi-level biological variability. Advances in high-throughput technologies have led to large-scale, high-dimensional data sets in cancer research, creating a pressing need for powerful computational techniques for successful data analysis. Current techniques may be inadequate for this purpose, thus underscoring the potential of artificial intelligence (AI) and machine learning (ML) for successful data analysis. This review provides a comprehensive pipeline for artificial intelligence/machine learning in cancer research, including preclinical research, clinical decision support, and real-world implementation. It emphasizes several important technologies, data integration, and implementation challenges. The review critically examines multi-omics fusion architectures, regularization-based machine learning, batch-effect harmonization, explainable AI, and federated learning, while addressing translational barriers including algorithmic bias, covariate drift, and regulatory asynchrony across Indian, US, and EU frameworks. Anchored by Decision Curve Analysis as a clinical utility benchmark, this narrative framework establishes that meaningful progress in precision oncology, early detection, and patient outcomes demands not only predictive accuracy but also externally validated, population-representative, and governance-compliant AI systems capable of sustained real-world oncology impact.
    Keywords:  Artificial intelligence; Big data; Cancer research; Clinical decision support; Machine learning; Multi-omics integration; Precision oncology
    DOI:  https://doi.org/10.1186/s12967-026-08503-5
  45. Clin Transplant Res. 2026 Jun 30. 40(2): 163-172
    Future of xenotransplantation in Korea.
    Ik Jin Yun.
      As the chronic shortage of human donor organs becomes an undeniable clinical reality, xenotransplantation has transitioned from a theoretical concept to the threshold of clinical integration. Recent successful pig-to-human kidney trials signify a pivotal milestone, shifting the scientific focus from feasibility to long-term sustainability and systemic implementation. This review critically evaluates the current status and future trajectory of xenotransplantation, challenging the "more is better" paradox of genetic engineering. It emphasizes the minimum viable edit set and the physiological superiority of miniature pigs overgrowth hormone receptor knockout models. Furthermore, the paper outlines a Korean-style governance model, integrating advanced digital transformation and specialized infrastructure. Key proposed strategies include (1) digital monitoring: implementing a noninvasive surveillance system utilizing donor-derived cell-free DNA, digital twins, and AI-driven early warning systems; (2) blockchain integration: establishing data integrity and tokenomics-based patient compliance through a sovereign medical coin system to incentivize lifelong surveillance; (3) infrastructure innovation: introducing the Hybrid Hospital Model, featuring a sterile barrier window between porcine and human surgical suites to achieve a zero-ischemia workflow. Finally, the study stresses the necessity of a Xenotransplantation Special Act and the collaboration between public organ procurement organizations and specialized private contract research organizations. By combining genetic minimalism and a robust legal framework, South Korea can establish itself as a global standard setter, transforming xenotransplantation into a standardized, manageable precision medical service.
    Keywords:  Hybrid hospital; Minimum viable edit
    DOI:  https://doi.org/10.4285/ctr.26.0026
  46. Glob Health Med. 2026 Jun 30. 8(3): 166-181
    Clinical artificial intelligence (AI) in Japan: Regulatory pathways, domain-specific evidence, and its data infrastructure from an international perspective.
    Kenji Karako, Wei Tang.
      Artificial intelligence (AI) has advanced rapidly across clinical domains, generating both a growing evidence base and dedicated regulatory frameworks for AI-based software as a medical device (SaMD). This review provides a comprehensive assessment of clinical AI across five major domains-diagnostic imaging, gastrointestinal endoscopy, cardiology and remote patient monitoring, diagnosis of infectious diseases, and an AI-ready data infrastructure-examining Japan's regulatory framework, approved device portfolio, and research contributions in an international context. We reviewed literature published between 2019 and 2026, using Japan's regulatory trajectory, approved device portfolio, and domain-specific research output as the primary lens for international comparison and prioritizing prospective studies, multicenter trials, and real-world implementation reports. The state of evidence varies markedly across the domains examined: endoscopy AI has the strongest randomized trial base, while diagnostic imaging AI has seen a systematic decline in real-world performance despite large-scale regulatory approval. Across the three dimensions examined, Japan has a distinctive profile: its strengths are a regulatory and clinical deployment infrastructure-evince by an established program medical device pathway and among the world's highest densities of diagnostic imaging systems and endoscopy volumes-while the data infrastructure lags, constrained by limited open-access resources relative to programs such as The Cancer Imaging Archive and the European Health Data Space. Large language models and generative AI, falling largely outside existing SaMD frameworks, carry the risk of hallucinations and gaps in oversight that healthcare systems in Japan and abroad are only beginning to address. Japan's established program medical device regulatory pathway, high-volume clinical deployment infrastructure, and proven regulatory-approval-to-reimbursement pathway provide a strong foundation for clinical AI adoption; post-approval change management frameworks and clinical accountability mechanisms need to be strengthened, AI-ready data accessibility needs to be expanded, and validated tools need to be embedded within reimbursed clinical workflows to translate this foundation into internationally competitive AI development and deployment.
    Keywords:  Japan; artificial intelligence (AI); data infrastructure; machine learning; software as a medical device
    DOI:  https://doi.org/10.35772/ghm.2026.01048
  47. Appl Microbiol Biotechnol. 2026 Jul 03.
    Perfusion development and its potential for cell therapy manufacturing with adherent cells.
    Samuel Lukas Schneider, Vivian Ott, Regine Eibl.
      Perfusion processing has established itself as a powerful intensification strategy for biopharmaceutical production processes of recombinant proteins. However, in the relatively young field of cell therapeutics manufacturing, this tool has been overlooked so far and with rising approvals, this field is in dire need of scalable and efficient production processes. In this regard, perfusion operation mode and related cell retention devices can be used to support upstream and downstream processing by automating operations, reducing contamination risk and ensuring stable cell quality. In this review, the history of cell retention technologies developed for suspension cell processing is laid out alongside the perfusion-based process intensification strategies they made possible. It is summarized how these technologies could be used to intensify the upstream processing of therapeutic adherent cells and to what degree perfusion processing of these demanding cells is already described in literature. Additionally, the applicability of cell retention devices for harvesting and downstream processing of therapeutic cells, which mainly consists of cell washing and formulation steps, is elaborated. In conclusion, through the implementation of scalable, single-use, good manufacturing practices compliant cultivation systems and cell retention devices, it should be possible substantially to accelerate the development of therapeutic adherent cell manufacturing strategies. KEY POINTS: • Perfusion can automate medium exchanges in therapeutic adherent cell manufacturing •  Perfusion technologies from suspension cell processing can be translated to adherent cell manufacturing • Scalable single-use perfusion systems are needed for the production of cell therapies.
    Keywords:  Cell retention device; Cell washing; Perfusion; Process intensification; Single-use technologies; Stem cell
    DOI:  https://doi.org/10.1007/s00253-026-13939-2
  48. Value Health Reg Issues. 2026 Jul 01. pii: S2212-1099(26)00060-9. [Epub ahead of print] 101645
    Real-World Evidence in Asian Health Technology Assessment: Evolving Roles, Practices, and Future Directions (2015-2024).
    Jing Wu, Daisuke Sato, Hae Sun Suh, Fei-Yuan Hsiao, Hong Li.
       OBJECTIVES: To examine the use of real-world evidence (RWE) in health technology assessment (HTA) for postlisting reimbursement decisions across 4 Asian healthcare systems-China, Japan, South Korea, and Taiwan-between 2015 and 2024.
    METHODS: We conducted a policy analysis and narrative literature review of HTA submissions, agency guidance documents, and published case examples from 2015 to 2024. Evidence on RWE use by country/region and therapeutic area was extracted from peer-reviewed literature, HTA reports, and official policy sources. Postlaunch evidence-generation mechanisms were summarized and qualitatively compared with practices in Europe (National Institute for Health and Care Excellence, Haute Autorité de Santé) and the United States (Centers for Medicare and Medicaid Services/Medicare).
    RESULTS: Use of RWE in Asian HTA increased steadily over the study period. In China, RWE is frequently used to inform epidemiology and economic parameters in National Reimbursement Drug List submissions. Japan applies RWE mainly for postlaunch price reassessment, particularly for oncology and orphan drugs. South Korea incorporates RWE into risk-sharing agreements and reassessment processes. Taiwan's Conditional Reimbursement Listing provides temporary coverage linked to real-world outcome generation. RWE use is most prominent in oncology and rare diseases.
    CONCLUSIONS: RWE is increasingly used to address postlisting uncertainty in Asian HTA. Structured, indication-specific RWE requirements following reimbursement are likely to expand, aligning Asian HTA systems more closely with international practice.
    Keywords:  Asian markets; China; HTA; Japan; RWE; South Korea; Taiwan; healthcare systems; postlaunch; reimbursement
    DOI:  https://doi.org/10.1016/j.vhri.2026.101645
  49. Appl Health Econ Health Policy. 2026 Jun 29.
    The Price of Speed: Estimating the Impact of List Prices on Time to Availability of New Medicines in 18 European Countries.
    Afschin Gandjour.
       OBJECTIVES: To examine whether higher national list prices for new medicines are associated with faster patient access across 18 European countries.
    METHODS: Data were drawn from the 2023 European Federation of Pharmaceutical Industries & Associations (EFPIA) Patients Waiting to Access Innovative Therapies (WAIT) Indicator Survey and the Swedish TLV's 2023 international price index. Time to availability was defined as the number of days between marketing authorisation and national reimbursement access. A multivariable linear regression model was applied, controlling for gross domestic product (GDP) per capita, population size, health technology assessment (HTA) duration, and the use of Managed Entry Agreements (MEAs). To address endogeneity, a two-stage least squares (2SLS) regression was conducted using a composite headquarters (HQ) Index as an instrumental variable for national list prices.
    RESULTS: In the multivariable model, each one-point increase in the list price index (European average = 100) was associated with a 7.9-day reduction in time to availability (p = 0.091). A slow HTA/reimbursement process was significantly associated with longer delays (p = 0.022). Managed entry agreement intensity was positively associated with longer delays but did not reach statistical significance (p = 0.103). In the 2SLS model, a one-point increase in the instrumented list price was associated with a 14.1-day reduction in access delays in the preferred parsimonious specification (p = 0.011). Sensitivity analyses showed that the negative association was generally preserved across alternative instrumental variable specifications and after exclusion of Poland, although effect sizes and first-stage strength varied.
    CONCLUSIONS: Higher national list prices may be associated with faster patient access to new medicines in European markets. Although the findings are consistent with a possible causal effect, they should be interpreted with caution given the sensitivity of the estimates to specification and sample composition, as well as concerns about instrument validity and strength. The results highlight a potential policy trade-off between affordability and timely availability in pharmaceutical pricing and access frameworks.
    DOI:  https://doi.org/10.1007/s40258-026-01053-3
  50. Sci Immunol. 2026 Jul 03. 11(121): eaeh4437
    The evolving biology of T cell memory: A dynamic continuum of function and persistence.
    Stephen J Turner, Daniel Thiele, Nicole L La Gruta.
      Immunological memory underpins long-term protection and vaccination. Although early work established the durability and recall capacity of memory T cells, understanding of CD8 T cell memory generation, maintenance, and plasticity has advanced substantially over recent decades. Initial models viewed memory as an outcome of peak effector responses and were defined mainly by persistence. Successive waves of technological innovation, from MHC tetramers and genetic lineage-tracing approaches to single-cell and epigenomic profiling and modern high-throughput gene-perturbation screens, have reshaped this view. These approaches reveal memory as a dynamic continuum of cellular states that is actively maintained, tissue-adapted, and epigenetically programmed. CD8 T cell memory is now understood as a flexible and regulated fate rather than a static end point. In this Review, we outline the historical development of the field, highlight how emerging technologies have refined core concepts, and present a modern framework in which memory is an actively enforced yet adaptable property of the CD8 T cell lineage.
    DOI:  https://doi.org/10.1126/sciimmunol.aeh4437
  51. Leukemia. 2026 Jul 03.
    CD7 chimeric antigen receptor T cells in patients with relapsed or refractory CD7-positive acute myeloid leukemia.
    Mingming Zhang, Lianxuan Liu, Shan Fu, Jingjing Feng, Haiqiong Zheng, Guoqing Wei, Ruimin Hong, Houli Zhao, Huijun Xu, Jiazhen Cui, Simao Huang, Xiaoyu Wu, Dongrui Wang, Alex H Chang, He Huang, Yongxian Hu.
      Although CAR-T cell therapy has revolutionized treatment for hematologic malignancies, its application in acute myeloid leukemia remains challenging. CD7 is expressed in approximately 30% of AML cases and represents a promising target. This phase I clinical trial (NCT04599556) evaluated CD7-targeted CAR-T cell therapy in patients with relapsed/refractory CD7-positive AML. Patients received a single infusion of autologous or donor-derived CD7 CAR-T cells using a standard 3 + 3 dose escalation design across two dose levels. The primary endpoint was the incidence of dose-limiting toxicities. Fourteen patients were enrolled. Treatment-related adverse events included cytokine release syndrome (92.9%), grade 3-4 cytopenia (100%), grade 1 neurotoxicity (7.1%), and viral reactivation (78.6%). The objective response rate was 92.3%, with an MRD-negative rate of 84.6%. Despite initial responses, seven patients relapsed with CD7-negative disease. At a median follow-up of 172.5 days, five patients remained in remission. The 1-year overall survival and leukemia-free survival rates were 34.3% and 34.1%, respectively. These initial results indicate that CD7 CAR-T cell therapy exhibits a manageable safety profile and preliminary efficacy in R/R AML patients, supporting further investigation in larger trials.
    DOI:  https://doi.org/10.1038/s41375-026-03017-x
  52. J Community Genet. 2026 Jul 01. pii: 82. [Epub ahead of print]17(4):
    Rare disease genomics and justice: overview of a workshop at the Fondation Brocher, 22-24 January 2025.
    Angus Clarke, Ruth Horn, Elena Avram, Siddarth Banka, Felicity Boardman, Victoria Charlton, Mike Drummond, Roseline Favresse, Angeline Ferdinand, David Freis, Ilaria Galasso, Nadine Z Großmann, Meghan Halley, Sasha Henriques, Hadewych Honné, Sofia Douzgou Houge, Salman Kirmani, Tamar Nov Klaiman, Teodora Lalova-Spinks, Charlotta Ingvoldstad Malmgren, Nick Meade, Elena Nicod, Kelly E Ormond, Barbara Prainsack, Hilde Van Esch, Ambroise Wonkam, Sarah L Wynn, Francesca Forzano.
      Genomics is transforming health care but its implementation raises challenges. This paper reports a 2025 workshop on justice in the implementation of genomics for rare disorders. The workshop goals were to develop a consensus understanding of the problems faced by rare disease patients and families where justice is at stake, to achieve a shared perspective on support for rare disease patients, and to consider the implications for justice in several areas of rare disease genomics, in both research and healthcare. We heard about the diverse experiences and needs of patients. Inequity between different rare diseases is marked. The need for coordination of care for rare disease patients is under-recognized but good models of rare disease care exist. The value of conscientious professionalism to nurture a rare disease mindset needs to be emphasized in the training of each new generation of healthcare students//trainees. The circumstances of different population groups differ systematically. The needs of indigenous and other historically marginalised groups must also be addressed. However, the subordination of individuals to the benefit of the population (i.e. eugenics) must be resisted. Those engaged in genomics projects or diagnostics may need protection from hype and misuse of their personal data, There are different perspectives on the fair allocation of resources to healthcare and research for rare conditions. Health economics and health technology assessment can be practised equitably, so as to meet the challenges of rare disease clinical trials and address the needs of patients and communities.
    DOI:  https://doi.org/10.1007/s12687-026-00911-w
  53. Transplant Cell Ther. 2026 Jul 02. pii: S2666-6367(26)00525-7. [Epub ahead of print]
    Impact of Disease Biology and Bridging Strategy on Outcomes After CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma.
    Irene Strassl, Alexander Nikoloudis, Lina Zoe Ruesing, Thomas Melchardt, Michael Leisch, Eduard Schulz, Annkristin Heine, Peter Neumeister, Normann Steiner, Dominik Wolf, Wolfgang Willenbacher, Petra Pichler-Izmir, Theresa Lentner, Johannes Clausen, Veronika Buxhofer-Ausch, Sigrid Machherndl-Spandl, Olga Saini, Dagmar Wipplinger, Holger Rumpold, Nina Worel, Werner Rabitsch, Axel Schulenburg, Hermine Agis, Maria-Theresa Krauth.
       BACKGROUND: Bridging therapy is commonly administered prior to B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory multiple myeloma (RRMM) to maintain disease control during the manufacturing period. However, the optimal choice and intensity of bridging therapy remain unclear, and it is debated whether outcomes are primarily influenced by bridging strategy or underlying disease biology.
    OBJECTIVES: We aimed to evaluate the impact of different bridging strategies on outcomes after BCMA-directed CAR-T cell therapy in RRMM, while accounting for disease biology, response prior to infusion, and baseline hematopoietic reserve.
    STUDY DESIGN: This retrospective multicenter real-world study included 90 consecutive patients with RRMM treated with BCMA-directed CAR-T cells (idecabtagene vicleucel or ciltacabtagene autoleucel) in Austria between January 2024 and July 2025. Bridging approaches were categorized as polychemotherapy (PCHT), talquetamab-based regimens (Tal), or other strategies. Survival outcomes were estimated using the Kaplan-Meier method, and factors associated with progression-free survival (PFS) were analyzed using univariable and multivariable Cox proportional hazards models. Logistic regression models were applied to assess associations with early toxicity.
    RESULTS: After a median follow-up of 9.9 months, estimated median PFS was 17.1 months. In unadjusted analyses, PCHT was associated with inferior PFS compared with other bridging approaches. However, this association was not retained after adjustment for extramedullary disease/plasma cell leukemia (EMD/PCL) and IMWG high-risk status. CAR-T product type and number of prior lines of therapy showed no effect on PFS. EMD/PCL emerged as the strongest independent predictor of inferior PFS in multivariable analysis (adjusted hazard ratio 4.85), whereas IMWG high-risk status was not independently prognostic. In a secondary model, achieving at least a very good partial response prior to CAR-T infusion was associated with a trend toward improved PFS but did not reach statistical significance. Talquetamab-based bridging was associated with numerically favorable PFS without increased toxicity. The CAR-HEMATOTOX score independently predicted inferior PFS. Importantly, PCHT was not associated with higher CAR-HEMATOTOX scores, prolonged cytopenia, increased infectious complications, or lower ALC levels as a surrogate for CAR-T expansion.
    CONCLUSIONS: In this nationwide real-world analysis, disease biology - particularly the presence of EMD/PCL - was the dominant determinant of outcome after CAR-T cell therapy, outweighing the impact of bridging strategy. These findings suggest that inferior outcomes observed after intensive bridging are largely driven by adverse baseline disease characteristics rather than treatment-related effects, supporting a biology-adapted approach to bridging and emphasizing the importance of achieving optimal disease control prior to CAR-T infusion.
    Keywords:  Bridging Therapy; Multiple myeloma; car-t; real-world data
    DOI:  https://doi.org/10.1016/j.jtct.2026.06.048
  54. Blood Adv. 2026 Jul 02. pii: bloodadvances.2025018015. [Epub ahead of print]
    Minor histocompatibility antigen TCR-T.
    Elizabeth F Krakow, Marie Bleakley.
      Minor histocompatibility antigens (MiHA) are polymorphic peptides presented by HLA molecules on recipient cells in allogeneic hematopoietic cell transplantation (allo-HCT) and are derived from proteins with genetic variants that differ between recipient and donor. Following allo-HCT, hematopoietic-restricted MiHA enable selective targeting of residual recipient-derived hematopoiesis, including malignant cells. Advances in engineering T cells with high-affinity MiHA-specific T-cell receptors (TCR; TCR-T) are enabling clinical translation of MiHA T cell immunotherapy. Early-phase trials of HA-1 and HA-2-specific TCR-T demonstrate safety, persistence, and durable anti-leukemic activity in high-risk or relapsed disease. To accelerate translation, the field should expand TCR-T development to additional MiHA targets to broaden HLA and population coverage, integrate MiHA genotyping into donor selection, and devise platform trials to include patients with various MiHA/HLA genotypes and to efficiently test combination therapies. MiHA-directed TCR-T represents a genetically precise, potentially routine HCT adjunct that promises to fortify graft-versus-leukemia effects and improve relapse-free survival.
    DOI:  https://doi.org/10.1182/bloodadvances.2025018015
  55. Transplant Cell Ther. 2026 Jun 27. pii: S2666-6367(26)00516-6. [Epub ahead of print]
    Allogeneic Hematopoietic Cell Transplant Following Standard of Care Brexucabtagene Autoleucel (Brexu-cel) in Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL): Results from the Real-World Outcomes Collaborative of CAR T in Adult ALL (ROCCA).
    Rawan G Faramand, Amy Zhang, Gregory W Roloff, Ibrahim Aldoss, Anjali S Advani, Minoo Battiwalla, Jacob Boccucci, Kenneth Byrd, Ryan D Cassaday, Matthew Connor, Kaitlyn C Dykes, Talal Hilal, Noam E Kopmar, Vamsi K Kota, Catherine J Lee, Jessica T Leonard, Georgia R Lill, Chenyu Lin, Aaron C Logan, Navneet S Majhail, Shahbaz A Malik, Ross McCauley, Jozal Moore, Luke Mountjoy, Timothy O'Connor, Kristen M O'Dwyer, Silvina Odstrcil Bobillo, Caspian H Oliai, Tamer Othman, Aravind Ramakrishnan, Karam Sandhu, Marc Schwartz, Paul Shaughnessy, Hrishikesh K Srinagesh, Katherine C Sutherland, Virginia Tan, Stephanie B Tsai, Matthew Ulrickson, Eunice S Wang, George Yaghmour, Noelle V Frey, Bijal D Shah, Lori S Muffly.
       INTRODUCTION: Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor T (CAR T) cell therapy approved for adults with relapsed/refractory (r/r) B-ALL. Despite encouraging outcomes, the majority of adults relapse following brexu-cel, highlighting the need for strategies to improve the durability of response. One such strategy is consolidative allogeneic stem cell transplant (alloHCT). Here, we report outcomes of adults with B-ALL who underwent consolidative alloHCT following commercial brexu-cel as part of the Real-world Outcomes Collaborative of CAR-T in Adult ALL (ROCCA).
    METHODS: We performed a retrospective multicenter analysis of adults with R/R B-ALL who underwent consolidative alloHCT in complete remission (CR) after commercial brexu-cel and were registered in ROCCA. ROCCA includes 41 US institutions contributing retrospective data for adults with B-ALL treated with brexu-cel between 2021-2025. Patients who received alloHCT after CAR T failure were excluded. Primary endpoints were 12-month overall survival (OS) and event-free survival (EFS); secondary endpoints included relapse, non-relapse mortality (NRM), and graft-versus-host disease (GVHD).
    RESULTS: Among 399 brexu-cel-treated patients, 65 underwent consolidative alloHCT including 56 patients who underwent a first alloHCT and nine who underwent 2nd alloHCT. Among recipients of first alloHCT, the median age was 34 years, and patients were heavily pretreated with a median of three prior lines of therapy. With a median follow-up of 11 months post-HCT, the estimated 1-year post-HCT OS and EFS were 79% (95% CI, 64-88) and 66% (95% CI, 51-77), respectively. The 1-year cumulative incidence of relapse was 19%, and NRM was 13%. Acute grade II-IV GVHD occurred in 18%, grade III-IV in 4%, and moderate-to-severe chronic GVHD in 12%. In univariable analysis, age ≥40 was associated with inferior OS (HR 4.31, 95% CI 1.40-13.3) and EFS (HR 3.36, 95% CI 1.43-7.91), whereas myeloablative conditioning was associated with improved EFS (HR 0.37, 95% CI 0.15-0.93). Among 2nd alloHCT recipients, 1-year EFS and OS were 59% (95% CI, 19-85). The 1-year cumulative incidence NRM was 41% and there were no relapses documented among these patients.
    CONCLUSIONS: In this large real-world cohort, consolidative alloHCT after brexu-cel was feasible and associated with encouraging survival, low relapse rates, and acceptable toxicity, particularly among HCT naive recipients. These findings support alloHCT as a viable consolidation strategy following CAR T-induced remission and highlight the need for prospective studies to refine patient selection, conditioning regimens and transplant approaches in the post CAR T setting.
    Keywords:  Acute Lymphoblastic Leukemia; Allogeneic stem cell transplant; CAR T cell therapy
    DOI:  https://doi.org/10.1016/j.jtct.2026.06.039
  56. Gut Microbes. 2026 Dec 31. 18(1): 2690686
    Identification of human DP8α regulatory T cell sub-populations reactive to health-associated anti-inflammatory gut commensals.
    Margaux de Seilhac, Margaux Verdon, Lucas Goisnard, Aurore Duquenoy, Nathalie Corvaia, Emilie Plantamura, Nicolas Lapaque, Fabienne Beguet-Crespel, Bastien Laperrousaz, Joel Doré, Frédéric Altare, Emmanuelle Godefroy.
      While the role of gut microbiota in health has been demonstrated, deciphering the involvement of individual bacterial species in diseases with unmet clinical needs represents a major research interest. Over the last decade, DP8α regulatory T cells (Tregs) have been identified to respond to Faecalibacterium duncaniae and protect against inflammatory bowel diseases (IBD) and acute graft-versus-host disease (aGvHD). To better understand, on the one hand, physiological DP8α Treg activation processes, and, on the other hand, the underlying mechanisms used by anti-inflammatory bacterial species to protect the host, we investigated whether additional key species could be recognized by DP8α Tregs. Here we showed that Blautia obeum, Roseburia intestinalis, and Akkermansia muciniphila indeed represent sources of antigens for DP8α Treg activation and priming, likely through their unique ability to induce tolerogenic antigen presenting cells. This study provides considerable mechanistic insight into the gut microbiota/regulatory T cell interplay and further establishes the role of DP8α Tregs, and their emerging dedicated ability to respond to gut microbiota, in local and systemic homeostasis.
    Keywords:  Akkermansia muciniphila; Blautia; Faecalibacterium duncaniae; Gut microbiota; Roseburia intestinalis; dendritic cells; human gut microbiota-specific Tregs; immune regulation; regulatory T cells
    DOI:  https://doi.org/10.1080/19490976.2026.2690686
  57. Semin Cancer Biol. 2026 Jul 03. pii: S1044-579X(26)00069-6. [Epub ahead of print]
    Role of oral microbiome in cancer immunotherapy.
    Wafa Khalil, Haicheng Song, Ziwei Li, Yan He, Chun Xu, Qingsong Ye.
      The oral microbiome is comparable to the gut microbiome in ecological complexity and is now recognized as a contributor to anticancer immune responses. Although the relationship between the gut microbiome and anticancer immunity is well established, the connection between the oral microbiome and anticancer immunity has received increasing attention, with accumulating evidence pointing to the direct effects of the oral microbiome on immune cell populations. The relationship between cancer and the oral microbiome is bidirectional: each influences the behavior of the other. The tumor microenvironment (TME) and oncological therapies such as chemotherapy and radiation can cause oral microbiome dysbiosis. Once dysbiosis is established, it creates conditions that favor tumor initiation and recurrence through chronic inflammation and impaired immune surveillance. Furthermore, the oral microbiome indirectly affects distant cancers and contributes to systemic inflammation and microbial dissemination through gastrointestinal, respiratory, hematogenous, neurological, and lymphatic pathways. Prebiotics, probiotics, postbiotics, and microbiota transplantation represent promising therapies targeting this microbial community to enhance the efficacy of cancer immunotherapy.
    Keywords:  Cancer immunotherapy; Microbiota metabolites; Oral microbiome; Oral microbiota transplantation (OMT)
    DOI:  https://doi.org/10.1016/j.semcancer.2026.06.006
  58. Front Microbiomes. 2026 ;5 1863308
    Fecal microbiota transplantation: from empirical remedy to precision medicine.
    Junsheng Zhao, Yiming Fan, Keda Yang, Hainv Gao.
      Fecal microbiota transplantation (FMT) has evolved from an empirical remedy for recurrent Clostridioides difficile infection (rCDI) into a foundational platform for precision microbiome-based therapeutics. This comprehensive review details FMT's journey, analyzing its multifaceted mechanisms of action-including restoration of colonization resistance, metabolic reprogramming via short-chain fatty acids and bile acids, and profound immunomodulation-which extend far beyond simple microbial replacement. We critically evaluate its established, high efficacy in rCDI and its expanding, albeit more variable, applications across a wide spectrum of gastrointestinal diseases (such as inflammatory bowel disease, irritable bowel syndrome, and constipation), neurological disorders (including Parkinson's and Alzheimer's disease), metabolic conditions, autoimmune diseases, and oncology (particularly in modulating response to immune checkpoint inhibitors and treating graft-versus-host disease). The review further discusses the critical challenges of donor-recipient variability, safety, and the lack of standardized protocols that have driven the field's technical evolution. This progression encompasses refined processing methods like washed microbiota transplantation (WMT), diverse delivery routes including oral capsules, and the exploration of non-bacterial components like bacteriophages through fecal filtrate transplantation (FVT). Ultimately, we highlight the field's trajectory toward next-generation, defined live biotherapeutic products (LBPs) and engineered microbial consortia, aiming to transition from the complex "black box" of whole stool to safer, more consistent, and rationally designed precision therapies that target the specific dysbiotic networks underlying diverse human diseases.
    Keywords:  Clostridioides difficile infection; dysbiosis; fecal microbiota transplantation (FMT); gut microbiome; gut-brain axis; inflammatory bowel disease (IBD); live biotherapeutic products (LBPs); microbiome-based therapeutics
    DOI:  https://doi.org/10.3389/frmbi.2026.1863308
  59. Clin Ther. 2026 Jul 03. pii: S0149-2918(26)00191-8. [Epub ahead of print]
    Early Feasibility Studies in Europe: A Multisite Qualitative Study of Operational Challenges and Site Selection Determinants at 6 University Hospitals.
    Adrian Valledor, Ornella Tangila Kayembe, Daniel Beltran, Tess Martin, Benedetta Brancadoro, Carmen Furno, Carlo Trani, Lise Kvistgaard, Sebastian Kuhn, Marlen Peseke, Tom Melvin, Majella Geraghty, Alexandra Herborg Cornelius Poulsson, Marit Erna Austeng, Laura Sampietro-Colom, Nicolas Martelli.
       PURPOSE: Early feasibility studies (EFS) are critical to high-risk medical devices development, providing initial insights into safety, performance, and usability. However, the lack of a harmonized European Union regulatory framework creates significant barriers to their consistent and efficient conduct. This study examined current EFS practices in European university hospitals to identify key regulatory and operational challenges and inform future harmonization efforts.
    METHODS: A qualitative, multisite study was conducted involving 6 European university hospitals in November 2024 and July 2025. Experts involved in EFS or comparable early-phase clinical investigations participated in semistructured interviews. Participants were eligible if they were currently involved in, or had prior experience with, early-phase medical device or methodologically comparable clinical research; no role-based exclusion criteria were applied. A standardized questionnaire covering 6 thematic areas including a weighted scoring system to assess site selection criteria was developed to guide the interviews, and data collection and analysis followed the Consolidated Criteria for Reporting Qualitative Research (COREQ) 32-item checklist. Site-level findings were analyzed through qualitative and descriptive content analysis validated by a multidisciplinary review team. Quantitative data from the site‑selection exercise were summarized using nonparametric descriptive statistics. As this was an organizational and process‑focused qualitative study, no clinical outcomes or adverse events were assessed.
    FINDINGS: Twenty-one participants representing clinical, regulatory, operational, and ethics roles were included. Investigator expertise and engagement emerged as the most influential determinants of EFS success and site selection, followed by institutional readiness and operational infrastructure. Participants consistently reported challenges related to regulatory fragmentation, variable interactions with ethics committees and competent authorities, contract and budget negotiation processes, and uneven clinical research organization experience in early-phase device research. Six overarching themes were identified: investigator capacity and engagement; clinical site readiness and feasibility; regulatory environment and governance; operational infrastructure and clinical research organization capacity; financial and organizational constraints; and structural and ecosystem-level factors. Several challenges paralleled those reported in the United States despite different regulatory contexts.
    IMPLICATIONS: The findings indicate that EFS implementation in Europe is constrained by interdependent regulatory, operational, and organizational barriers linked to the absence of a harmonized European Union EFS framework. Although the limited number of sites and qualitative design restrict generalizability, the results provide empirically grounded insight into current European EFS practices. These findings support the need for coordinated guidance, standardized processes, and structured stakeholder interaction to improve the feasibility, consistency, and efficiency of early-phase medical device investigations in Europe.
    Keywords:  Clinical investigation; Early feasibility studies; European clinical investigations; European medical device regulation; Hospital practices; Qualitative analysis
    DOI:  https://doi.org/10.1016/j.clinthera.2026.06.003
  60. Int J Telerehabil. 2026 ;18(1): 6747
    AI Privacy and Security in Healthcare: A Systematic Literature Review.
    Diane Dolezel, Karima Lalani, Valerie Watzlaf, Kerryn Butler-Henderson, Elise V Z Lambert, Mary Morton, Jamie Sand, David Gibbs, Susan Fenton.
       Background: Artificial intelligence is expanding into telemedicine and telerehabilitation, yet significant privacy and security concerns persist.
    Scope: To synthesize empirical evidence on privacy and security approaches in health care, particularly those relevant to distributed home care.
    Methodology: A systematic review identified 80 studies (2019 to 2025), and Latent Dirichlet Allocation (LDA) topic modeling characterized the privacy and security themes.
    Results: Sixty-six studies addressed privacy, only seventeen addressed security, and three studies addressed both. LDA identified four themes: patient data privacy, federated learning for medical imaging, encrypted training and secure computation, and healthcare data governance. Most studies emphasized privacy-preserving approaches, like federated learning, encryption, and differential privacy. Almost half were conducted outside healthcare environments, limiting insight into real teleclinical and telerehabilitation workflow.
    Conclusion: Securing healthcare AI will require a multi-layered governance framework, broader global representation, and integration of privacy and security protections into routine clinical workflows.
    Keywords:  Artificial intelligence; Privacy; Security; Systematic review; Telerehabilitation
    DOI:  https://doi.org/10.63144/ijt.2065.6747
  61. Res Synth Methods. 2026 Jul 03. 1-34
    Doubly robust augmented weighting estimators for the analysis of externally controlled single-arm trials and unanchored indirect treatment comparisons.
    Harlan Campbell, Antonio Remiro-Azócar.
      Externally controlled single-arm trials are critical to assess treatment efficacy across therapeutic indications for which randomized controlled trials are not feasible. A closely-related research design, the unanchored indirect treatment comparison, is often required for disconnected treatment networks in health technology assessment. We present a unified causal inference framework for both research designs. We develop an estimator that augments a popular weighting approach based on entropy balancing-matching-adjusted indirect comparison (MAIC)-by fitting a model for the conditional outcome expectation. The predictions of the outcome model are combined with the entropy balancing MAIC weights. While the standard MAIC estimator is singly robust where the outcome model is non-linear, our augmented MAIC approach is doubly robust (DR), providing increased robustness against model misspecification. This is demonstrated in a simulation study with binary outcomes and a logistic outcome model, where the augmented estimator demonstrates its DR property, while exhibiting higher precision than all non-augmented weighting estimators and near-identical precision to G-computation. We describe the extension of our estimator to the setting with unavailable individual participant data for the external control, illustrating it through an applied example. Our findings reinforce the understanding that entropy balancing-based approaches have desirable properties compared to standard "modeling" approaches to weighting, but should be augmented to improve protection against bias and guarantee double robustness.
    Keywords:  covariate adjustment; data fusion; evidence synthesis; external control; indirect treatment comparison; single-arm trial
    DOI:  https://doi.org/10.1017/rsm.2026.10106
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