bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–08–30
68 papers selected by
Luca Bolliger, lxBio
  1. CAR-T cell therapy for multiple sclerosis.
  2. From Prediction to Intervention: Artificial Intelligence for Adaptive Response and Toxicity Modeling in Cellular Therapies for Hematologic Malignancies.
  3. CAR-T cell therapy: potential for paediatric brain tumours-an update.
  4. Advances in Oncohematology Immunotherapy: Monoclonal Antibodies and CAR T-Cell Therapies.
  5. Bioengineered cell therapies for pediatric solid tumors: unmet needs and a measurement-integrated approach.
  6. Navigating CAR-T translation in Australia: lessons from an academic program.
  7. From Joint Clinical Assessment to National Decisions: EU HTA Implementation and Implications for Patient Access.
  8. Cell-Type-Tailored Hydrogels for Adoptive Cell Therapy in Cancer.
  9. Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges.
  10. Functional genomics-guided design of CAR-T and CAR-NK therapies in hematological malignancies: aligning cellular engineering with immune escape and microenvironmental resistance.
  11. The European Union's Health Technology Assessment Regulation (EU-HTA R) Will Prosper Despite Major Setbacks.
  12. Late Complications After European Medicines Agency-Approved Chimeric Antigen Receptor T-Cell Therapy in Hematological Malignancies: A Scoping Review.
  13. The New Cardio-Oncology Frontier in Hematologic Cancers: Cardiovascular Toxicities of CAR-T Cells and Bispecific T-Cell Engagers.
  14. Cellular Immunotherapy for Cervical Cancer: Next Therapeutics Frontiers.
  15. CAR-T cells and CAR-Treg cells for treatment of inflammatory bowel diseases.
  16. B Cell Aplasia Following CAR T Cell Therapy: Incidence, Kinetics, Prognostic Implications, and Clinical Management.
  17. The Evolution of FAP-Targeted CAR T-Cell Therapy in Solid Tumors: From Immunotherapy to Immunotheranostic Applications.
  18. Health equity in rheumatology-the uneven landscape of cellular therapy.
  19. Natural killer cells at the interface of tumor immune escape and immunotherapy resistance in endometrial cancer.
  20. Biomarker-driven immunotherapy and adoptive cell therapy in recurrent pancreatic ductal adenocarcinoma.
  21. Adaptive bridging and holding therapy frequently reduces tumor burden and is associated with reduced toxicity after CAR-T cell therapy in multiple myeloma: A single-center real-world experience.
  22. Logic-gated nanoregulators: A paradigm shift from drug delivery to pre-programmed multi-target immunotherapy.
  23. A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.
  24. Disseminated intravascular coagulation in chimeric antigen receptor T-cell therapy: a 6-year nationwide analysis of clinical outcomes and health care resource utilization in patients with hematologic malignancies.
  25. Organization from cell to tissue derived delivery systems for immunotherapy.
  26. Phosphorylation shapes antigen presentation and immune recognition: mechanistic insights and translational perspectives.
  27. Automating cost-effectiveness models with agentic artificial intelligence: Case study and implications for value assessment.
  28. The New Oncology Blueprint: Integrating Clinical Intelligence for Sustainable Value.
  29. Chimeric antigen receptor T-cell therapy in dermatologic autoimmunity: Mechanisms, applications, and future directions.
  30. Immunotherapy in Asia: current insights and prospects in Southeast Asia and Malaysia.
  31. An inducible signal 1 booster overcomes limited access to antigen for solid tumor cell therapy.
  32. CAR-T and GvHD: Have We Engineered GvHD Out of Allogeneic CAR‑T Therapy?
  33. Challenges and Opportunities of γδ T Cell-Based Immunotherapy for Glioblastoma.
  34. Humanized CD70-targeted CAR-T cells with reduced fratricide demonstrate potent antitumor activity against AML and RCC.
  35. Expedited pathway portfolios, trial complexity, and FDA approval timelines in oncology and neurology: A comparative analysis.
  36. Cross-jurisdictional access to innovative drugs and devices: a five-year policy and practice review of the Hong Kong and Macao medicine and equipment connect in the Greater Bay Area of China.
  37. Alignment of registered cell therapy trial protocols with regulatory guidance on preclinical evidence: a systematic, cross-sectional, protocol-level analysis.
  38. From product to knowledge: the life cycle of health technologies 2.0 as a framework for health system improvement.
  39. Target-Product and Translational Design Principles for Inhalable RNA Nanomedicines.
  40. Multi-omics-driven precision medicine.
  41. Antibody-Drug Conjugates in Contemporary Oncology: A Clinical Perspective on Dose Optimization, Sequencing, and Combination Strategies.
  42. Nanomaterial-based drug delivery systems: From intelligent delivery to clinical translation and precision nanomedicine.
  43. Clinical Translation of Functional Magnetic Nanoparticles for Intracellular Hyperthermia and Cancer Immunotherapy.
  44. Targeting Regnase-1 in B7-H3-CAR T cells reprograms the tumor microenvironment and enhances antitumor efficacy for osteosarcoma.
  45. Timing of hemoadsorption in sepsis: redefining early through mediator-guided therapy.
  46. CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial.
  47. The GENIE Data Model: A Solid Tumor, Person-Centric Framework for Scalable, Harmonized Precision Oncology Data Collection.
  48. Real-world outcomes of ide-cel and cilta-cel in relapsed/refractory multiple myeloma: A nationwide, retrospective analysis in Austria.
  49. Development and clinical application of recombinant polyclonal antibodies.
  50. Extracting adverse event nature, severity, timelines and resulting interventions from clinical notes of patients receiving CAR-T cell therapy using large language models.
  51. Beyond maximum grade: the role of real-world digital health technologies to capture, predict, and manage treatment toxicity in haematological cancers.
  52. Agentic AI for trustworthy synthetic microbial genomics: a perspective on generation, validation, and governance.
  53. Immunoglobulin constant domains as targets for T-cell receptor-based treatment of multiple myeloma.
  54. Ex vivo live macrophage engineering strategies in immunotherapy.
  55. Effect of adding umbilical cord blood derived stem cells to haploidentical stem cell transplant (haplo-cord) on post-transplant survival and graft-versus-host disease in patients with hematological malignancies: A systematic review and meta-analysis.
  56. From Algorithm to Policy: A Bibliometric Analysis of Implementation Science and Governance Frameworks in AI Healthcare Research (2016-2026).
  57. Data-centric feedback loops for next-generation immunotherapy development.
  58. Temporal Data Structure Is Not Causal Identification: A Practical Framework for Appraising Causal Claims in Prevention and Population Health Research.
  59. Integrating population heterogeneity in drug research and early development: a proactive strategy.
  60. AI-Enabled Real-World Evidence in Oncology: A Statistical Perspective for Regulatory Decisions.
  61. Targeting Immune Checkpoint Proteins in Cancer Therapy and the Potential of RNAi-Based Immunotherapy.
  62. Manufacturing Complexity and Scale-Up: Hidden Contributors to Drug Safety Risk.
  63. Healthcare Digital Twins Across Scales: A Narrative Review and Five-Level Conceptual Framework.
  64. Advances in gene transfer technologies: comparing viral and non-viral vectors for therapeutic applications.
  65. The landscape for in vivo CAR T cell therapies.
  66. Suspension-Adapted HEK293FT Cells Enable High-Density Transfection for Efficient Lentiviral Vector Production in CAR-T Therapy.
  67. B-cell depletion therapy in systemic lupus erythematosus: emerging strategies and challenges.
  68. Neurologic Complications of Cancer Immunotherapy.
  1. Nat Rev Drug Discov. 2026 Aug 28.
    CAR-T cell therapy for multiple sclerosis.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-026-00142-1
  2. Cancers (Basel). 2026 Aug 12. pii: 2598. [Epub ahead of print]18(16):
    From Prediction to Intervention: Artificial Intelligence for Adaptive Response and Toxicity Modeling in Cellular Therapies for Hematologic Malignancies.
    Behzad Amoozgar, Ayrton Bangolo, Danielle C Thor, Shibhani Rajanna, Shareif Abdelwahab, Ahmed S Mohamed, Charlene Mansour, Syed Usman Ehsanullah.
      Hematologic malignancies, including acute myeloid leukemia, myelodysplastic syndromes, lymphoma, and multiple myeloma, are characterized by profound biological heterogeneity and highly dynamic treatment trajectories that conventional, static prognostic systems incompletely capture. Cellular therapies, such as chimeric antigen receptor T-cell therapy and hematopoietic stem cell transplantation, offer potentially curative options for relapsed or refractory disease, yet outcomes remain highly variable, and management decisions regarding conditioning intensity, lymphodepletion, immunosuppression, and toxicity surveillance continue to be largely protocol-driven rather than individually adapted. Artificial intelligence (AI) and machine learning (ML) have demonstrated substantial promise in diagnostic support, prognostic stratification, and multimodal data integration across hematologic malignancies, but existing models remain predominantly static and related to pre-treatment in orientation, limiting their utility for real-time clinical guidance. This review summarizes current AI applications in hematologic oncology; critically compares the strengths, limitations, and clinical applicability of major AI model classes, including traditional machine learning, deep learning, multimodal integrative frameworks, reinforcement learning, digital twins, and emerging foundation models and large language models; and proposes an adaptive, multimodal paradigm. We examine key enabling technologies and address the clinical, regulatory, ethical, and implementation challenges that must be resolved before these systems can be deployed at the bedside. We argue that the central challenge facing the field is no longer whether AI can predict outcomes, but whether it can actively guide real-time therapeutic decisions, and that achieving this transition will require interdisciplinary collaboration, prospective validation, and governance frameworks capable of ensuring interpretability, equity, and clinical trustworthiness.
    Keywords:  AI; CAR-T cell therapy; cellular therapy; hematology; hematopoietic stem cell transplant; machine learning; oncology
    DOI:  https://doi.org/10.3390/cancers18162598
  3. J Neurooncol. 2026 Aug 28. pii: 62. [Epub ahead of print]179(2):
    CAR-T cell therapy: potential for paediatric brain tumours-an update.
    Alexandra Zehner, Benjamin Draper, Darren Hargrave, Laura K Donovan, John Anderson.
      Central nervous system (CNS) tumours are the deadliest cancer for children and currently present limited treatment options. Chimeric antigen receptor (CAR)-T cell therapies have emerged as an innovative approach supported by encouraging clinical results. Current clinical trials using CAR-T cells in the treatment of paediatric CNS cancers differ in a number of variables, including the CAR-T cell route of delivery, presence of lymphodepletion, identified target antigen, and CAR engineering features. Considering early learnings across these areas is an essential step to developing more effective treatment options, especially given the challenges of immunosuppressive tumour microenvironments, various toxicities, CAR-T cell exhaustion, and tumour antigen heterogeneity. In sum, while there is a need for continued innovation, CAR-T cells represent a promising treatment approach for this devastating category of diseases.
    DOI:  https://doi.org/10.1007/s11060-026-05604-5
  4. Cells. 2026 Aug 10. pii: 1439. [Epub ahead of print]15(16):
    Advances in Oncohematology Immunotherapy: Monoclonal Antibodies and CAR T-Cell Therapies.
    Fanny Mathias, Cyril Fersing, Véronique Bourgarel, Jean Gabert, Florence Peyron.
      The role of immunotherapy in oncohematology is well established. Monoclonal antibodies have undergone substantial development in recent years, targeting a wide range of molecules (including surface antigens, immune checkpoints, and cytokines) and have demonstrated clinical utility across various hematologic malignancies, including leukemias, lymphomas, and myelomas. The emergence of advanced therapy medicinal products (ATMPs), particularly chimeric antigen receptor (CAR) T cells, has provided an additional and promising therapeutic option. This rapidly evolving field continues to expand therapeutic possibilities. The objective of this literature review is to summarize novel immunotherapeutic strategies in oncohematology, including monoclonal antibody- and CAR T-cell-based approaches, and to review the key findings from recent clinical trials.
    Keywords:  CAR T-cells; immunotherapy; monoclonal antibodies; oncohematology
    DOI:  https://doi.org/10.3390/cells15161439
  5. Prog Biomed Eng (Bristol). 2026 Aug 28.
    Bioengineered cell therapies for pediatric solid tumors: unmet needs and a measurement-integrated approach.
    Ana M Sandoval-Castellanos, Yu-Rim Ahn, Robert J Canter, Erin G Brown, Jinhwan Kim.
      Pediatric solid tumors continue to pose a major therapeutic challenge, with survival gains lagging behind those achieved in pediatric hematologic malignancies. While traditional approaches have focused on dose escalation and intensification of systemic therapies to improve survival, this strategy is often limited by significant short- and long-term morbidity from intensive multimodal treatment. Because children have developing organs and decades of life ahead, therapeutic strategies must balance durable tumor control with preservation of neurodevelopment, organ function, and quality of life. Immunotherapy has generated significant interest as an alternative to dose escalation; however, clinical translation in pediatric solid tumors has been limited by antigen heterogeneity, tumor plasticity, immune-cold or immune-excluded phenotypes, and a profoundly immunosuppressive tumor microenvironment. Bioengineered cellular therapies, particularly chimeric antigen receptor (CAR) T cells and CAR-modified natural killer (CAR NK) cells, provide a modular platform to address these barriers through synthetic receptor design, multi-antigen targeting, controlled activation, and improved trafficking to anatomically restricted sites such as the brain. However, engineering advances alone are unlikely to achieve durable benefit without parallel integration of quantitative in vivo monitoring capable of reporting biodistribution, persistence, and functional engagement. Non-invasive imaging and measurement-enabled approaches can provide mechanistic insight into therapeutic performance, discriminate between delivery failure and functional dysfunction, and support rational iteration of construct design, dosing, and route of administration. In this perspective, we review the current status of CAR T and CAR NK therapies in pediatric solid malignancies, outline key biological and engineering challenges, and propose a pediatric-centered development framework that integrates controllable cell engineering with quantitative, non-invasive assessment of in vivo behavior. By embedding measurement into the therapeutic design loop and prioritizing long-term safety and developmental outcomes alongside efficacy, next-generation engineered cell therapies may evolve toward adaptable, precision-guided systems capable of improving both survival and quality of life for children.
    Keywords:  CAR NK; CAR T; cancer immunotherapy; non-invasive imaging; pediatric solid tumor
    DOI:  https://doi.org/10.1088/2516-1091/aea045
  6. Front Med (Lausanne). 2026 ;13 1920197
    Navigating CAR-T translation in Australia: lessons from an academic program.
    Rui Ping Amanda Tan, Robyn Walsh, Geoffrey McCowage, Geraldine M O'Neill, Kavitha Gowrishankar.
      Adoptive cell therapies utilizing both gene-modified and unmodified immune cells have revolutionized treatments for cancer and infection. Seven Chimeric antigen receptor (CAR) T cell products have been approved as therapies, providing the momentum to expand their clinical benefit to several cancer types. Many novel receptor-expressing cell therapies remain in preclinical development and require robust clinical testing Translating these into early-phase clinical trials requires navigating manufacturing, quality, and regulatory systems that are often not documented explicitly for academic investigators. This manuscript provides a stage-by-stage roadmap for translating academic CAR T-cell research into an investigator-led Phase I clinical trial in the Australian public sector. It draws on the E2CAR program, the first clinical translation of an EphA2-directed CAR T-cell product into pediatric bone sarcoma, conducted at the Children's Hospital at Westmead. We present our experience across six stages: construct finalization and vector strategy, manufacturing process development, quality infrastructure, assay development and validation, multi-entity operational coordination, and CTA regulatory engagement and provide recommendations for researchers at each stage. We also present a consolidated program timeline, minimum personnel requirements, and indicative costs to support grant applications and institutional planning. While the operational framework described here was developed specifically for our Health Precinct some of the recommendations we provide are likely to benefit academic groups navigating constraints in comparable settings.
    Keywords:  CAR - T therapy; guidelines; investigator led trial; regulatory approval; translation
    DOI:  https://doi.org/10.3389/fmed.2026.1920197
  7. J Mark Access Health Policy. 2026 Aug 19. pii: 50. [Epub ahead of print]14(3):
    From Joint Clinical Assessment to National Decisions: EU HTA Implementation and Implications for Patient Access.
    Kalpana D'Oca, Ada Adriano, Eline Darquennes, Natalie Steck.
      The introduction of Joint Clinical Assessments (JCAs) under the European Union Health Technology Assessment Regulation (EU HTAR) represents a major structural reform aimed at reducing fragmentation and duplication in clinical evidence assessment across Member States. While JCAs are intended to support national health technology assessment (HTA) processes through a common EU-level clinical evaluation, their integration into established national HTA and reimbursement systems remains untested at this early stage of implementation. This paper reports findings from two surveys conducted in 2025 among local affiliate representatives with expertise in relevant HTA and market access activities across 25 European countries (comprising 24 EU Member States and Norway), capturing early national perspectives on key aspects of JCA implementation. The surveys explored anticipated impact on national reimbursement timelines, current opportunities for early HTA advice and PICO input, approaches to handling post-JCA data availability, and nationally prioritised policy and implementation issues. Results indicate mixed expectations regarding the potential impact of JCA on reimbursement timelines, with perceived risks of delay largely viewed as possibly transitional and mitigable through national process adaptation. Respondents emphasised the importance of transparency in PICO consolidation and clarity on the use of JCA reports in national appraisals. Overall, the findings suggest that JCA may represent a reconfiguration rather than a centralisation of evidence assessment, with national influence exercised earlier in the assessment lifecycle. These insights provide policy-relevant input to inform ongoing EU HTA implementation and future refinement of the JCA framework.
    Keywords:  EU HTA; JCA; PICO scoping; national reimbursement timelines
    DOI:  https://doi.org/10.3390/jmahp14030050
  8. Gels. 2026 Aug 01. pii: 678. [Epub ahead of print]12(8):
    Cell-Type-Tailored Hydrogels for Adoptive Cell Therapy in Cancer.
    Jin Hak Shin, Yeonju Song, Jeehun Park.
      Hydrogel-enabled adoptive cell therapy (ACT) offers a localized and controllable strategy for improving cellular immunotherapy in solid tumors. Hydrogels can enhance cell retention and persistence, support immune cell function within the tumor microenvironment, and reduce systemic toxicity associated with broadly delivered immune stimulants. However, delivery of living immune cells imposes practical constraints on hydrogel selection, including cytocompatible encapsulation, minimal handling and injection stress, adequate transport of oxygen and soluble cues, and an appropriate balance between local retention and timely cell egress. This review summarizes natural, synthetic, and hybrid hydrogel platforms and compares physical/supramolecular assembly, covalent and enzymatic crosslinking, and photo-crosslinking. Injectable in situ-forming depots and shear-thinning/self-healing gels are highlighted for locoregional administration. Key design and reporting dimensions of hydrogels are linked to immune cell outcomes relevant to ACT. These properties include mechanics and viscoelasticity, porosity and mass transport, degradability and remodeling, bioadhesion and extracellular matrix (ECM) mimicry, and immunogenicity versus immune shielding. Finally, a cell-type-tailored framework is presented for chimeric antigen receptor T (CAR-T), T cell receptor-engineered T (TCR-T), and tumor-infiltrating lymphocyte (TIL) products, natural killer (NK) cells, and dendritic cells (DCs) or macrophage/monocyte-derived effectors. Distinct biological requirements are used to motivate corresponding material architectures and cue presentation strategies. The review also provides quantitative reporting guidance, identifies evidence gaps for γδ T cells, and discusses in vivo validation, combination ACT strategies, and translational handling constraints.
    Keywords:  CAR-NK cells; CAR-T; adoptive cell therapy; cancer immunotherapy; dendritic cells; gamma-delta T cells; granular hydrogels; immune cell delivery; injectable hydrogels; macrophage engineering
    DOI:  https://doi.org/10.3390/gels12080678
  9. Front Immunol. 2026 ;17 1881360
    Regulatory T cells in autoimmune diseases: biological mechanisms, clinical translation, and translational challenges.
    Jingchang Li, Jia Pang, Peipei Wu, Enmei Wang, Shijun J Zheng, Qingguo Ruan, Ruiling Liu.
      Autoimmune diseases (ADs) are a group of inflammatory disorders triggered by aberrant immune responses against autoantigens and the breakdown of immune tolerance. Current therapeutic strategies, such as glucocorticoids and immunosuppressants, exert largely non-specific immunomodulation and are frequently associated with substantial adverse effects upon long-term administration. As such, these approaches are often insufficient to re-establish immune homeostasis. In recent years, regulatory T cell (Treg)-based therapeutics have undergone rapid advancement, with continuously updated therapeutic modalities broadening the application boundary of immune tolerance intervention. This review comprehensively outlines the progress of Treg-based therapeutics, spanning from fundamental biological research to translational applications in autoimmune diseases. We describe the developmental characteristics, suppressive machinery, and heterogeneity of Tregs, and highlight the preclinical and clinical advancements of diverse Treg therapeutic modalities, including polyclonal and antigen-specific Tregs, TCR-engineered Tregs, and CAR-Tregs. Furthermore, we emphasize current optimization strategies for enhancing Treg stability, antigen specificity, and in vivo fitness within inflammatory microenvironments. Additionally, we objectively address the major translational bottlenecks of Treg therapy and provide future perspectives to facilitate the clinical implementation of Treg-based immunotherapies for autoimmune diseases.
    Keywords:  autoantigen; autoimmune disease; immune tolerance; immunotherapy; regulatory T cell
    DOI:  https://doi.org/10.3389/fimmu.2026.1881360
  10. Front Genome Ed. 2026 ;8 1878460
    Functional genomics-guided design of CAR-T and CAR-NK therapies in hematological malignancies: aligning cellular engineering with immune escape and microenvironmental resistance.
    Shiqi Cai, Yang Tan, Qian Yang, Juan Huang.
       Background: Chimeric antigen receptor T-cell therapy has changed the treatment landscape of relapsed or refractory hematological malignancies, but primary non-response and post-infusion relapse remain frequent clinical problems. In aggressive B-cell lymphomas, acute leukemias, and multiple myeloma, treatment failure is often driven by overlapping mechanisms rather than a single resistance pathway. These include antigen loss or reduced antigen density, impaired immune recognition, defective inflammatory signaling, checkpoint-mediated suppression, metabolic stress, and limited effector-cell persistence within suppressive disease niches.
    Main Body: Genome engineering has become an important tool for both identifying and addressing these resistance mechanisms. CRISPR-based functional screening, single-cell perturbation approaches, and multi-omics profiling allow immune escape and tumor microenvironment-mediated resistance to be defined more functionally, rather than inferred only from correlative datasets. These insights can inform the design of CAR-T and CAR-NK therapies through multi-target or logic-gated receptors, checkpoint or exhaustion-pathway editing, cytokine-supported and armored constructs, metabolic fitness enhancement, and selected multiplex-editing strategies. In parallel, CAR-NK cells, universal allogeneic CAR-T products, and stem-cell-derived platforms may provide additional options in relapse-prone or heavily pretreated patients, particularly when autologous T-cell fitness, manufacturing feasibility, or repeat dosing is a concern.
    Conclusion: A resistance-guided approach may help align engineered cellular therapy design with the dominant mechanisms of treatment failure in high-risk hematological malignancies. Rather than simply increasing engineering complexity, future CAR-T and CAR-NK development should link each modification to a measurable resistance mechanism, a feasible biomarker, and a clinically testable benefit. Prospective validation, genomic safety assessment, manufacturing consistency, and long-term monitoring will be essential before resistance-matched cellular immunotherapy can be broadly integrated into clinical practice.
    Keywords:  CAR-NK cell therapy; CAR-T cell therapy; genome editing; immune escape; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgeed.2026.1878460
  11. J Mark Access Health Policy. 2026 Aug 03. pii: 45. [Epub ahead of print]14(3):
    The European Union's Health Technology Assessment Regulation (EU-HTA R) Will Prosper Despite Major Setbacks.
    Mondher Toumi, Imen Soussi, Bruno Falissard, Steven Simoens, Asma Jouini, Maarten Postma, Juergen Wasem, Oriol Solà-Morales, Laurent Boyer, Claude Dussart, Borislav Borissov, Renato Bernardini, Stefano Capri, Jaime Espin, Pascal Auquier.
      Background: The EU Health Technology Assessment Regulation (EU-HTA R), effective January 2025, mandates Joint Clinical Assessments (JCAs) to harmonize HTA across Member States. However, its implementation raises fundamental questions about methodological coherence, institutional capacity, and epistemological alignment. Objectives: This manuscript (1) systematically assesses whether the stated strategic and operational objectives of the EU-HTA R are achievable under current implementation conditions; (2) examines the implications for EU institutional legitimacy if these objectives are not met; and (3) proposes an epistemological framework as a prerequisite for developing a coherent joint HTA methodology. Methods: We conducted a critical policy analysis of the EU-HTA R, its implementing guidance documents, and published templates, supplemented by a comparative review of Member State HTA methodologies and their underlying philosophical foundations. Results: The analysis reveals that the EU-HTA R is unlikely to achieve its strategic goals under current conditions. Key findings include: guidance documents of substandard methodological quality; a restricted assessment scope that excludes scientific judgement and contextualization; insufficient resources and additional workload for national HTA bodies without reducing existing obligations; unresolved epistemological divergences among Member States spanning Bayesian vs. frequentist approaches, Fisher vs. Neyman-Pearson frameworks, and utilitarian vs. deontological ethical foundations; and procedural shortcomings in stakeholder consultation and expert involvement. These shortcomings risk undermining the epistemic authority and legitimacy of EU institutions. Conclusions: Prior epistemological and normative alignment across Member States is a prerequisite for any robust shared HTA methodology. Revisions to the EU-HTA R and comprehensive updates of guidance documents are necessary, with concrete safeguards-including independent peer review, identified authorship, and adequate resourcing-to ensure substantive rather than merely nominal implementation. A phased roadmap is proposed: establishing clear objectives, aligning epistemological foundations, developing institutional structures, and creating operationally consistent guidance.
    Keywords:  EU-HTA; disguised; semantic HTA EU-HTA regulation; words signification
    DOI:  https://doi.org/10.3390/jmahp14030045
  12. Curr Oncol. 2026 Aug 01. pii: 461. [Epub ahead of print]33(8):
    Late Complications After European Medicines Agency-Approved Chimeric Antigen Receptor T-Cell Therapy in Hematological Malignancies: A Scoping Review.
    Michael Eisenmann, Zhounan Zhu, Volker Arndt, Melissa S Y Thong.
      Chimeric antigen receptor T-cell (CAR-T) therapy has substantially improved outcomes for patients with B-cell-associated hematological malignancies. While acute and early toxicities are well characterized, late complications (LCs) remain poorly understood. This scoping review aimed to identify and map the existing evidence on LCs in adult patients with hematological malignancies treated with CAR-T products approved by the European Medicines Agency (EMA). PubMed, Web of Science, and the Cochrane Library were searched for primary studies published from 2018 onwards. We included studies of adult patients receiving EMA-approved CAR-T therapies targeting CD19 or CD269. LCs were defined as diagnosis-based adverse events occurring ≥12 months after CAR-T infusion. Of 7715 records identified, 261 studies underwent full-text screening and 18 met the inclusion criteria. LCs clustered mainly as infections and secondary malignancies (SMs). Non-relapse mortality was reported in seven studies, with infections and SMs frequently reported as causes when cause-of-death data were available. Future studies should place emphasis on long-term clinical events after CAR-T therapy to improve the management of LCs and ultimately support better long-term outcomes for patients.
    Keywords:  chimeric antigen receptor T-cell; hematological malignancies; late complications; non-relapse mortality
    DOI:  https://doi.org/10.3390/curroncol33080461
  13. J Clin Med. 2026 Aug 18. pii: 6371. [Epub ahead of print]15(16):
    The New Cardio-Oncology Frontier in Hematologic Cancers: Cardiovascular Toxicities of CAR-T Cells and Bispecific T-Cell Engagers.
    Andrea Tedeschi, Nicolò Pasini, Marco Talassi, Federico Barocelli, Iacopo Fabiani, Vincenzo Quagliariello, Nicola Maurea, Maria Laura Canale, Stefano Oliva, Giampaolo Niccoli, Daniela Aschieri.
      Chimeric antigen receptor T-cell therapy and bispecific T-cell engagers have transformed treatment of relapsed and refractory hematologic malignancies, achieving unprecedented response rates. However, their clinical adoption has revealed a complex spectrum of cardiovascular toxicities, differing in frequency and pattern between the two technologies. Manifestations range from common hemodynamic perturbations-hypotension and tachycardia-to severe events, including malignant arrhythmias, left ventricular dysfunction, myocardial infarction, and cardiogenic shock. These complications seem to have different pathophysiological pathways that are yet to be completely understood: on the one hand, they are frequently intertwined with cytokine release syndrome, the hallmark immune complication of T-cell-redirecting therapies, as seen with chimeric antigen receptor T-cell therapy; on the other, a substantial proportion of cardiovascular events-particularly with bispecific T-cell engagers-occur independently of cytokine release syndrome. Proposed cardiotoxic mechanisms include on-target, off-tumor antigen recognition and consequent damage; interleukin-6-driven systemic inflammation; and off-target, off-tumor antigen cross-reactivity. Effective management requires proactive baseline risk stratification, serial cardiac biomarker monitoring, and timely immunosuppressive intervention-primarily tocilizumab-to mitigate cytokine release syndrome-driven injury. Despite rapid clinical expansion, critical gaps remain: long-term cardiovascular outcomes are poorly characterized, validated surveillance protocols are lacking, and cardiovascular endpoints are rarely included in pivotal trials. This narrative review appraises the pathophysiology, clinical spectrum, and management of cardiovascular toxicities associated with these therapies, aiming to define this emerging cardio-oncology frontier, inform multidisciplinary care frameworks and propose a clinical management algorithm.
    Keywords:  CAR-T cell therapy; bispecific T-cell engagers; cardio-oncology; cardiovascular toxicity; cytokine release syndrome
    DOI:  https://doi.org/10.3390/jcm15166371
  14. Oncol Res. 2026 ;34(9): 9
    Cellular Immunotherapy for Cervical Cancer: Next Therapeutics Frontiers.
    Danning Zhao, Qin Liu.
      Cervical cancer, particularly its advanced stages, requires novel therapeutic paradigms. Cellular immunotherapy exploits the constitutive expression of HPV E6/E7 oncoproteins as near-ideal tumor-specific antigens. This review systematically evaluates four principal platforms under investigation: tumor-infiltrating lymphocytes (TILs), TCR-engineered T cells, CAR-T cells, and CAR-NK cells. We critically analyze the preclinical rationale, clinical trial landscape, safety considerations, and manufacturing challenges for each modality. TIL therapy has achieved durable complete responses and an FDA Breakthrough Therapy designation. TCR-T cells enable precise targeting of intracellular viral epitopes but are HLA-restricted. CAR-T cells offer potent, MHC-independent recognition, yet face on-target/off-tumor toxicity and a suppressive tumor microenvironment. CAR-NK cells present a favorable safety profile and off-the-shelf potential. We conclude that the future of this field lies in rational combination strategies (e.g., with immune checkpoint blockade) and next-generation engineering (e.g., armored CARs, logic gates, allogeneic platforms) to overcome manufacturing complexity, toxicity, and high costs. Overcoming these barriers is essential to extend these therapies to resource-limited settings where the burden of cervical cancer is highest.
    Keywords:  Cell therapy; T-cell receptor (TCR)-engineered T cells; cervical cancer; chimeric antigen receptor (CAR)-T cells; clinical trials; immunotherapy; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.32604/or.2026.084736
  15. EULAR Rheumatol Open. 2026 Sep;2(3): 100224
    CAR-T cells and CAR-Treg cells for treatment of inflammatory bowel diseases.
    Markus F Neurath.
      Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are therapeutically challenging chronic inflammatory diseases of the intestine. Despite major advances in biologic and small-molecule therapies, many patients with IBD experience primary nonresponse, secondary loss of response, or severe complications, underscoring the need for innovative therapeutic strategies that lead to sustained immune recalibration. Chimeric antigen receptor (CAR)-based cellular therapies represent an emerging new concept for transformative medicine. These CAR-T cells are engineered to recognise defined surface antigens, such as CD19, and are therefore ideally suited to eliminate selected pathogenic immune cell populations, such as B lymphocytes. In IBD, this concept has gained momentum through evidence implicating mucosal B cells, plasmablasts, and disease-associated humoral responses as potential disease drivers in UC. A recent case report suggested that CD19-directed CAR-T cell therapy may induce profound remission in multirefractory UC. In parallel, CAR regulatory T cells (CAR Tregs) may offer a complementary approach for IBD therapy by redirecting suppressive immune function in the inflamed intestine. Particularly, interleukin-23 receptor-targeted CAR Tregs provide a mechanistically attractive strategy to modulate T helper-type 17-driven mucosal inflammation in CD. Safety considerations and translational challenges are potential concerns with regard to CAR-T and CAR-Treg therapies in IBD. However, these technologies may enable precision immune engineering for selected refractory disease endotypes in IBD.
    DOI:  https://doi.org/10.1016/j.ero.2026.100224
  16. Cancers (Basel). 2026 Aug 19. pii: 2680. [Epub ahead of print]18(16):
    B Cell Aplasia Following CAR T Cell Therapy: Incidence, Kinetics, Prognostic Implications, and Clinical Management.
    Malak Khalifeh, Malini Surapaneni, Huda Salman.
      B cell aplasia (BCA), the sustained depletion of circulating CD19-positive B cells, is the defining on-target, off-tumor consequence of anti-CD19 chimeric antigen receptor (CAR) T cell therapy. Despite its occurrence across all approved CAR T cell products and all responding patients, BCA has not been systematically reviewed as a standalone clinical and biological phenomenon. This review synthesizes data from landmark trials and real-world cohorts across B cell-acute lymphoblastic leukemia (B-ALL), large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia to characterize BCA incidence, recovery kinetics, prognostic significance, and management implications. Anti-BCMA products, which mechanism of action differs fundamentally, depleting plasma cells rather than B cell precursors, are intentionally excluded from this review. BCA is observed in all responders and is consistently absent in non-responders across reported cohorts , making it a reliable pharmacodynamic marker of CAR T cell activity. Its prognostic significance is disease-specific: in lymphoma, BCA recovery does not predict relapse and durable remission is achievable independent of sustained aplasia; in B-ALL, early BCA recovery within six months is a robust independent predictor of CD19-positive relapse, while persistent BCA correlates with sustained remission. CD19-negative antigen-escape relapse occurs preferentially in the presence of intact BCA and high pre-infusion tumor burden. Combining BCA kinetics with bone marrow next-generation sequencing minimal residual disease assessment at day 28 and month 3 constitutes the most powerful post-infusion risk-stratification framework currently available. BCA is mechanistically dissociated from hypogammaglobulinemia: IgM declines rapidly and profoundly, IgA more slowly, while IgG-maintained by CD19-negative long-lived plasma cells-is the most preserved isotype. No B cell count threshold below which hypogammaglobulinemia becomes clinically significant has been established. Evidence-informed IVIG replacement thresholds are proposed, though no randomized trial data exist to support them, representing a critical gap requiring prospective investigation.
    Keywords:  B cell aplasia; CAR T cell therapy; CD19; axicabtagene ciloleucel; hypogammaglobulinemia; immunoglobulin replacement; minimal residual disease; relapse; tisagenlecleucel
    DOI:  https://doi.org/10.3390/cancers18162680
  17. Int J Mol Sci. 2026 Aug 19. pii: 7425. [Epub ahead of print]27(16):
    The Evolution of FAP-Targeted CAR T-Cell Therapy in Solid Tumors: From Immunotherapy to Immunotheranostic Applications.
    Hugo Boutier, Anja Feldmann, Michael Bachmann.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of hematologic malignancies but has demonstrated limited efficacy in solid tumors, mainly due to the complex and immunosuppressive tumor microenvironment (TME). Among the strategies to overcome this challenge, targeting the tumor stroma rather than the tumor cells themselves has gained increasing interest. In this context, fibroblast activation protein alpha (FAP), a cell surface protease overexpressed by cancer-associated fibroblasts, represents a promising target. With the aim of remodeling the TME, enhancing immune infiltration, and suppressing tumor growth, numerous FAP-directed CAR T-cell therapies have been developed in the last decade, leading to the clinical translation of two candidates. To improve the flexibility and safety profile of CAR T-cell therapies, several groups have designed more controllable and modular approaches, including adapter CAR T-cell systems, which enable on-demand activation of effector cells through the administration of an adapter molecule. In parallel, the development of FAP-targeted radiotracers, particularly FAP inhibitors (FAPIs), has enabled high-contrast imaging of solid tumors and introduced attractive opportunities for radioligand therapy. The convergence of these advances has given rise to immunotheranostic strategies that integrate CAR T-cell immunotherapy and radioligand delivery within a unified framework. This review traces the evolution of FAP-directed CAR T-cell strategies, from conventional designs to adapter-based and theranostic platforms, and examines how modular adapters bring immunotherapy and radioligand delivery together within a single immunotheranostic framework, across preclinical and clinical settings.
    Keywords:  CAR T-cell; FAPI; adapter CAR platform; fibroblast activation protein (FAP); immunotheranostics; targeted radioligand delivery; theranostics; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27167425
  18. Clin Rheumatol. 2026 Aug 25.
    Health equity in rheumatology-the uneven landscape of cellular therapy.
    Sharon Dowell, Grace C Wright.
      Cellular therapies may effectively "reset" the immune system and fundamentally alter the long-term course of chronic autoimmune rheumatic diseases. Clinical application in systemic lupus erythematosus resulting in drug-free remission has driven inquiry into other rheumatic disorders-systemic sclerosis, inflammatory myositis, Sjogren's disease-with early signals of significant therapeutic response. The substantial costs, complex manufacturing processes, and need for intensive patient monitoring limit cellular therapy delivery to certified academic centers-making it out of reach for many patients. The promise of remarkable therapeutic advances is therefore countered by the risk of deepening existing inequities, with limited access fueled by cost and compounded by the complexity of treatment. In this editorial, we argue that this early phase of cellular therapy in rheumatology presents a critical window for rheumatologists, trialists, industry partners and policymakers to embed equity into trial design, access frameworks and reimbursement pathways.
    Keywords:  Autoimmune rheumatic disease; Cellular therapy; Health equity
    DOI:  https://doi.org/10.1007/s10067-026-08367-6
  19. Front Immunol. 2026 ;17 1784443
    Natural killer cells at the interface of tumor immune escape and immunotherapy resistance in endometrial cancer.
    Alessandro Poggi, Valentina Bruno, Anna Di Spirito, Lorenzo Mortara, Denisa Baci.
      Endometrial cancer (EC) is characterized by significant molecular and immunological heterogeneity, which influences both disease progression and response to therapy. Although immune checkpoint blockade has improved the clinical management of selected EC subtypes, durable responses remain limited in many patients, particularly in tumors with poorly inflamed or mismatch repair-proficient/microsatellite-stable profiles. In this context, natural killer (NK) cells represent an important but still insufficiently explored component of anti-tumor immunity. NK cells can recognize transformed or stressed cells independently of antigen-specific priming, which may be relevant in EC tumors characterized by altered antigen presentation, immune exclusion, or limited T-cell responsiveness. Within the EC tumor microenvironment, NK-cell dysfunction is likely shaped by a complex interplay between defective recruitment, altered receptor-ligand interactions, suppressive cytokine networks, and tumor-driven immune remodeling. These mechanisms may reduce NK-cell cytotoxicity and favor immunoregulatory or tolerance-like phenotypes, some of which resemble programs involved in maternal-fetal immune tolerance. Here, we examine how EC may reshape NK-cell recruitment, phenotype, and function, and discuss how these alterations intersect with molecular tumor heterogeneity, immune escape, and emerging NK-directed therapeutic strategies. Particular attention is given to how NK-directed and NK-complementary approaches, including cytokine-based activation, NK-cell engagers, adoptive NK-cell transfer, chimeric antigen receptor natural killer cell (CAR-NK) platforms, and their integration with immune checkpoint blockade, may help address resistance in EC.
    Keywords:  endometrial cancer; immune escape; immunotherapy; natural killer cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1784443
  20. Front Med (Lausanne). 2026 ;13 1900701
    Biomarker-driven immunotherapy and adoptive cell therapy in recurrent pancreatic ductal adenocarcinoma.
    Tao He, Guoan Li, Fuzhen Qi.
      Recurrent pancreatic ductal adenocarcinoma (PDAC) includes circulating tumor DNA (ctDNA)-defined molecular residual disease (MRD), isolated or oligometastatic relapse, disseminated measurable recurrence, and heavily pretreated refractory disease. These states differ in tumor burden, treatment urgency, tissue accessibility, and immune competence and should not be treated as one population. Immune checkpoint blockade has minimal activity in unselected PDAC, and randomized trials have not shown consistent benefit from adding checkpoint inhibitors to chemotherapy. However, rare microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) tumors and selected antigen- or human leukocyte antigen (HLA)-defined subgroups support precision immune intervention. This Mini Review evaluates biomarkers for immunotherapy and adoptive cell therapy, including ctDNA kinetics, tumor mutational burden, KRAS and neoantigen profiles, antigen presentation and target-antigen density, effector immune state, myeloid and fibroblast-mediated suppression, and spatial immune exclusion. It compares checkpoint blockade, personalized and KRAS-directed vaccines, chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor natural killer-cell (CAR-NK), and T-cell receptor (TCR)-engineered therapies by recurrence setting, evidence maturity, feasibility, and failure mechanisms. Checkpoint blockade is currently most defensible for MSI-H/dMMR disease; vaccines and cell therapies remain investigational and are best tested in biomarker-selected trials, especially in low-burden or molecular recurrence. We propose a five-step workflow to classify recurrence, identify actionable biomarkers, match evidence-appropriate interventions, assess feasibility, and monitor response and immune escape. This framework supports trial design and disciplined clinical translation rather than empiric immunotherapy in unselected recurrent PDAC.
    Keywords:  Car-T; adoptive cell therapy; biomarker; circulating tumor DNA; immunotherapy; molecular residual disease; pancreatic ductal adenocarcinoma; recurrence
    DOI:  https://doi.org/10.3389/fmed.2026.1900701
  21. Transplant Cell Ther. 2026 Aug 27. pii: S2666-6367(26)00685-8. [Epub ahead of print]
    Adaptive bridging and holding therapy frequently reduces tumor burden and is associated with reduced toxicity after CAR-T cell therapy in multiple myeloma: A single-center real-world experience.
    Jule Cecilia Artzenroth, Ricardo Kosch, Maximilian Al-Bazaz, Leandra Bartke, Leon Cords, Corinna Güsmer, Marie Harzer, Fabian Heinrich, Abdulaziz Kamili, Lisa Leypoldt, Ramin Madanchi, Malte Benedikt Monin, Christoph Schaefers, Theresa Schlemmer, Johan Seibel, Carsten Bokemeyer, Katja Weisel, Winfried Alsdorf.
       BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has transformed the treatment of relapsed/refractory multiple myeloma (RRMM) but is associated with substantial toxicity. The association between pre-infusion disease control and post-infusion toxicity remains underexplored, and no treatment standards exist for bridging therapy in RRMM.
    OBJECTIVE: To characterize the holding and bridging regimens used in clinical practice, evaluate their effectiveness in achieving pre-infusion disease response, and assess the association between the depth of pre-infusion response and the incidence of post-infusion toxicity.
    STUDY DESIGN: In this single-center retrospective analysis, 88 consecutive RRMM patients received idecabtagene vicleucel (n=22) or ciltacabtagene autoleucel (n=66). Pre-infusion response was assessed using International Myeloma Working Group criteria. The primary endpoint was a composite of any ≥Grade 2 toxicity across six categories: cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, early and late immune effector cell-associated hematotoxicity, and infection, evaluated using log-link regression to estimate risk ratios (RR).
    RESULTS: Among the 88 patients included in the analysis, the median number of prior lines of therapy was 4. Holding and bridging therapy were administered in 80 (90.9%) and 87 (98.9%) patients, respectively. Twenty-four different therapeutic regimens were administered. Among the 79 patients who received both holding and bridging therapy, 32 (40.5%) changed regimens after apheresis due to insufficient response. Overall, 60/88 patients (68.2%) achieved ≥ partial response before infusion. Patients achieving ≥ very good partial response (VGPR) had a composite ≥Grade 2 toxicity rate of 8/35 (22.9%) compared with 25/53 (47.2%) in those with <VGPR (RR 0.48, 95% CI 0.25-0.95; p=0.035); this association persisted in the adjusted model including all 88 patients (adjusted RR 0.50, 95% CI 0.26-0.98; p=0.042). One case of CAR-T induced Guillain-Barré syndrome and seven cranial nerve palsies were observed, no parkinsonism occurred. Non-relapse mortality was 2/88 (2.3%). Alkylator-based holding therapy did not lead to an increased number of out-of-specification product.
    CONCLUSION: Deeper pre-infusion response was associated with significantly lower toxicity after BCMA-directed CAR-T therapy, identifying pre-infusion disease control as a potentially modifiable determinant of toxicity. Intensified holding and bridging strategies were feasible and effective in reducing disease burden in highly pretreated patients, supporting prospective validation of response-adapted bridging to improve the safety of CAR-T therapy in RRMM.
    Keywords:  BCMA CAR-T cell therapy; bridging therapy; cytokine release syndrome; multiple myeloma; neurotoxicity; pre-infusion response
    DOI:  https://doi.org/10.1016/j.jtct.2026.08.044
  22. Biomaterials. 2026 Aug 17. pii: S0142-9612(26)00575-2. [Epub ahead of print]337 124551
    Logic-gated nanoregulators: A paradigm shift from drug delivery to pre-programmed multi-target immunotherapy.
    Yimao Wu, Feiyang Tang, Junying Lee, Yalun Liang, Gokhan Zengin, Qian Zhang, Wenlong Sun, Meng-Yao Li.
      Cancer immunotherapy has reshaped oncology, yet its broad application is constrained by an immunosuppressive tumor microenvironment and the systemic toxicities of conventional treatments. This review traces the evolution of nanomedicine from a passive drug delivery vehicle to a therapeutic program encoded in a physical structure. The tumor microenvironment poses physical and cellular barriers that operate not as independent hurdles but as self-reinforcing systems, an architecture that dictates a target-selection logic whereby nanocarriers must engage paired targets simultaneously rather than sequentially. This logic translates into three coupled engineering requirements, namely co-loading of physicochemically diverse agents, spatial coordination across subcellular compartments, and temporal synchronization of release. Pre-programmed stimuli-responsive systems embody the current capability for meeting these demands. The boundary between pre-programmed computation and adaptive feedback is further evaluated, with the latter defined by the capacity to sense therapeutic outcomes and modulate subsequent release, a feat that remains unrealized in vivo. Finally, three translational challenges are assessed, all converging on whether the execution of a nanocarrier's therapeutic program can be trusted in the patient. Trust becomes possible when the carrier's trajectory hinges on biological processes conserved across patients, when its fabrication preserves the structural features encoding its function, and when its material composition dictates a predictable clearance pathway. These are not translational afterthoughts but the design constraints that will determine whether the next generation of cancer nanomedicines fulfills its clinical promise.
    Keywords:  Cancer immunotherapy; Immune modulation; Immunogenic cell death; Nanomedicine; Nanoplatforms; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.biomaterials.2026.124551
  23. EMBO Mol Med. 2026 Aug 27.
    A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.
    Tingxi Guo, Kaya R Epstein, Maegan E Hoover, Nathan W Zammit, Jennifer Y Yam, Scott Hussell, Sophia Hernandez, Abigail Doherty, Payam Zarin, Martina Sassone-Corsi, Lindsay Webb, Gene I Uenishi, Thomas Wickham, Christopher L Moore.
      Allogeneic cell therapies offer a scalable and off-the-shelf alternative to the autologous approach, but immune rejection, particularly by natural killer (NK) cells following human leukocyte antigen (HLA) ablation, remains a major barrier to their persistence. Here, we report an improved synthetic NKG2A engager to selectively inhibit NKG2A⁺ NK cells while avoiding activation of NKG2C⁺ subsets, thereby overcoming a key limitation of the natural ligand HLA-E. Engineered regulatory T cells (EngTregs) lacking HLA and expressing the engager were protected from in vitro NK cell-mediated cytotoxicity more effectively than previously reported NK inhibitory strategies. In humanized mouse models, EngTregs persisted for up to 12 weeks, whereas unprotected cells were rapidly rejected. Incorporation of the engager into a clinically compatible dual-AAV EngTregs preserved Treg identity and function while conferring resistance to immune rejection. Together, these findings establish the improved NKG2A engager as an effective synthetic immune-evasion strategy and provide a clinically translatable approach to enable durable persistence of off-the-shelf EngTreg therapies.
    DOI:  https://doi.org/10.1038/s44321-026-00507-4
  24. Res Pract Thromb Haemost. 2026 Jul;10(5): 106886
    Disseminated intravascular coagulation in chimeric antigen receptor T-cell therapy: a 6-year nationwide analysis of clinical outcomes and health care resource utilization in patients with hematologic malignancies.
    Adamsegd Isac Gebremedhen, Abdu Mohammad, Samhitha Gundakaram, Semere Tesfamariam, Reesha Bodiwala, Mamdouh Souleymane, Muhammad Jamil.
       Background: Disseminated intravascular coagulation (DIC) is a recognized complication of chimeric antigen receptor (CAR) T-cell therapy and contributes to treatment-related morbidity and mortality. However, data on its clinical and financial impact remain limited.
    Objectives: This study examined the characteristics and outcomes associated with DIC among hospitalizations for hematologic malignancies undergoing CAR-T cell therapy using national U.S. data.
    Methods: Adult hospitalizations with acute lymphoblastic leukemia, non-Hodgkin lymphoma, or multiple myeloma who received CAR T-cell therapy (2017-2022) were identified from the National Inpatient Sample. Hospitalizations were stratified by DIC status, and survey-weighted analyses were performed to generate national estimates. Multivariable regression was used to assess differences in mortality and other outcomes (P < .05).
    Results: Among 10,450 weighted CAR T-cell therapy hospitalizations, 220 (2.1%) developed DIC. In-hospital mortality was significantly higher in hospitalizations with DIC (22.7% vs 2.4%; adjusted odds ratio [aOR], 10.96; 95% confidence interval [CI], 4.78-25.09). DIC was associated with higher odds of acute kidney injury (aOR, 6.01), respiratory failure (aOR, 9.96), and shock (aOR, 18.55) and greater use of renal replacement therapy, mechanical ventilation, and vasopressors. DIC was also associated with higher odds of gastrointestinal hemorrhage (aOR, 12.41) and greater transfusion needs. DIC was associated with longer hospital stays (β = +17.6 days; P < .001) and higher hospitalization charges (β = +$523,323; P = .02).
    Conclusions: DIC is an infrequent yet severe complication of CAR T-cell therapy, associated with increased mortality, organ dysfunction, critical care utilization, transfusion needs, prolonged hospitalization, and higher charges. These findings underscore the importance of clinical vigilance and early intervention strategies.
    Keywords:  CAR T-cell therapy; disseminated intravascular coagulation; hematologic malignancy
    DOI:  https://doi.org/10.1016/j.rpth.2026.106886
  25. Mater Today Bio. 2026 Oct;40 103570
    Organization from cell to tissue derived delivery systems for immunotherapy.
    Xi Tan, Mutang Li, Dandan Luo, Hongjun Li.
      Dysregulation of the immune system drives a broad spectrum of diseases, including cancers, autoimmune disorders, and neuro-immune conditions. Immunotherapy has advanced from small-molecule drugs to biomacromolecular agents and living cell therapies, yet conventional synthetic delivery platforms struggle to preserve the structural integrity, bioactivity, and long-term viability of these complex payloads in vivo. Biologically derived drug delivery systems (BDDS) have emerged as a promising class of carriers that harness natural organelles, cells, and tissues to achieve high loading capacity, inherent biocompatibility, bioresponsive targeting, and controlled release. This review systematically examines the hierarchical organization of BDDS across nanoscale, microscale, and macroscale levels and emphasizes their distinct biological advantages, engineering features, and translational potential. We detail the material sourcing, isolation techniques, drug-loading, surface modification, and genetic engineering strategies, as well as considerations for scalable manufacturing. Representative platforms are highlighted for their ability to cross biological barriers, modulate immune microenvironment, and treat cancers, autoimmune diseases, and neuroinflammation. In addition, the emerging biosynthetic alternatives including membraneless organelle condensates, artificial cells, and advanced organoids, are discussed as next-generation platforms that may overcome the limitations of natural BDDS. Finally, we outline current challenges in the heterogeneity, large-scale production, and clinical translation, while proposing future directions including the reasonable administration routes, cross-scale hierarchical integrated platform designs and emerging computational and engineering technologies to accelerate the development of BDDS-based immunotherapies.
    Keywords:  Biological platforms; Drug delivery; Hierarchical organization; Immunotherapy
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103570
  26. Front Immunol. 2026 ;17 1824717
    Phosphorylation shapes antigen presentation and immune recognition: mechanistic insights and translational perspectives.
    Ramesh Rijal, Alexandre F Marques.
      Phosphorylation is a reversible post-translational modification that dynamically regulates immune responses by reshaping the antigen profiles. Phosphoproteomics and immunopeptidomics studies reveal that phosphorylated peptides (phosphopeptides) are naturally processed and presented by MHC class I and II molecules and can elicit robust T-cell responses. These epitopes influence proteasome cleavage, TAP transport, and MHC loading, defining the immunopeptidome under physiological and pathological states. Structurally, phosphate groups enhance MHC binding and immunogenicity, positioning phosphorylated neoantigens as promising targets for cancer immunotherapy and vaccine development. Beyond adaptive immunity, phosphorylation regulates innate signaling through Toll-like receptors (TLRs) and antigen-presenting cell activation, linking post-translational modifications to immune plasticity. Infections by parasites and bacteria such as Mycobacterium tuberculosis exploit phosphoregulation to evade antigen presentation, revealing conserved mechanisms of immune modulation. Integrating phosphoproteomic data with immune profiling may uncover new biomarkers and therapeutic strategies. This review summarizes how phosphorylation shapes antigen presentation and immune recognition across cancer, infection, and inflammation, and outlines future directions for phosphoantigen-based immunotherapy.
    Keywords:  MHC class I presentation; T cell recognition; antigen processing; host–pathogen interactions; immune evasion; phosphopeptides
    DOI:  https://doi.org/10.3389/fimmu.2026.1824717
  27. J Manag Care Spec Pharm. 2026 Sep;32(9): 1090-1100
    Automating cost-effectiveness models with agentic artificial intelligence: Case study and implications for value assessment.
    Rahul Mudumba, A B Modi, Kevin Mayo.
       BACKGROUND: Health economic modeling is conceptually sophisticated but operationally repetitive and resource intensive. Recent advances in large language models suggest potential for automating components of cost-effectiveness model development.
    OBJECTIVE: To evaluate whether an agentic artificial intelligence (AI) system can reliably automate cost-effectiveness model development in the context of targeted therapies for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC).
    METHODS: We developed the Agentic Health Economic Modeling Platform (A-HEMP) to construct a cost-effectiveness model for ALK+ NSCLC therapies without access to existing models in that clinical context. Modeling decisions and extracted parameters were compared with a previously published manual cost-effectiveness analysis. A-HEMP automated PICO-based scoping, modeling approach recommendation, systematic literature review, and structured parameter extraction. Performance was evaluated across 3 domains: model structure concordance, evidence identification concordance, and parameter value alignment. Deterministic cost-effectiveness outputs were calculated externally for benchmarking.
    RESULTS: A-HEMP identified a modeling framework aligned with the published cost-effective analysis and retrieved all primary clinical trials used for clinical efficacy inputs. Concordance in model structure and assumptions was observed in 27% of modeling dimensions, with 36% partially concordant and 36% divergent. Divergences were most prominent in survival extrapolation and intracranial progression handling. Evidence identification concordance was high for primary clinical trials (100%) but moderate for cost inputs, with 25% of evidence domains fully concordant and 38% partially concordant. Parameter value alignment was high for clinical efficacy inputs and progression-free health state utilities (<2% deviation), whereas greater variability was observed for sicker health states (12% deviation) and downstream disease management costs (25%-55% deviation).
    CONCLUSIONS: Agentic AI can reliably automate upstream components of cost-effectiveness model development. However, nuanced modeling decisions with less standardized methodological guidance remain areas requiring expert oversight. These findings support a hybrid paradigm in which AI augments, but does not replace, health economists in value assessment and formulary decision support within managed care settings.
    DOI:  https://doi.org/10.18553/jmcp.2026.32.9.1090
  28. Am J Manag Care. 2026 07 01. 32(7): e217-e221
    The New Oncology Blueprint: Integrating Clinical Intelligence for Sustainable Value.
    Vivian T E Tar.
      Oncology is one of the most exciting yet most challenging areas of health care. Scientific advances in immunotherapies, targeted agents, and cell and gene therapies are transforming survival, but costs are rising just as quickly. Global oncology spending is projected to exceed $400 billion by 2028, with more than half concentrated in just 5 tumor types. These dynamics present a critical challenge for payers-pharmacy benefit managers and health plans-to sustain access to innovation while protecting the long-term viability of the health care system. Traditional tools such as step therapy, prior authorization, and formulary tiers, although important in many areas of care, struggle to keep pace with oncology, where treatment is adaptive, evidence evolves rapidly, and care decisions are highly personalized. Fragmented benefits and siloed data further obscure the total cost of care and hinder coordination across the patient journey. This article outlines a sustainable path forward: a systems-level blueprint that places patient and system outcomes at the center, supported by clinically intelligent utilization management tools, aligned incentives across benefits, whole-patient support, and collaborative partnerships. Together, these levers create a unified framework that enhances patient experience while enabling payers and providers to focus on value, not volume.
    DOI:  https://doi.org/10.37765/ajmc.2026.89985
  29. J Invest Dermatol. 2026 Aug 22. pii: S0022-202X(26)02676-X. [Epub ahead of print]
    Chimeric antigen receptor T-cell therapy in dermatologic autoimmunity: Mechanisms, applications, and future directions.
    Catherine Z Shen, David Shon, Yvonne Kuo, Christoph T Ellebrecht.
      Autoimmune skin diseases impose substantial morbidity despite therapeutic advances, with current treatments requiring lifelong immunosuppression without eliminating pathogenic immune responses. Chimeric antigen receptor (CAR) T-cell therapy is a promising approach to achieve durable remission through the targeted elimination of immune cells followed by immune reconstitution. This review examines CAR-T therapy in dermatologic autoimmunity, discussing CD19- and B-cell maturation antigen-targeted approaches alongside precision strategies such as chimeric autoantibody receptor T cells. Early clinical data demonstrate drug-free remissions with favorable safety profiles, although longer follow-up and randomized trials are needed to establish durability and comparative effectiveness before CAR-T therapy can fulfill its potential.
    Keywords:  Autoimmune disease; CAR-T-cell therapy; Immune reconstitution; Pemphigus; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.jid.2026.06.1293
  30. Front Oncol. 2026 ;16 1847284
    Immunotherapy in Asia: current insights and prospects in Southeast Asia and Malaysia.
    Ros Suzanna Ahmad Bustamam, Yee Peng Phoon.
      Cancer immunotherapy has transformed the global oncology landscape, offering durable responses across malignancies once considered untreatable. In Asia and Southeast Asia, regions facing a rising cancer burden, countries such as Malaysia are progressively integrating immunotherapeutic approaches, including immune checkpoint inhibitors and CAR-T cell therapies. Regional progress is supported by investments in research infrastructure, expanding clinical trial participation, and cross-border regulatory collaboration. However, significant challenges persist. Diverse genetic and epidemiological profiles complicate treatment generalizability, while disparities in healthcare access, limited biomarker validation, and high costs restrict widespread implementation, particularly in low- and middle-income settings. In Southeast Asia, including Malaysia, these challenges are intensified by urban-rural disparities in healthcare access and financial limitations. However, emerging opportunities such as biomarker-informed precision immunotherapy, artificial intelligence-enabled treatment personalization, expanded telemedicine services, and enhanced access frameworks offer promising pathways forward. This review highlights the current landscape, ongoing challenges, and future prospects of cancer immunotherapy in Asia and Southeast Asia, with a particular focus on Malaysia's growing role in this evolving field. Cross-regional cooperation, regulatory harmonization, and personalized treatment strategies are crucial for equitable access to cancer therapies across this region. By synthesizing fragmented and underrepresented evidence from Southeast Asia within a broader Asia-focused immunotherapy framework, this review aims to provide a consolidated reference that can guide future research prioritization, strengthen regional policy development, and support the design of more inclusive and scalable immunotherapy implementation strategies.
    Keywords:  Malaysia; Southeast Asia; antibody; biomarker; cancer immunotherapy; car-t; cell therapy; regulation
    DOI:  https://doi.org/10.3389/fonc.2026.1847284
  31. Mol Ther Oncol. 2026 Sep 17. 34(3): 201315
    An inducible signal 1 booster overcomes limited access to antigen for solid tumor cell therapy.
    Kelly C Radecki, Diane Manry, Charles Kirsh, Navneet Kumar, Ethan McLeod, Anagha Krishnagiri, Aaron D Flynn, Alaia Sima, Julyun Oh, Alexander C Partin, Breanna DiAndreth, Alexander Kamb.
      Antigen (signal 1) is the ignition and fuel for T cell responses. Chimeric antigen receptors (CARs) co-opt T cell receptor (TCR) signaling domains (e.g., ITAM elements) to redirect T cell responses to specific antigens. Most efforts to enhance potency have added elements intended to preserve antigen dependence while boosting sensitivity, persistence, etc. However, solid tumors pose unique challenges compared to blood cancers. For example, access to tumor tissues that express target antigen is highly restricted by the blood vessel walls and, with limiting antigen, it is unclear how antigen-dependent boosters can be brought into action. Here, we describe a simple circuit that addresses this problem by mimicking an antigen stimulus with a small molecule to boost signaling downstream of the CAR. These signal 1 boosters are variants of the previously identified MyD88-CD40 fusion protein but mitigate the excessive antigen sensitization of this molecule. We identified a booster that, when expressed with CAR or Tmod, produces small-molecule-inducible T cell expansion and activation while maintaining a favorable safety profile in a surrogate normal-tissue mouse model.
    Keywords:  CAR-T; LILRB1; LIR-1; Tmod; booster; cell therapy; persistence; rimiducid; signal 1; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.omton.2026.201315
  32. Transplant Cell Ther. 2026 Aug 23. pii: S2666-6367(26)00680-9. [Epub ahead of print]
    CAR-T and GvHD: Have We Engineered GvHD Out of Allogeneic CAR‑T Therapy?
    Nabeel Ahmed, Jawaria Jabeen.
       BACKGROUND: Autologous CAR-T has transformed lymphoma therapy, but 40-60% of patients still relapse, and manufacturing is slow/expensive. Allogeneic CAR-T cells (from healthy donors or iPSCs) could overcome these issues. They can avoid patient leukapheresis and reliance on heavily pretreated autologous T cells, reduce the need for bridging therapy, permit advance manufacture, and allow deliberate donor and cell-subset selection. However, they face two main immunologic barriers: (1) GvHD, in which donor T cells' native TCRs may recognize patient tissues as foreign, causing acute/chronic GvHD; and (2) host-versus-graft rejection, in which the patient's immune system may reject the donor cells2. In mismatched stem cell transplant (alloHCT), GvHD occurs in ∼50-80% of cases without intervention3. By analogy, unmodified donor αβ T cells with CARs might similarly attack HLA-mismatched host tissues. Thus, successful allogeneic CAR-T must reduce donor-to-host alloreactivity while managing the distinct host-versus-graft barrier. This focused Perspective asks whether GvHD directed engineering has made clinically significant product-associated GvHD rare.
    Keywords:  Allogenic CAR-T; CAR-T; GVHD; Immunotherapy; graft-versus-host-disease
    DOI:  https://doi.org/10.1016/j.jtct.2026.08.039
  33. Biomedicines. 2026 Aug 06. pii: 1770. [Epub ahead of print]14(8):
    Challenges and Opportunities of γδ T Cell-Based Immunotherapy for Glioblastoma.
    Chun-Chieh Chao, Hsieh-Tsung Ethan Shen, Bo-Xiang Benjamin Zhang, Ting-Hsuan Collette Chao, Ching-Dong William Wang, Chung-Che Wu.
      Glioblastoma remains the most lethal primary malignancy of the central nervous system, and the modest gains achieved with maximal surgery, radiotherapy and temozolomide have not been matched by the immune checkpoint inhibitors and antigen-specific vaccines that reshaped the treatment of many extracranial cancers. The recurrent disappointment of these approaches has been attributed less to a single molecular lesion than to a confluence of obstacles: profound intratumoural heterogeneity, a densely immunosuppressive and myeloid-rich microenvironment, sequestration and exhaustion of conventional T cells, and the practical difficulty of delivering effectors across the blood-brain barrier. Against this background, γδ T cells have attracted interest as an unconventional effector population that recognises transformed cells through stress-associated and metabolic cues rather than peptide-major histocompatibility complex (MHC) complexes, that kills in an MHC-unrestricted manner, and that can be expanded from healthy donors for allogeneic, off-the-shelf use with little expectation of graft-versus-host disease. This narrative review examines, with a deliberately critical lens, the biological rationale and the experimental evidence for γδ T cell-based immunotherapy of glioblastoma. We summarise the developmental biology and functional subsets of human γδ T cells, the natural killer group 2 member D (NKG2D)-, DNAX accessory molecule 1 (DNAM-1)- and T-cell-receptor-dependent mechanisms through which they engage glioblastoma cells and glioma stem-like cells, and the in vitro and animal-model studies that underpin the field, taking care not to overstate efficacy that has so far been demonstrated only in preclinical or early-phase settings. We then weigh the principal opportunities-locoregional and repeated dosing, combination with chemoradiotherapy, checkpoint blockade and antibody-based redirection-against barriers that include limited persistence, uncertain intratumoural trafficking, donor and manufacturing variability, and the unsettled requirements of potency testing and trial design. We give particular weight to what becomes of γδ T cells inside a hostile tumour-the exhaustion-like dysfunction that follows chronic stimulation, the oxygen and glucose dependence of their effector programme, the interleukin-17-polarising signals generated by activated microglia and by genotoxic therapy, and the confounding effect of corticosteroids-together with the engineering and pharmacological strategies proposed to counter them. The first peer-reviewed phase 1 report of intracranially delivered, drug-resistant γδ T cells has now appeared and documents tolerability in a small, single-arm cohort without establishing survival benefit. Throughout, γδ T cells are presented as a biologically plausible but still investigational strategy whose clinical value will be determined by adequately powered trials rather than by mechanistic appeal alone.
    Keywords:  NKG2D; Vγ9Vδ2; Vδ1; adoptive cell therapy; glioblastoma; interleukin-17; off-the-shelf cellular immunotherapy; tumour hypoxia; tumour microenvironment; γδ T cells
    DOI:  https://doi.org/10.3390/biomedicines14081770
  34. Int Immunopharmacol. 2026 Aug 27. pii: S1567-5769(26)01172-0. [Epub ahead of print]188 117325
    Humanized CD70-targeted CAR-T cells with reduced fratricide demonstrate potent antitumor activity against AML and RCC.
    Mengjia Zhang, Zhihao Wang, Cheng Gao, Tingting Wang, Jinping Zhao, Kaixuan Zhu, Huiting Wu, Chang Liu, Qiong Wu, Yan Qiao, Yurong Chai, Yanan Jiang, Tao Wang, Guoming Li, Jimin Zhao, Kangdong Liu.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in B-cell malignancies, but its application in acute myeloid leukemia (AML) and renal cell carcinoma (RCC) remains challenging due to the lack of ideal target antigens. CD70 is highly expressed on AML and RCC tumor cells, while its expression in normal tissues is largely restricted to activated lymphocytes, making it a promising immunotherapeutic target. However, CD70 expression on activated T cells can trigger fratricide in CD70-targeted CAR-T cells, posing a major challenge for their preparation and efficacy. Using an analog of the clinical-stage anti-CD70 antibody ARGX-110 as a reference, we screened a phage display library from immunized mice and identified high-affinity anti-CD70 antibodies, which were then used to construct a panel of second-generation CARs. Functional characterization identified a lead candidate, A174-CAR-T, with high CAR expression, strong in vitro antitumor activity, and low fratricide. We further humanized its single-chain variable fragment to generate A174-hu1-CAR. Compared with the parental construct, A174-hu1-CAR-T cells exhibited enhanced expansion and markedly reduced surface expression of CD70, consistent with improved cis-masking (i.e., surface shielding on the same cell). Molecular docking and surface electrostatic potential analyses suggested that humanization optimized the scFv-CD70 binding interface, which together with increased CAR surface expression contributed to the enhanced masking and reduced fratricide. Functionally, A174-hu1-CAR-T cells maintained potent cytotoxicity and showed enrichment of proliferative and central memory T-cell subsets. In xenograft models, A174-hu1-CAR-T infusion demonstrated potent antitumor efficacy against both AML and RCC, with a favorable safety profile. Overall, we developed a humanized CD70-targeted CAR-T cell therapy, A174-hu1-CAR-T, with reduced fratricide and potent antitumor activity, providing a preclinical foundation to support further translational development.
    Keywords:  Acute myeloid leukemia; CD70; Chimeric antigen receptor T cells; Fratricide; Renal cell carcinoma
    DOI:  https://doi.org/10.1016/j.intimp.2026.117325
  35. PLoS One. 2026 ;21(8): e0355495
    Expedited pathway portfolios, trial complexity, and FDA approval timelines in oncology and neurology: A comparative analysis.
    Ahmed M Sayed, Nada M Ezzelarab, Nguyen Tien Huy.
      FDA expedited programs are intended to facilitate development and review for therapies addressing serious conditions with unmet medical need, but their use may depend on whether the evidentiary package is compatible with regulatory acceleration. We compared FDA original approvals in oncology and neurology from 2015 to 2024 to evaluate whether differences in approval timing reflected expedited pathway portfolio intensity, pivotal evidence architecture, or alignment between the two. We conducted a retrospective comparative cohort study of 195 original FDA approvals, including 136 oncology products and 59 neurology products. Product-level regulatory data were curated from FDA approval materials. Pivotal or registrational trials supporting first approval were identified from FDA labels and review documents and enriched through exact National Clinical Trial identifier matching to AACT. The final evidence dataset included 221 curated product-trial links. Regulatory pathway-portfolio intensity was summarized using a Regulatory Bundling Index incorporating Fast Track, Breakthrough Therapy designation, Priority Review, Accelerated Approval, and Orphan designation. Outcomes included regulatory approval time, clinical development time, total time to approval, and pivotal evidence architecture. Oncology products had higher pathway intensity than neurology products, with median Regulatory Bundling Index 3 [IQR, 2-4] versus 2 [IQR, 0-3] (p < 0.001). Neurology products had longer regulatory approval time than oncology products: 362 days [IQR, 245-366] versus 234 days [IQR, 182-329] (p < 0.001). In contrast, clinical development time and total time to approval did not differ significantly. Neurology pivotal evidence was more often randomized, masked, and late phase, while oncology evidence was more often single group. Trial enrollment did not differ significantly. In exploratory counterfactual analyses, increasing neurology pathway intensity to the oncology median was associated with a median predicted review-time reduction of 37.8 days. Differences in FDA approval timing between oncology and neurology appear to reflect both pathway configuration and pivotal evidence architecture. These findings support a pathway-evidence alignment framework rather than a simple model in which more expedited designations alone explain faster approval.
    DOI:  https://doi.org/10.1371/journal.pone.0355495
  36. Front Med (Lausanne). 2026 ;13 1897761
    Cross-jurisdictional access to innovative drugs and devices: a five-year policy and practice review of the Hong Kong and Macao medicine and equipment connect in the Greater Bay Area of China.
    Bingxin Peng, Zhenjie Mo, Yan Yuan, Hui Yao, Liangkui Xu.
      Launched in 2020, the "Hong Kong and Macao Medicine and Equipment Connect" (HKMEC) policy introduced a novel delegated-authority model in China's Greater Bay Area (GBA), enabling designated hospitals to use Hong Kong- or Macao-approved drugs and devices through Guangdong provincial approval, thereby bypassing standard National Medical Products Administration (NMPA) registration. To synthesize five-year implementation evidence, this review followed PRISMA-ScR guidelines and systematically searched Chinese (CNKI, Wanfang, VIP) and English (PubMed, Embase, ScienceDirect) databases covering 2020 to May 2026, supplemented by official documents. By early 2026, the in-use catalog comprised 115 products (45 drugs and 70 devices), while cumulative approvals reached 140 products across 71 institutions, serving more than 17,000 documented patient encounters (as of December 2025; Guangdong Provincial Health Commission, 8 December 2025), mainly in the fields of oncology, rare diseases, and chronic disease. While reliance on external approvals accelerated access, challenges remain, including fragmented real-world data (RWD) infrastructure, self-pay barriers, institutional disparities, and limited cross-border integration. Overall, HKMEC demonstrates a pragmatic delegated regulatory governance model with implications for subnational and transnational pathways, although three priority tasks remain: establishing a regulation-grade RWD platform, advancing financing reforms beyond self-pay, and pursuing substantive collaboration with Hong Kong and Macao. Sustained evidence-driven iteration will be essential to transform this pilot into a robust, scalable model bridging accelerated access and formal regulatory approval.
    Keywords:  Guangdong-Hong Kong-Macao Greater Bay Area; Hong Kong and Macao medicine and equipment connect; cross-jurisdictional drug access; delegated regulatory governance; expedited drug approval pathway; pharmaceutical regulation; real-world evidence
    DOI:  https://doi.org/10.3389/fmed.2026.1897761
  37. EBioMedicine. 2026 Aug 28. pii: S2352-3964(26)00340-3. [Epub ahead of print]131 106456
    Alignment of registered cell therapy trial protocols with regulatory guidance on preclinical evidence: a systematic, cross-sectional, protocol-level analysis.
    Matthew S Jeffers, Wimonchat Tangamornsuksan, Brian Dorus, Patrick Bedford, Jonathan Kimmelman, Daniel I McIsaac, Dean A Fergusson, Manoj M Lalu.
       BACKGROUND: Cell therapies often advance into clinical trials based on supportive preclinical evidence, yet it remains unclear whether such evidence is presented in trial protocols in ways that explicitly justify translation to humans. We assessed whether preclinical efficacy evidence in cell therapy trial protocols aligns with regulatory guidance principles (e.g., mechanism of action, evidence of disease modification, clinically relevant model selection).
    METHODS: We systematically searched ClinicalTrials.gov for cell therapy trials with available protocols. The primary outcomes were the proportions of protocols explicitly reporting 20 predefined preclinical evidence elements corresponding to regulator-derived translational principles. Secondary outcomes included the types and sources of evidence used to justify trial initiation and differences in reporting across trial contexts.
    FINDINGS: We identified 305 eligible trials with protocols, of which 209 (68·5%) incorporated preclinical evidence. Reporting was uneven across domains of translational principles: at least one therapeutic mechanism of action element was explicitly reported in 95% of trials (95% confidence interval [CI], 91-97, n = 198/209), preclinical evidence of disease modification in 70% (95% CI, 63-76, n = 146/209), evidence informing trial intervention parameters in 69% (95% CI, 62-75, n = 144/209), and explicit justification of model relevance in 24% (95% CI, 19-31, n = 51/209). Protocol-level reporting of translational principles was generally higher in trials incorporating large-animal or original preclinical data, and lower in trials citing prior human data or sponsored by industry. Preclinical evidence was more often used to demonstrate biological plausibility than to justify key aspects of trial design.
    INTERPRETATION: Although key translational principles are partially reflected in current practice, domains central to translational validity remain underrepresented. While additional preclinical evidence may be available in investigator brochures or regulatory submissions, publicly available protocols are important documents through which investigators formalise and communicate the rationale for trial initiation. Strengthening how preclinical evidence is structured in protocols may improve trial justification, regulatory evaluation, and support more reliable clinical translation.
    FUNDING: Canadian Stem Cell Network Impact Awards: Ethical, Legal, and Social Impact Stream.
    Keywords:  Biomedical; Cell therapy; Clinical trials; Evidence; Preclinical; Regulatory guidance; Translational science
    DOI:  https://doi.org/10.1016/j.ebiom.2026.106456
  38. Front Pharmacol. 2026 ;17 1869110
    From product to knowledge: the life cycle of health technologies 2.0 as a framework for health system improvement.
    M Otte, I Gutiérrez-Ibarluzea, H P Dauben.
       Background: Existing life cycle frameworks for health technologies have mainly adopted a product-oriented perspective. They treating evidence as a linear input to discrete regulatory and coverage decisions, and failing to capture the iterative, context-dependent, stakeholder-specific nature of knowledge generation needed for contemporary health-technology governance.
    Objectives: This article introduces the Life Cycle of Health Technologies 2.0 (LC 2.0), an updated conceptual framework building on the Life Cycle of Health Technologies (2017, LC 1.0). It traces the evolution from LC 1.0 to LC 2.0, conceptualises LC 2.0 as a knowledge life cycle, and outlines illustrative use cases. LC 2.0 integrates existing conceptual approaches to explore how knowledge about a health technology develops across stakeholder groups across different processes. In line with the Health for All Policies concept, it links this knowledge life cycle to societal, system and patient needs within and beyond the health sector.
    Methods: A mixed-methods approach was applied comprising multi-stakeholder workshops and use-case validation across four technology types.
    Results: Workshops identified revision requirements in LC 1.0 across macro, meso and micro levels, centring on structural inflexibility, implicit post-market learning and limited integration of contextual and stakeholder knowledge. The LC 2.0 framework addresses these through an infinity-loop structure with six phases and twelve subprocesses. It makes knowledge generation an explicit function at every phase and maps knowledge requirements to stakeholder roles. It also incorporates flexible, non-sequential pathways, including a cross-phase transition point (X) as governance decision point between research and development and between continued optimisation and more fundamental revision.
    Conclusion: LC 2.0 reconceives the health-technology life cycle as an iterative knowledge-generation and decision-supporting service, structuring what must be learned, by whom and when, to support appropriate technology use, needs-driven innovation and regulator-appropriate evidence generation, and to provide a shared reference framework for stakeholders inside and adjacent to healthcare and regulatory systems. This shared structure also facilitates easier exchange between different health-system contexts.
    Keywords:  evidence-based medicine; health system governance; health technology assessment; knowledge generation; life cycle framework; real-world evidence; stakeholder engagement
    DOI:  https://doi.org/10.3389/fphar.2026.1869110
  39. Pharmaceutics. 2026 Jul 27. pii: 918. [Epub ahead of print]18(8):
    Target-Product and Translational Design Principles for Inhalable RNA Nanomedicines.
    Hossein Omidian, Sumana Dey Chowdhury, Luigi X Cubeddu.
      Inhalable ribonucleic acid (RNA) nanomedicines are emerging as versatile therapeutics for respiratory diseases and pulmonary metastases, enabling localized delivery of messenger RNA (mRNA), small interfering RNA (siRNA), antisense oligonucleotides, microRNA (miRNA) mimics, self-amplifying RNA, and genome-editing systems. This review synthesizes the available evidence and argues that the field has moved beyond asking whether RNA can reach the lungs. The more consequential translational question is whether RNA cargo, nanocarrier, excipients, manufacturing process, inhalation device, and pulmonary target cell can be integrated into a reproducible therapeutic product. Current research demonstrates progress in disease-corrective mRNA expression, silencing of inflammatory and fibrotic pathways, mucosal vaccination, antiviral therapy, and localized cancer treatment, alongside advances in ionizable lipid nanoparticles, lipid-polymer hybrids, chitosan and polyethyleneimine (PEI) polyplexes, dendrimers, peptide carriers, biomimetic systems, and dry-powder formulations. Translational maturity, however, remains uneven. Many studies demonstrate carrier feasibility, reporter expression, or preclinical activity, whereas fewer establish device-compatible aerosolization, preservation of RNA integrity during processing, traversal of pulmonary barriers, target-cell engagement, repeat-dose tolerability, and clinically meaningful benefit. Development should therefore be target-defined, analytically gated, device-specific, and outcome-centered. Inhalable RNA nanomedicines are best understood as integrated pulmonary products whose success depends on preserving RNA function throughout manufacturing, aerosolization, post-deposition barrier navigation, intracellular delivery, and disease-relevant pharmacodynamic activity.
    Keywords:  aerosol formulation; inhalable RNA nanomedicine; lipid nanoparticles; pulmonary delivery; translational pharmacodynamics
    DOI:  https://doi.org/10.3390/pharmaceutics18080918
  40. Imeta. 2026 Aug 25. e70165
    Multi-omics-driven precision medicine.
    Huibo Li, Zhe Zhao, Yifan Zhang, Yao Ma, Gaofei Hu, Min Zeng, Zhanqun Yang, Zixuan Zhao, Xin Zhou, Wei Hu, Yuxuan Sun, Meng Su, Jun Li, Matthew Whiteman, Wei Fu, Chao Zhong, Lemin Zheng, Long Chen, Hairong Lv, Rongsheng Zhao, Yi Zhun Zhu.
      Precision medicine is increasingly constrained not by a lack of molecular data but by the absence of frameworks that can translate multidimensional biological information into actionable clinical decisions. Multi-omics-driven precision medicine (MODPM) addresses this lack by integrating genomics, epigenomics, transcriptomics, proteomics, metabolomics, microbiome, and clinical context into a multiscale framework that links molecular mechanisms, tissue organization, and patient trajectories. In this review, we propose a conceptual framework for MODPM and examine how advances in multi-omics technologies, artificial intelligence (AI), and foundation models are reshaping disease modeling, drug development, and precision intervention. We summarize the biological contributions of major omics layers and discuss how AI supports cross-modal representation learning, contextual modeling, and perturbation-aware prediction. We highlight drug development as a key translational application of MODPM and further discuss its clinical relevance across three major disease contexts: cancer, autoimmune diseases, and metabolic disorders, including cardiometabolic and renal-metabolic diseases. These examples illustrate how MODPM can support target discovery, disease endotyping, treatment response prediction, and clinical monitoring by analyzing shared mechanisms such as immune dysregulation, metabolic remodeling, chronic inflammation, tissue microenvironmental changes, and gene-environment interactions. Across these settings, MODPM enables finer molecular stratification, the identification of pathway-dominant disease states, improved response prediction, and dynamic treatment monitoring. We also discuss key barriers to implementation, including data heterogeneity, limited cohort diversity, polygenic complexity, workflow constraints, cost, and ethical issues related to privacy, consent, and data ownership. Overall, the value of MODPM lies not in stacking additional data layers but in building a multiscale, continuously learnable framework to link biological heterogeneity to clinically interpretable and actionable decisions.
    Keywords:  artificial intelligence; clinical decision‐making; multi‐omics; precision medicine; translational medicine
    DOI:  https://doi.org/10.1002/imt2.70165
  41. Cancers (Basel). 2026 Aug 17. pii: 2652. [Epub ahead of print]18(16):
    Antibody-Drug Conjugates in Contemporary Oncology: A Clinical Perspective on Dose Optimization, Sequencing, and Combination Strategies.
    Alexander Philipovskiy, Scott Shurmur, Muhammad Bilal Abid.
      Antibody-drug conjugates (ADCs) have matured from a technically challenging concept into an established therapeutic platform across hematologic and solid malignancies. By linking a monoclonal antibody to a potent cytotoxic payload, ADCs seek to increase tumor-directed drug delivery while limiting systemic exposure; however, clinical performance depends on much more than target expression. Target accessibility, antigen density and heterogeneity, internalization, intracellular trafficking, linker stability, payload properties, drug-to-antibody ratio, bystander effect, tumor penetration, and host-tissue handling jointly shape efficacy and toxicity. This review provides a clinician-oriented assessment of the contemporary ADC landscape and the principal biologic and pharmacologic determinants of benefit. We discuss signature toxicities, including interstitial lung disease and ocular injury, and summarize evolving mechanisms of resistance and biomarker development. Particular emphasis is placed on three translational problems that are becoming increasingly important as ADCs move into earlier lines and overlapping disease settings: dose optimization beyond the maximum tolerated dose, sequencing across targets and payload classes, and biologically rational combination strategies. We also present a conceptual Sequential Tumor Attack Model as a hypothesis-generating framework for tumor-access priming, ADC-mediated cytotoxic injury, and immune amplification, while explicitly recognizing that the complete model has not been clinically validated. The future impact of ADCs will depend not only on next-generation constructs, but also on rigorous evidence for how these agents should be dosed, ordered, and combined in practice.
    Keywords:  antibody–drug conjugates; biomarkers; combination strategies; dose optimization; interstitial lung disease; linker; payload; resistance; sequencing; translational oncology
    DOI:  https://doi.org/10.3390/cancers18162652
  42. Biomed Pharmacother. 2026 Aug 27. pii: S0753-3322(26)00924-8. [Epub ahead of print]203 119888
    Nanomaterial-based drug delivery systems: From intelligent delivery to clinical translation and precision nanomedicine.
    Yi Li, Rui Luo, Yuxuan Li, Zhi Liu, Xing Duan, Shugang Qin, Zhongshan He, Shengbin Liu.
      Nanomaterial-based drug delivery systems (NDDS) have become enabling technologies for small-molecule reformulation, RNA medicines, vaccines, gene editing, immunotherapy, and regenerative therapeutics. Their clinical performance, however, is determined not only by cargo loading and release but also by protein-corona evolution, immune recognition, biological-barrier navigation, intracellular trafficking, manufacturing control, and regulatory fit. This review provides a cross-platform comparison of lipid nanoparticles, polymeric nanoparticles, inorganic nanomaterials, extracellular vesicles (EVs), and biomimetic nanocarriers with respect to cargo compatibility, targeting potential, circulation behavior, scalability, clinical maturity, and regulatory status. Passive, active, biomimetic, and organ-selective targeting strategies are critically compared, and recent advances in extrahepatic lipid nanoparticle delivery, biodegradable ionizable lipids, programmable polymers, EV manufacturing, and nano-bio interactions are evaluated. We further integrate disease applications with quantitative lessons from approved products and representative clinical attrition, and compare regulatory expectations across major US, European, Japanese, Chinese, and ICH frameworks. Emerging computational approaches-including high-throughput screening, machine-learning-guided material discovery, autonomous formulation laboratories, generative design, and digital twins-are discussed alongside their validation requirements. A structured translational roadmap is proposed that prioritizes biologically predictive design, fit-for-purpose safety assessment, scalable good manufacturing practice production, early regulatory alignment, and clinically meaningful benefit over unnecessary structural complexity.
    Keywords:  Clinical translation; Drug delivery systems; Nano-bio interactions; Nanomaterials; Precision targeting; Regulatory science
    DOI:  https://doi.org/10.1016/j.biopha.2026.119888
  43. Int J Nanomedicine. 2026 ;21 629846
    Clinical Translation of Functional Magnetic Nanoparticles for Intracellular Hyperthermia and Cancer Immunotherapy.
    Takeru Fukushima, Masahiro Kaneko, Akira Ito.
      Magnetic hyperthermia, in which magnetic nanoparticles (MNPs) generate heat under an alternating magnetic field, has emerged as a promising strategy for cancer therapy. Among numerous magnetic hyperthermia platforms, direct intratumoral administration has achieved the greatest clinical progress because it enables localized heat generation while overcoming the limited tumor accumulation associated with systemic nanoparticle delivery. The development of functional MNPs capable of efficient cellular interaction and intracellular localization has further expanded magnetic hyperthermia beyond conventional tissue heating toward intracellular hyperthermia and cancer immunotherapy. This review summarizes the historical evolution and clinical translation of functional MNPs with particular emphasis on the design principles that have facilitated successful clinical development. We discuss how advances in nanoparticle engineering have improved intratumoral retention, intracellular delivery, thermal dose optimization, and therapeutic efficacy. We further review the emerging role of magnetic hyperthermia as an in situ vaccination strategy capable of inducing immunogenic cell death and stimulating systemic antitumor immunity, providing a biological rationale for combination with immunotherapies. Finally, we discuss current challenges limiting widespread clinical translation, together with future perspectives on multifunctional therapeutic and theranostic nanoplatforms. These advances position functional MNPs as promising platforms for next-generation cancer therapy.
    Keywords:  alternating magnetic field; cancer therapy; magnetic hyperthermia; magnetic nanoparticles; nanomedicine
    DOI:  https://doi.org/10.2147/IJN.S629846
  44. Cell Rep Med. 2026 Aug 25. pii: S2666-3791(26)00425-8. [Epub ahead of print] 103008
    Targeting Regnase-1 in B7-H3-CAR T cells reprograms the tumor microenvironment and enhances antitumor efficacy for osteosarcoma.
    Adeleye O Adeshakin, Hao Shi, S Scott Perry, Heather Sheppard, Phuong Nguyen, Xiang Sun, Peipei Zhou, Jean-Yves Métais, Trevor Cunningham, Anil Kc, Liqing Tian, Vivek Peche, Mollie S Prater, Deanna M Langfitt, Carla O'Reilly, Jeoungeun J Park, Ashley Chabot, Sheng Zhou, Azusa Matsubara, GaHyun Lee, Shengdar Q Tsai, Shondra M Pruett-Miller, Lindsay J Talbot, Jason T Yustein, Giedre Krenciute, Christopher DeRenzo, Hongbo Chi, Stephen Gottschalk.
      The microenvironment in solid tumors represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether it can be reshaped by the deletion of negative regulators in CAR T cells. To address this knowledge gap, we evaluated the intrinsic and extrinsic effects of deleting the negative regulator Regnase-1 (Reg-1) in B7-H3-CAR T cells for the immunotherapy of osteosarcoma. Reg-1 knockout (KO) improved the antitumor activity of human and murine B7-H3-CAR T cells in vivo. In immune-competent models, Reg-1 KO also endowed murine B7-H3-CAR T cells with the ability to create a proinflammatory landscape characterized by an influx of interferon gamma (IFN-γ)-producing endogenous T cells and natural killer (NK) cells and a reduction of inhibitory myeloid cells, including M2-like macrophages. Thus, deleting Reg-1 has cell- and non-cell-autonomous benefits, nominating Reg-1 KO B7-H3-CAR T cells as a promising cell product for early-phase clinical testing in patients with solid tumors.
    Keywords:  B7-H3; CAR; Regnase-1; T cell therapy; gene editing; immunotherapy; osteosarcoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103008
  45. J Intensive Care. 2026 Aug 25. pii: 79. [Epub ahead of print]14(1):
    Timing of hemoadsorption in sepsis: redefining early through mediator-guided therapy.
    Prit Kusirisin, John A Kellum, Nattachai Srisawat.
       BACKGROUND: Hemoadsorption is gaining acceptance as an adjunctive extracorporeal blood purification strategy in sepsis and septic shock; however, its clinical value remains contingent on two closely linked variables: when therapy is initiated and in whom it should be used. This review synthesizes the pathophysiological rationale, conceptual models of mediator removal, available devices, and clinical evidence for hemoadsorption in sepsis, with particular attention to patient selection.
    MAIN BODY: Sepsis is driven by a self-amplifying mediator cascade in which exogenous pathogenic substances and host response mediators increase rapidly, progressively committing potentially salvageable organs to injury and failure. Mechanistic theories of blood purification provide a rationale for early hemoadsorption, when mediator concentrations are high and dysregulated. Clinical evidence, however, remains limited: polymyxin B hemoadsorption guided by the endotoxin activity assay has demonstrated a survival benefit in a randomized trial, whereas supportive findings for cytokine adsorption derive largely from small trials, observational cohorts, and subgroup or post hoc analyses. These findings remain hypothesis-generating and require prospective validation in biomarker-enriched, phenotype-guided randomized trials.
    CONCLUSION: Current evidence supports moving beyond a fixed hours-from-onset definition of "early" treatment toward a biological definition, in which hemoadsorption is initiated in patients with a dysregulated hyperinflammatory host response, after key inflammatory mediators have crossed a toxic threshold and before irreversible organ injury becomes established.
    Keywords:  Cytokines; Endotoxin; Extracorporeal blood purification; Hemoadsorption; Hemoperfusion; Host response; Sepsis; Septic shock
    DOI:  https://doi.org/10.1186/s40560-026-00932-0
  46. Nat Med. 2026 Aug 27.
    CD19 CAR T cell therapy for treatment-refractory seropositive rheumatoid arthritis: a phase 1 trial.
    Fredrik N Albach, Marie C Rehm, Marie Luise Hütter-Krönke, Thanh Hang Le, Julia M Giezen, Murat Torgutalp, Arne Sattler, Ioanna Minopoulou, Robert Biesen, Edgar Wiebe, Vincent Casteleyn, Thorben Witte, Christian Furth, Jan Zernicke, Melanie Nuesch Germano, Johan Verhagen, Artur Wilhelm, Maria Dzamukova, Klaus Engel, Simon Schallenberg, Aimo Kannt, Nicole Ziegler, Michaela Fehringer, Udo Schneider, Nadine Unterwalder, Mark Beling, Alexander Pfeil, Elpida Phithak, Martin Krusche, Olaf Penack, Tobias Alexander, Werner Stenzel, Manfred Wuhrer, Kamran Movassaghi, Thomas Dörner, Eicke Latz, Thomas Vogl, Antonia Busse, Georg Schett, Hans Ulrich Scherer, Rene E M Toes, Arnd Kleyer, Ulrich Keller, Lars Bullinger, David Simon, Gerhard Krönke.
      Chimeric antigen receptor (CAR) T cell-mediated B cell depletion has demonstrated efficacy in several autoimmune diseases. Here we report clinical and molecular data obtained during the nonrandomized phase 1 part of the phase 1/2 COMPARE trial, evaluating safety and efficacy of mivocabtagene autoleucel (miv-cel), an autologous fully human CD19 CAR T cell therapy, in rheumatoid arthritis (RA). Six patients (three men, three women) with severe, treatment-refractory, anti-citrullinated protein antibody (ACPA)-positive RA received a single infusion of miv-cel after stopping all disease-modifying antirheumatic drug treatments and after standard lymphodepletion therapy. Patients were followed for 36-52 weeks for safety and efficacy. Primary endpoints were the incidence and severity of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) and adverse events (AEs) within the first 4 weeks after treatment. Secondary and explorative endpoints assessed clinical efficacy and cellular and humoral immune responses. CRS occurred in all patients and was limited to grade 1 and 2 events. No ICANSs or serious AEs occurred; one dose-limiting toxicity was recorded (grade 3 transaminase elevation, resolved without sequelae). The primary endpoint was met with acceptable safety findings, allowing advancement to phase 2. CAR T cell therapy resulted in depletion of CD19+ B cells across blood and tissue, coinciding with a continuous decline of autoantibodies with seroconversion in four of the six patients for ACPAs against mutated citrullinated vimentin and five of six for rheumatoid factor immunoglobulin M. Despite cessation of immunosuppressive treatments, disease activity improved in all patients (median 34% DAS28-CRP reduction at the latest follow-up with DAS28-CRP remission and American College of Rheumatology 70% response in 3 of 6 patients). CD19 CAR T cells showed acceptable short-term tolerability in patients with treatment-refractory RA, justifying further evaluation. ClinicalTrials.gov identifier: NCT06475495 .
    DOI:  https://doi.org/10.1038/s41591-026-04603-3
  47. Cancer Res Commun. 2026 Aug 27.
    The GENIE Data Model: A Solid Tumor, Person-Centric Framework for Scalable, Harmonized Precision Oncology Data Collection.
    Jennifer N Hoppe, Jocelyn Lee, Tomi F Akinyemiju, Danielle S Bitterman, Michael Brudno, Michelle F Green, Vojtech Huser, Jafi A Lipson, Sanjay Mishra, Daniel P Nussbaum, Jai N Patel, Valentina I Petkov, Kelli M Rasmussen, Sahussapont Joseph Sirintrapun, Patricia A Spears, Sebastiaan Van Sandijk, Anne-Marie Meyer, Umit Topaloglu, Jeremy L Warner.
      Adequately powered analyses in precision oncology often require combining cohorts across institutions. Yet integration is constrained by the least granular source and may become infeasible when data elements are too heterogeneous to harmonize and map to a common data model. This challenge is acute in multi-institutional precision oncology research, where real-world evidence requires harmonized clinico-omic data integration. Existing models often lack sufficient treatment patterns, outcomes, and genomic data, limiting interoperability and scalability. To address these gaps, AACR Project GENIE™ (Genomics Evidence Neoplasia Information Exchange) developed the GENIE Data Model (GDM), a comprehensive, open-source, oncology data model for scalable, consistent, and interoperable data collection across solid tumors designed to effectively capture the patient's journey with cancer. Through iterative consensus-building, four working groups comprising 13 subject matter experts defined data elements across multiple clinical domains: patient characteristics, imaging, diagnosis, surgery, histopathology, biomarkers, systemic therapy, radiation, clinical trial history, disease response and outcomes, and social determinants of health. Elements were defined using standardized terminologies and permissible values to support mapping to HL7 FHIR, OMOP, and other existing oncology standards. The model architecture distinguishes manually abstracted elements from computationally collected elements, enabling parallel workflows. The GDM provides an extensible framework that addresses critical gaps and enables scalable, harmonized data collection essential for precision oncology and real-world evidence generation.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0148
  48. Br J Haematol. 2026 Aug 26.
    Real-world outcomes of ide-cel and cilta-cel in relapsed/refractory multiple myeloma: A nationwide, retrospective analysis in Austria.
    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.
      B-cell maturation antigen-directed chimeric antigen receptor (CAR) T cells have revolutionized the treatment of relapsed/refractory multiple myeloma. However, no randomized head-to-head comparison of idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) is available, and real-world data suggest differences in efficacy and toxicity. We performed a nationwide retrospective real-world analysis (RWA) of Austrian patients treated with ide-cel or cilta-cel between January 2024 and July 2025. Ninety patients were included, with largely balanced baseline characteristics and frequent high-risk features. Bridging therapy was administered to 94.4% of patients, resulting in high response rates prior to lymphodepletion. After a median follow-up of 17.6 months, no early separation of the progression-free survival (PFS) curves was observed between CAR-T products. Multivariable analyses showed a trend towards improved PFS with cilta-cel, whereas true extra-medullary disease (EMD) and prior bispecific antibody treatment before T-cell apheresis were associated with inferior PFS. Although previous RWA have demonstrated an early divergence in PFS between cilta-cel and ide-cel, this pattern was not observed in our cohort. The high effectiveness of bridging therapy may have contributed to these findings. Our results support further investigation of optimal bridging strategies and treatment sequencing while highlighting the persistent unmet need of patients with true EMD.
    Keywords:  CAR‐T; myeloma; real‐world analysis
    DOI:  https://doi.org/10.1111/bjh.70773
  49. Front Immunol. 2026 ;17 1849298
    Development and clinical application of recombinant polyclonal antibodies.
    Jiaqi Jin, Guojiang Chen, Fenghao Peng, Jijun Yu, Xinying Li, Ming Yu, Chenghua Liu, Yan Wen, Jiannan Feng, Chunxia Qiao.
      Monoclonal antibodies (mAbs) have transformed the treatment of cancer and immune disorders, but their single-target nature limits efficacy against heterogeneous tumors and mutating pathogens. Recombinant polyclonal antibodies (RPABs)-defined as mixtures of typically 2-25 defined mAbs produced as a single drug substance from one mixed master cell bank-were proposed to combine the epitope breadth of polyclonal antibodies with the manufacturing consistency of mAbs. This review critically analyzes the four RPABs candidates that have entered clinical trials to date (Sym001, Sym004, Sym013, and Sym015), all developed by Symphogen using its proprietary Sympress™ platform. We identify seven interrelated barriers that collectively explain why no RPABs product has yet received regulatory approval: modest efficacy restricted to biomarker-selected subgroups, significant toxicity, pharmacokinetic mismatch among components, instability of mixed cell banks, lack of standardized quality control methods, regulatory uncertainty, and commercial deprioritization after acquisition. Critically, we distinguish between scientific failure (Sym013, discontinued after early termination of its Phase I trial due to tolerability concerns and pharmacokinetic mismatches) and strategic discontinuation (Sym001 and Sym015, which showed clinical signals but were deprioritized for commercial reasons). All clinical and manufacturing data analyzed in this review are derived exclusively from Symphogen's proprietary Sympress™ platform, as no other RPABs candidate from independent developers has entered clinical trials. We conclude that without independent validation of manufacturing consistency, pharmacokinetic-based component ratio design, and a dedicated regulatory pathway, RPABs face an uncertain future. Recommendations for future development are provided.
    Keywords:  antibody mixture; mixed master cell bank; recombinant polyclonal antibody; site-specific integration; symphogen
    DOI:  https://doi.org/10.3389/fimmu.2026.1849298
  50. PLOS Digit Health. 2026 Aug;5(8): e0001426
    Extracting adverse event nature, severity, timelines and resulting interventions from clinical notes of patients receiving CAR-T cell therapy using large language models.
    Jordan Guillot, Brenda Miao, Arvind Suresh, Madhumita Sushil, Christopher Y K Williams, Rohit Vashisht, Tomiko T Oskotsky, Marina Sirota, Atul J Butte.
      Chimeric Antigen Receptor T-cell (CAR‑T) therapy, genetically engineered patient T cells targeting tumor antigens, has transformed care for hematologic malignancies but requires careful tracking of adverse events (AEs) often documented only in unstructured electronic health record (EHR) notes. We evaluated a Large Language Model (LLM)-based approach in UCSF's secure environment to extract AEs, dates, grades, and interventions within 30 days post‑infusion for six commercial CAR‑T products (2012-2023), benchmarking against two evaluators. Using GPT‑4‑0314 in a zero‑shot setting with four prompts (prespecified AEs, non‑prespecified AEs, CRS, ICANS), we compared outputs against dual annotations on a random sample of 50 notes using accuracy, precision, recall, F1, and Cohen's kappa. From 4,762 progress notes for 293 patients (median age 65.6), CRS occurred in 80.2% (median onset 4 days); neutropenia 70.0% (16 days); neutropenic fever 64.8% (4 days); ICANS in 34.8%. Interventions included tocilizumab and corticosteroids. Grades were frequently undocumented (CRS 62.3%, ICANS 56.1%); documented cases were mainly CRS grade 1 (59.4%) and ICANS grade 2 (28.0%). Performance was high on CRS and ICANS grading (accuracy of 0.97 and 0.91, respectively). Moderate performances were assessed for prespecified AE extraction (accuracies 0.62-0.76), and non‑prespecified AEs (accuracies 0.76-0.84). Inter‑rater reliability (IRR) was strong for CRS/ICANS presence and grade (kappa 0.86-0.96), moderate for dates and interventions, and weaker for broader AE attributes. LLM‑derived insights can augment AE monitoring and real‑world evidence generation by unlocking unstructured clinical detail and characteristic timelines after CAR T. However, performance varied for broader AE attributes, warranting cautious use. Performance was highest for detecting and grading CRS and ICANS, with strong to near-perfect IRR. While cautious use of LLMs is warranted due to the variable performance observed in this study, these results support further evaluation of supervised CRS/ICANS extraction in controlled EHR-based research or pilot settings, with monitoring and prospective validation.
    DOI:  https://doi.org/10.1371/journal.pdig.0001426
  51. Lancet Haematol. 2026 Sep;pii: S2352-3026(26)00126-2. [Epub ahead of print]13(9): e679-e689
    Beyond maximum grade: the role of real-world digital health technologies to capture, predict, and manage treatment toxicity in haematological cancers.
    Tarec Christoffer El-Galaly, Irène Buvat, Raul Córdoba, Matteo G Della Porta, Jan Geissler, Tufia C Haddad, Malte Jacobsen, Guido Kobbe, Michelle L McGowan, Clémentine Sarkozy, Gita Thanarajasingam, Diego Villa.
      Real-world data are essential for understanding treatment-related toxicities in haematology, but traditional analyses are limited by data access, sharing constraints, and reduced data granularity. Emerging digital health technologies (DHTs), such as electronic patient-reported outcomes and wearable devices, can be used to capture continuous, patient-generated data not reliably captured by current post-marketing toxicity assessments. Artificial intelligence, synthetic data, and digital twins can be used to predict and simulate toxicity at a much larger scale beyond the capacity of traditional methodologies. These emerging DHTs could overcome barriers, such as data fragmentation and lack of harmonisation, between existing real-world toxicity data sources. However, they also come with new challenges, including data quality and interpretability, integration into existing clinical workflows, privacy protection, and data governance. Developing and implementing them in partnership with patients, clinicians, payers, and regulators is necessary to maximise their impact in both individual patient and population-level clinical care.
    DOI:  https://doi.org/10.1016/S2352-3026(26)00126-2
  52. Front Bioinform. 2026 ;6 1903746
    Agentic AI for trustworthy synthetic microbial genomics: a perspective on generation, validation, and governance.
    Fahim Sufi.
      Synthetic microbial genomic data are becoming increasingly important for benchmarking microbial genome analysis pipelines, simulating rare taxa, evaluating metagenomic workflows, and supporting reproducible computational biology. Recent genomic foundation models demonstrate that biological sequences can be modelled at unprecedented scale, with emerging capacity for genome-level interpretation, generation, and design. However, the scientific value of synthetic microbial genomic data depends not only on whether sequences can be generated, but whether they are biologically plausible, computationally useful, reproducible, and responsibly governed. This Perspective argues that agentic AI can provide the missing orchestration layer for trustworthy synthetic microbial genomics. Rather than treating synthetic data generation as a single model output, agentic workflows can coordinate specialised roles for sequence generation, biological plausibility assessment, taxonomic validation, functional annotation, contamination detection, downstream benchmarking, provenance logging, and governance review. I propose a validation-first agentic framework in which synthetic microbial genomes, plasmids, phages, and metagenomic profiles are iteratively generated, evaluated, revised, and documented before release or downstream use. Such a framework can help transform synthetic microbial genomic data from computational artefacts into auditable scientific infrastructure with explicit validation gates, escalation criteria, and machine-readable provenance.
    Keywords:  agentic AI; biosecurity; genome scale benchmarking; genomic foundation models; metagenomics; reproducibility; synthetic data validation; synthetic microbial genomics
    DOI:  https://doi.org/10.3389/fbinf.2026.1903746
  53. Blood. 2026 Aug 24. pii: blood.2025032234. [Epub ahead of print]
    Immunoglobulin constant domains as targets for T-cell receptor-based treatment of multiple myeloma.
    Miranda H Meeuwsen, Anne K Wouters, Johannes C Wellershoff, Tassilo L A Wachsmann, Dennis F G Remst, Renate S Hagedoorn, Michel G D Kester, Dirk M van der Steen, Arnoud H de Ru, Els P van Hees, Masashi Matsuda, Fumihiko Ishikawa, Peter A van Veelen, J H Frederik Falkenburg, Mirjam H M Heemskerk.
      Despite major progress with chimeric antigen receptor (CAR) T-cell therapy, multiple myeloma (MM) remains largely incurable, and most patient relapse. To broaden therapeutic options and overcome antigen escape, we explored T-cell receptor (TCR)-based targeting of intracellular antigens derived from immunoglobulin (Ig) heavy chain constant domains. Using HLA class-I peptidomics, we identified nine IgG- or IgA- derived peptides presented by common HLA alleles (HLA-A*01:01, HLA-A*02:01, HLA-A*03:01, and HLA-B*07:02). High-avidity T-cell clones recognizing four of these epitopes were isolated from HLA-mismatched healthy donors. Transfer of these immunoglobulin-specific TCRs into donor T cells conferred potent and selective recognition of IgG- or IgA-expressing MM cell lines while sparing antigen-negative cells. Safety profiling confirmed strict HLA-restricted specificity without cross-reactivity toward other HLA alleles, non-B-lineage tumor cell lines, or healthy tissues, except for depletion of isotype-matched B cells. Immunoglobulin-TCR T cells efficiently lysed patient-derived MM cells ex vivo and eradicated established IgA- or IgG-expressing MM tumors in murine xenograft models. Mechanistic studies revealed that dendritic cells could cross-present immunoglobulin peptides at high serum concentrations, potentially enhancing T-cell activation in vivo. Importantly, subtype-specific depletion of B cells implies that immunoglobulin-TCR T-cell therapy could partly preserve humoral immunity, reducing the need for antibody replacement compared with pan-B-cell depletion strategies. Collectively, these findings establish immunoglobulin heavy chain constant domains as promising targets for TCR-based cellular immunotherapy in MM and potentially other Ig-producing malignancies or autoantibody-mediated autoimmune diseases.
    DOI:  https://doi.org/10.1182/blood.2025032234
  54. Biotechnol Adv. 2026 Aug 24. pii: S0734-9750(26)00228-4. [Epub ahead of print]93 109022
    Ex vivo live macrophage engineering strategies in immunotherapy.
    Eunha Kim, Minkyoung Park, Kyobum Kim.
      Immune cell-based therapies have transformed immuno-oncology by converting living cells into therapeutic agents able to recognize, infiltrate, and eliminate diseased tissues. While T cell, NK cell, and dendritic cell platforms have delivered meaningful clinical advances, in solid tumors and chronically inflamed tissues, poor trafficking and retention, and functional suppression within hostile microenvironments, often constrain their efficacy. Macrophages provide a complementary therapeutic platform because they are abundant tissue-resident sentinels, professional phagocytes, and key coordinators of local inflammation and adaptive immunity. However, successful macrophage immunotherapy requires solving two central in vivo determinants: preserving a therapeutically favorable functional state despite suppressive cues, and achieving robust, disease-selective localization and engagement. These determinants map onto two defining macrophage properties (i.e., plasticity and homing), which serve as central engineering levers. Here, we review recent strategies that (1) reprogram and stabilize engineered macrophage phenotypes within the disease environment, and (2) enhance targeting, retention, and contact-dependent functions through engineered recognition modules. We further highlight emerging combinatorial designs that integrate phenotype maintenance with improved tissue targeting and discuss design considerations to translate both genetic and non-genetic macrophage engineering approaches into effective therapy in complex disease microenvironments.
    Keywords:  Adoptive cell therapy; Disease targeting immunotherapy; Ex vivo macrophage engineering; Macrophage plasticity; Phenotype stabilization
    DOI:  https://doi.org/10.1016/j.biotechadv.2026.109022
  55. Transpl Immunol. 2026 Aug 26. pii: S0966-3274(26)00089-4. [Epub ahead of print]98 102431
    Effect of adding umbilical cord blood derived stem cells to haploidentical stem cell transplant (haplo-cord) on post-transplant survival and graft-versus-host disease in patients with hematological malignancies: A systematic review and meta-analysis.
    Muhammad Zain Raza, Anas Babar, Hafiz Muhammad Ehsan Arshad, Musab Maqsood, Muhammad Asad Shabbir, Ali Ahmad Nadeem.
       BACKGROUND AND OBJECTIVES: Haploidentical stem cell transplantation (haplo-SCT) carries a substantial risk of graft-versus-host disease (GvHD), whereas umbilical cord blood (UCB) transplantation offers lower GvHD risk but slower engraftment. The haplo-cord approach combines both graft sources, aiming to mitigate GvHD while ensuring timely engraftment. This meta-analysis compares haplo-cord transplantation with haplo-SCT alone for the treatment of hematological malignancies.
    METHODS: Four electronic databases and two clinical trial registries were systematically searched. Effect sizes from eligible studies were pooled using odds ratios (ORs) for dichotomous outcomes and hazard ratios (HRs) for time-to-event outcomes.
    RESULTS: Twelve studies met the inclusion criteria. Haplo-cord was associated with a statistically significant reduction in chronic GvHD (OR = 0.62, 95%-CI: 0.42-0.93), while no significant difference was observed for grade II-IV acute GvHD (OR = 0.75, 95%-CI: 0.52-1.09). Survival outcomes favored haplo-cord, with lower HRs for overall survival (HR = 0.68, 95%-CI: 0.53-0.86) and event-free survival (HR = 0.61, 95%-CI: 0.52-0.72), while non-relapse mortality was not significant. Relapse at 3 years was significantly lower with haplo-cord (OR = 0.54, 95%-CI: 0.35-0.82). Haplo-cord also demonstrated higher day-30 engraftment, along with lower relapse-related and GvHD-related mortality, while CMV and EBV viremia showed no difference between groups. CD34 selection in the haplo graft significantly influenced effect sizes and heterogeneity in both subgroup analyses and meta-regression for acute GvHD.
    CONCLUSION: Haplo-cord transplantation improves GvHD outcomes, survival, and relapse risk compared with haplo-SCT alone. However, whether protocol optimization, possibly via CD34 selection, confers additional benefit remains uncertain and requires confirmation in future studies.
    Keywords:  CD34 positive stem cells; Graft-versus-host disease; Haplo-cord; Haploidentical stem cell transplant; Umbilical cord blood
    DOI:  https://doi.org/10.1016/j.trim.2026.102431
  56. Healthcare (Basel). 2026 Aug 12. pii: 2506. [Epub ahead of print]14(16):
    From Algorithm to Policy: A Bibliometric Analysis of Implementation Science and Governance Frameworks in AI Healthcare Research (2016-2026).
    Omar Sabri, Salem Ahemd Alabdali.
      This study presents a bibliometric analysis of AI healthcare research related to implementation science and governance frameworks from 2016 to 2026. A systematic search of the Scopus database identified 3780 peer-reviewed articles published across 1500 sources. The dataset was analyzed using Biblioshiny. The findings show an annual growth rate of 47.65% in governance-focused publications, exceeding the growth rate of technical AI research. Four main research themes were identified: regulatory compliance, ethical frameworks with limited operational measures, organizational readiness, and clinical workflow integration. The United States, China, and the United Kingdom are the leading contributors, while the Journal of Medical Internet Research and BMJ Open are among the main publication outlets. International collaboration (34.66%) remains concentrated among high-income countries. Thematic development has progressed from general ethical discussions to pandemic-related applications and more specific regulatory frameworks. Three research gaps contribute to the algorithm-to-policy translation deficit: the principles-practice gap, the regulatory-evidence gap, and the innovation-implementation gap. This study proposes an integrated governance framework based on five evidence-based principles. The framework is a conceptual model derived from bibliometric findings and requires further empirical validation in clinical settings before practical adoption. The study contributes by providing a bibliometric analysis of AI governance research and introducing the concept of the "algorithm-to-policy translation deficit" as an analytical framework. It also offers a structure to support future research and practice toward safe, effective, and equitable clinical implementation of AI. These findings guidance for regulators, healthcare organizations, AI developers, and researchers.
    Keywords:  artificial intelligence; bibliometric analysis; healthcare governance; implementation science; regulatory frameworks
    DOI:  https://doi.org/10.3390/healthcare14162506
  57. Nat Biomed Eng. 2026 Aug 28.
    Data-centric feedback loops for next-generation immunotherapy development.
    Rotem Shalita, Ido Amit.
      Despite explosive growth in biomedical data generation, driven largely by genomics, and in computational capabilities, the probability that a candidate entering phase I ultimately reaches approval has remained stubbornly low over the past decades. This paradox points to a central bottleneck not in data generation, but in converting biological and clinical data into decisions that govern progression, redesign or termination. Here we argue that drug development should be reframed from a linear pipeline into an iterative learning system driven by continuous data feedback. We outline a data-centric framework in which high-dimensional, multimodal molecular and perturbation data, particularly single-cell and spatial readouts, are used to iteratively refine disease models, therapeutic hypotheses, molecular designs and patient stratification strategies across discovery and clinical stages. Using immunotherapies as a proof-of-concept domain, we propose that single-cell molecular readouts from therapeutic perturbations can both de-risk development and deepen mechanistic understanding of immune responses in humans. Finally, we draw parallels to reinforcement learning, in which human molecular and clinical data provide the feedback signal that updates mechanistic models and guides the design of subsequent interventions. Embracing this paradigm offers a path towards more mechanistically grounded, context-aware therapies with higher translational success.
    DOI:  https://doi.org/10.1038/s41551-026-01785-6
  58. J Prev (2022). 2026 Aug 28.
    Temporal Data Structure Is Not Causal Identification: A Practical Framework for Appraising Causal Claims in Prevention and Population Health Research.
    Sunday Azagba, Galappaththige S R de Silva.
      Temporal data structure is not an identification strategy. In manuscript review and reporting, cross-sectional and longitudinal labels are sometimes used as shorthand for judging whether causal claims are appropriate. Whether a causal claim is credible depends on the effect being considered, what makes the comparison informative, what assumptions are required, and whether the analysis and supporting evidence address the main threats. We define temporal data structure as the temporal and sampling organization of measurement and distinguish it from causal identification, which concerns whether a causal estimand can be recovered under explicit assumptions. Longitudinal data can establish measurement order and show how outcomes, exposures, and other relevant factors change over time, but these advantages do not by themselves address confounding, selection, attrition, or measurement error. Conversely, cross-sectional or repeated cross-sectional data may contribute to causal inference when temporal ordering is established by design or substantive knowledge and identification arises from credible adjustment, assignment rules, thresholds, policy timing, or other design features. Using prevention examples, we show where causal leverage can come from, explain what repeated measurement adds and what it cannot establish by itself, and propose five plain-language questions for authors, reviewers, and editors. We also distinguish limitation language appropriate for associational analyses from qualified causal interpretations made under explicit assumptions. Temporal structure informs causal appraisal, but it does not determine it.
    Keywords:  Causal identification; Causal inference; Peer review; Prevention science; Research reporting; Temporal data structure
    DOI:  https://doi.org/10.1007/s10935-026-00948-0
  59. Drug Discov Today. 2026 Aug 27. pii: S1359-6446(26)00195-9. [Epub ahead of print] 104790
    Integrating population heterogeneity in drug research and early development: a proactive strategy.
    Thierry Lavé, Bruno Jolain, Ken Wang, Léa-Isabelle Proulx, Cristina Santini, Juliana Bessa, Valerie Crowell, Patricia Sanwald-Ducray, Ruma Bhagat, Nicole Richie.
      Population heterogeneity in disease biology, drug exposure and treatment response is often addressed only after development has progressed, limiting generalizability and increasing late-stage risk. We propose an anticipate-verify-influence framework to integrate clinically relevant variability from research through development. The approach combines diverse human-derived models, real-world data, model-informed drug development and AI/ML to identify drivers of heterogeneity, test their clinical relevance early and translate validated findings into trial design, dosing and patient selection. Rather than pursuing demographic representation alone, the framework emphasizes mechanistic and quantitative understanding of intrinsic and extrinsic determinants of response. Earlier characterization of meaningful heterogeneity could improve development decisions, trial representativeness and evidence generation for patients who are frequently underrepresented.
    Keywords:  Population heterogeneity; anticipate-verify-influence framework; digital twins; drug discovery and early development; health equity; modeling and simulation
    DOI:  https://doi.org/10.1016/j.drudis.2026.104790
  60. Ther Innov Regul Sci. 2026 Aug 26.
    AI-Enabled Real-World Evidence in Oncology: A Statistical Perspective for Regulatory Decisions.
    Lei Gao, Dai Feng, Binbing Yu.
      Artificial intelligence (AI) has the potential to strengthen real-world evidence (RWE) for regulatory decision-making, but its contribution varies by application and methodological maturity. RWE remains limited by challenges in data quality, population selection, treatment characterization, outcome assessment, and statistical methodology. Machine learning and generative AI (genAI), combined with causal inference frameworks, may address these challenges. We review applications, limitations, including reproducibility, bias, transportability, uncertainty quantification, and regulatory acceptability, and methodological priorities for fit-for-purpose AI-enabled RWE.
    Keywords:  AI; Causal inference; Dataset shift; Decision making; RWE; Regulatory; Transportability
    DOI:  https://doi.org/10.1007/s43441-026-01036-5
  61. Pharmaceuticals (Basel). 2026 Aug 01. pii: 1212. [Epub ahead of print]19(8):
    Targeting Immune Checkpoint Proteins in Cancer Therapy and the Potential of RNAi-Based Immunotherapy.
    Katherine Kaixin Wang, Ai-Ming Yu.
      Cancer immunotherapy via targeting immune checkpoint proteins (ICPs) has transformed the treatment of multiple malignancies, offering improved clinical outcomes over conventional therapies. Immune checkpoint inhibitors (ICIs), including FDA-approved monoclonal antibodies against CTLA-4, PD-1, and PD-L1, as well as emerging agents targeting novel ICPs, have demonstrated strong therapeutic efficacy by restoring antitumor immune responses. In parallel, RNA interference (RNAi)-based approaches involving microRNAs (miRNAs) and small interfering RNAs (siRNAs) have emerged as promising alternative strategies for modulating ICP expression at the posttranscriptional level, enabling selective and simultaneous regulation of multiple immune checkpoint pathways. Preclinical and early clinical studies have indicated effective downregulation of target ICP expression and enhanced antitumor immunity across diverse cancer models. Due to the inherent instability of RNA molecules, the development of RNAi therapeutics has been accompanied by advances in delivery platforms. In this review, we discuss the biological functions of established and novel ICPs, along with immunotherapeutics approved by the FDA and under Phase III clinical development. We also provide an overview of the RNAi mechanism of miRNAs and siRNAs, highlight endogenous miRNAs that regulate immune checkpoint pathways, and summarize ICP-targeting RNAi agents and their corresponding delivery systems under preclinical and clinical development. Collectively, these advances underscore the potential of RNAi-based immune checkpoint modulation, complementing existing ICIs and expanding the next generation of cancer immunotherapy.
    Keywords:  RNA interference; cancer immunotherapy; immune checkpoint inhibition; immune checkpoint proteins; microRNA; small interfering RNA
    DOI:  https://doi.org/10.3390/ph19081212
  62. Clin Ther. 2026 Aug 25. pii: S0149-2918(26)00283-3. [Epub ahead of print]
    Manufacturing Complexity and Scale-Up: Hidden Contributors to Drug Safety Risk.
    Eric Hacherl.
       PURPOSE: Drug safety is typically assessed through clinical outcomes: adverse events, dose-response relationships, and postmarketing surveillance. This commentary argues that this framing, while appropriate, can obscure manufacturing's role in determining what patients actually receive. Its purpose is to examine drug safety from a Chemistry, Manufacturing, and Controls (CMC) perspective and to make the case for integrating manufacturing considerations more explicitly into safety assessment across the product lifecycle.
    METHODS: The analysis draws on engineering and CMC experience, established regulatory guidance, and published examples of manufacturing-related safety events, rather than on clinical trial data or pharmacovigilance analysis. It examines how manufacturing complexity, contamination and impurity risk, and process scale-up introduce safety-relevant uncertainty that evolves throughout the product lifecycle, and how existing regulatory and quality tools address it.
    FINDINGS: Manufacturing complexity creates latent safety risks through operational variability and system design. Contamination and impurities function as system-level hazards rather than isolated quality failures. Scale-up constitutes a critical inflection point at which assumptions about process robustness are stress-tested under real-world constraints. These risks are difficult to detect through clinical frameworks because they are often low frequency, system driven, and surfaced through quality investigations rather than adverse event reporting. Existing tools, including continuous manufacturing, process analytical technology, real-time release testing, quality by design, and lifecycle-management guidance, mitigate but do not eliminate this uncertainty.
    IMPLICATIONS: Recognizing manufacturing as part of the drug safety system, and coordinating CMC and pharmacovigilance functions during process changes and scale-up would strengthen patient protection by addressing risks that originate upstream of clinical use but manifest as patient exposure over time.
    Keywords:  Comparability; Contamination control; Drug safety; Manufacturing complexity; Process scale-up
    DOI:  https://doi.org/10.1016/j.clinthera.2026.08.002
  63. Healthcare (Basel). 2026 Aug 07. pii: 2445. [Epub ahead of print]14(16):
    Healthcare Digital Twins Across Scales: A Narrative Review and Five-Level Conceptual Framework.
    Leonard Azamfirei, Dorin Bica, Andrei Calin Dragomir, Emoke Almasy.
      Background/Objectives: Healthcare digital twins are being developed at scales ranging from individual organs to regional health systems. However, the literature at these different scales has largely evolved independently. This narrative review examines how the concept changes as the represented object grows, and proposes a five-level framework: physiological, patient, care-delivery, hospital and health-system twins proposed by the authors as an analytical framework. Methods: Web of Science, Scopus, PubMed and Google Scholar were searched between June and July 2026 for English-language records published from January 2022 onwards. Sources were eligible if they described a virtual representation of an identified physical counterpart in healthcare, updated from that counterpart's own data and used to produce decision-relevant predictions. Editorials, abstract-only records, static models and work outside healthcare were excluded. The included literature was examined to identify recurring patterns in the representation and application of healthcare digital twins. These patterns informed the development of the authors' proposed five-level conceptual framework. As no formal quality appraisal was undertaken, conclusions regarding evidence maturity and implementation should be interpreted cautiously. Results: Forty-four publications form the evidence base: 10 original studies, 26 reviews and 8 conceptual or consensus papers. Patient-specific applications were described primarily at the physiological and patient levels, particularly in cardiology and oncology. External validation remained uncommon, and prospective evaluation was rare across all five levels. Care-delivery twins were reported mainly in critical care, emergency and perioperative settings, whereas hospital and health-system applications were largely limited to prototypes and simulations. Conclusions: This review suggests that the challenges associated with healthcare digital twins evolve as applications move from physiological models to health-system settings. Beyond technical complexity, interoperability, organisational, governance and equity considerations become increasingly important. Prospective evidence of patient benefit, operational effectiveness and system-level impact remains limited across all five levels.
    Keywords:  clinical decision support; digital health; digital twin; governance; health system intelligence; healthcare simulation; interoperability; learning health system; narrative review; precision medicine; validation
    DOI:  https://doi.org/10.3390/healthcare14162445
  64. 3 Biotech. 2026 Sep;16(9): 381
    Advances in gene transfer technologies: comparing viral and non-viral vectors for therapeutic applications.
    Praveen Halagali, Raagul Seenivasan, Amatha Sreedevi, Virendra S Ligade, Parashuram Bugadannavar, Himanshu Sharma, Sachchida Nand Rai, Vamshi Krishna Tippavajhala.
      Gene and cell therapies have emerged as transformative approaches for treating a wide range of genetic and acquired diseases. Central to their success is the development of safe and effective gene delivery systems, categorized broadly into viral and non-viral vectors. Each system has its own advantages and limitations, requiring careful consideration of the target tissue, disease, and the balance between safety, efficacy, and scalability. Viral vectors, including adeno-associated viruses, retroviruses, lentiviruses, herpes simplex viruses, and adenoviruses, offer high transduction efficiency and specificity but raise concerns about immunogenicity and production challenges. Non-viral systems, such as lipid nanoparticles (LNPs) and other synthetic carriers, provide scalable, cost-effective, and potentially safer alternatives but often face hurdles in transduction efficiency and targeted delivery. This review provides a comprehensive overview of the current status of these vector systems for in vivo and ex vivo applications. Key comparisons are made across safety, efficacy, scalability, and immune responses, highlighting recent advancements and innovative approaches. We also discuss the outlook for next-generation gene transfer technologies, focusing on improvements in vector design, manufacturing, and application versatility. By addressing these considerations, we aim to inform the development of optimized therapeutic strategies that leverage the unique strengths of each delivery system.
    Keywords:  Ex vivo gene transfer; Gene transfer; Genetic engineering; In vivo gene transfer; Non-viral vectors; Viral vectors
    DOI:  https://doi.org/10.1007/s13205-026-05016-2
  65. Nat Rev Drug Discov. 2026 Aug 28.
    The landscape for in vivo CAR T cell therapies.
    Margot Bleys, Kelly Farley, Bonnie Walton, Minsoo Khang, John Wu.
      
    DOI:  https://doi.org/10.1038/d41573-026-00140-3
  66. Bioengineering (Basel). 2026 Jul 24. pii: 856. [Epub ahead of print]13(8):
    Suspension-Adapted HEK293FT Cells Enable High-Density Transfection for Efficient Lentiviral Vector Production in CAR-T Therapy.
    Alexandr Shevtsov, Aitolkyn Kydyrbayeva, Gaziza Nigmatulla, Viktoriya Keyer, Tolganay Kulatay, Gulzat Zauatbayeva, Bakytkali Ingirbay, Maral Zhumabekova, Dinara Zharlyganova, Alexandr V Shustov.
      Lentiviral vector (LV) production for CAR-T therapy remains challenging due to the limited scalability of adherent HEK293 cell cultures. To address this, we adapted HEK293FT cells directly to serum-free FreeStyle 293 Expression Medium, generating a novel suspension cell line, HEK293FT-DS. We characterized growth kinetics, stability over 35 passages, and transient transfection parameters (PEI:DNA ratio, cell density). The suspension-adapted cells grew with >93% viability and a specific growth rate of 0.54 day-1, and maintained stable viable cell density (1.51 ± 0.03 × 106 cells/mL) over 35 passages. The optimal PEI:DNA ratio was 2.5:1, and increasing the transfection cell density to 16 × 106 cells/mL boosted functional titers to approximately 9 × 106 TU/mL in clarified supernatant. Scaled production (1 L culture supernatant per batch) yielded up to 5 × 109 TU. The resulting vectors efficiently transduced primary human T cells (57% CAR-positive cells) in a CliniMACS Prodigy-based process. The platform based on suspension-adapted HEK293FT-DS cells enables high-density transfection and provides a cost-effective, scalable alternative to commercial LV production systems, particularly suited for academic CAR-T cell manufacturing.
    Keywords:  CAR-T therapy; HEK293FT cells; PEI transfection; cell line development; high-density transfection; lentiviral vectors; serum-free medium; suspension adaptation; transient transfection; viral vector manufacturing
    DOI:  https://doi.org/10.3390/bioengineering13080856
  67. Expert Opin Biol Ther. 2026 Aug 28.
    B-cell depletion therapy in systemic lupus erythematosus: emerging strategies and challenges.
    Tsz Ching Mok, Chi Chiu Mok.
       INTRODUCTION: B cell plays a pivoting role in the pathogenesis of systemic lupus erythematosus (SLE). In addition to the production of autoantibodies, B cells present antigens to activate the T cells and release proinflammatory cytokines that are relevant for disease activity. B cell modulation remains the spotlight in the development of novel therapeutics in SLE.
    AREAS COVERED: This article summarizes strategies to enhance B cell depletion in SLE and lupus nephritis (LN). Data on the efficacy of recent clinical trials of B cell depletion in SLE/LN are discussed along with their challenges.
    EXPERT OPINION: Evidence suggests that deep tissue B cell depletion and delayed repopulation of autoreactive B cells may enhance the durability of response in SLE. Newer generation anti-CD20 biologics, sequential use of anti-CD20 and anti-BAFF, simultaneous inhibition of BAFF and APRIL, as well as the dual action anti-BAFF-R biologic, increase the potency of B cell depletion. However, the major concern of these approaches is the increased risk of infection. Careful selection of SLE patients for B cell modulation therapy and monitoring for infective complications is mandatory while the longer-term results of newer modalities such as the bispecific T cell engagers and chimeric antigen receptor (CAR) therapies are anticipated.
    Keywords:  B-cell; CAR-T; Lupus; depletion; modulation; obinutuzumab; rituximab; strategies
    DOI:  https://doi.org/10.1080/14712598.2026.2726422
  68. Semin Neurol. 2026 Aug 26.
    Neurologic Complications of Cancer Immunotherapy.
    Alexandra Balshi, Prashanth Rajarajan, Caleb R S McEntire, Giovanna S Manzano.
       Abstract: The use of oncologic-directed immunotherapies, including immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T cell (CAR-T) therapy, has risen exponentially in recent years. Although these therapies have been shown to improve long-term survival and quality of life in responsive patients, their nonspecific immune system activation can lead to unanticipated neurotoxicity, among other complications. Immune-related adverse events (irAEs) may involve any location in the entire neuroaxis, posing a diagnostic challenge, and may cause severe, life-threatening complications. ICI-related neurotoxicities may include peripheral neuropathies, myositis, myasthenia gravis, encephalitis, aseptic meningitis, myelitis, and demyelinating disorders. CAR-T therapies carry a comparatively higher risk of neurologic irAEs, most notably immune effector cell-associated neurotoxicity syndrome. In this review, neurotoxicity syndromes associated with ICI and CAR-T therapies are outlined, along with diagnostic approaches and management strategies.
    DOI:  https://doi.org/10.1055/a-2936-4931
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