bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–10–18
fifty-nine papers selected by
Luca Bolliger, lxBio
  1. Toward the next generation of CAR T cell therapies for cancer.
  2. Review Article: The Evolution and Future of Immunotherapy: The Promise of CAR T Cell-Derived Extracellular Vesicles.
  3. Review Article: Overcoming Antigen Expression Barriers in CAR-T Therapy for Solid Tumors.
  4. Cost-Effectiveness of AI-Powered Decentralized Production for Advanced Therapies in the Hospital-Generated Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma From a German Hospital Perspective: Early Health Technology Assessment Study.
  5. GAN-enhanced digital twins for biomarker-guided cancer immunotherapy and adoptive cell therapy: a mini review.
  6. Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review.
  7. Next-generation natural killer cell therapy: bench to bedside and beyond.
  8. Sterility testing in the era of decentralised cell therapy: Challenges, innovations, and future directions.
  9. CAR T cells from code to clinic: Framing modeling approaches with current translational research goals.
  10. Review Article: The Extracellular Matrix as a Barrier for CAR-T Cell Therapy in Solid Tumors.
  11. Zelig Eshhar: The Pioneer Who Re-Engineered the T-Cells and Brought CAR-T into the World.
  12. NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands.
  13. Clinical trial landscape and translational priorities for adoptive T-cell and NK-cell therapies in gynecologic malignancies.
  14. Considerations for Improving Equity and Access to CAR-T Therapies.
  15. Inhibitory receptor profiles for joint prediction of benefit and toxicity in immune checkpoint blockade.
  16. Review Article: Chimeric MHC Class I Receptors for Diverse Clinical Applications.
  17. Claudin 18.2: From a Tight Junction Protein to a Breakthrough Target in Solid Tumor Immunotherapy.
  18. Comparing harmonization in medicines regulation and health technology assessment in Europe: lessons for the EU HTA regulation.
  19. Review Article: Does CAR-T Cell Therapy of Solid Cancer Need the Activation of an Innate Immune Response?
  20. Biomaterial-Enabled In vivo T Cell Engineering: A New Paradigm for Cell Therapy.
  21. Advances in CAR-T and CAR-NK cell therapy in follicular lymphoma: a review.
  22. CAR-T-centered sequential therapy: current status, challenges, and future clinical perspectives.
  23. Restricted mean survival time ratio in oncology cost-effectiveness analysis: stability and data-driven support for treatment-effect waning modeling and survival extrapolation.
  24. Antigen-Presentation Competence in Gynecologic Cancers: Mechanisms, Evidence and Translational Priorities.
  25. Mapping pharmacist roles across the chimeric antigen receptor T-cell therapy care continuum: A scoping review.
  26. Engineering monocytes and macrophages for therapeutic control.
  27. A guide to studying tumour-T-cell interactions using in vitro coculture assays.
  28. Advancing a drug-development program is not the same as de-risking it.
  29. Cardiovascular Toxicities of Contemporary Cancer Immunotherapies: A Narrative Review of Immune Checkpoint Inhibitors, Bispecific T-Cell Engagers, and CAR-T Cell Therapies.
  30. Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study.
  31. Chimeric Antigen Receptor T-Cell Therapy in T Cell/Histiocyte-Rich Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis.
  32. Leveraging Real-World Evidence to Drive Advances in Oncology Care in the Asia-Pacific Region: Recommendations From the Asia-Pacific Oncology Drug Development Consortium Working Group.
  33. Functional Exhaustion Limits CAR-NK Therapy in Glioblastoma but Can Be Mitigated by Early Repeated Dosing.
  34. Glucocorticoid-induced TNF receptor ligand-dependent B-cell expansion of regulatory T cells as an immune cell therapy strategy.
  35. Artificial Intelligence as a Catalyst for Novel Therapeutic Opportunities in Precision Oncology.
  36. Rewiring the Tumor-Immune Ecosystem: Extracellular Vesicles in the Next Era of Cancer Immunotherapy.
  37. Efficacy and safety of immunotherapy in pediatric malignant brain tumors: a systematic review and exploratory meta-analysis.
  38. Bone Marrow Adipocytes in Multiple Myeloma: Emerging Immunometabolic Interactions and Implications for Immunotherapy.
  39. Virus-like particle vaccines: from antigen architecture to antigen presentation and adaptive immune responses.
  40. Single-Cell and Multi-Omics Profiling of the Multiple Myeloma Immune Niche: From Bone Marrow Architecture and Metabolic Reprogramming to Immunotherapy Response.
  41. Case Report: CD20/BCMA bispecific CAR-T therapy for progressive multiple sclerosis.
  42. Editorial: The functional plasticity of innate immune cells.
  43. Current understanding and new promises of umbilical cord blood in emerging clinical applications.
  44. The advances and challenges of mRNA-LNP application in fields of hematology and oncology therapeutics.
  45. Advances in γδ T cell-mediated immune surveillance in cervical cancer.
  46. Stromal-myeloid-lymphoid crosstalk in immune evasion and immunotherapy resistance in solid tumors.
  47. Cilta-cel CAR T-cell expansion and neurotoxicity.
  48. Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.
  49. Glycome remodeling programs pathogenic γδ T17 cell responses in autoimmunity.
  50. Remote Patient Monitoring in Hospital at Home: Bibliometric Analysis of the Field and Scoping Review of Nursing Practice.
  51. Antiviral T cells doing double-duty to fight cancer.
  52. BCMA CAR T-cell therapy in a patient with heavily pretreated relapsed/refractory POEMS Syndrome: a case report.
  53. Using Joint Models in Phase I Dose-Finding Designs in Oncology: Considerations for Frequentist Approaches.
  54. Comprehensive Molecular Profiling for Precision Diagnostics: Integrating Genomic, Proteomic, and Epigenetic Landscapes in Human Pathology.
  55. AI-Driven Feedback on Bitewing Radiographic Technique: A Comparative Study of Large Language Models.
  56. Empowering regulatory science for medical devices in Europe.
  57. Trained immunity in cancer immunotherapy and vaccine development: mechanisms, evidence gaps, and translational opportunities.
  58. Special Issue "Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition".
  59. Microbial cues for a stem-like lymphoid niche.
  1. Cancer Cell. 2026 Oct 12. pii: S1535-6108(26)00424-1. [Epub ahead of print]44(10): 1936-1962
    Toward the next generation of CAR T cell therapies for cancer.
    Diren Usta, Crystal L Mackall.
      With seven products approved by the US Food and Drug Administration (FDA) for 15 indications and more than 2,600 active clinical trials, chimeric antigen receptor (CAR) T cell therapy is firmly established as an effective therapeutic modality for cancer treatment, and promising early data demonstrate its potential in autoimmune diseases. Key challenges facing the field include extending efficacy to solid tumors and reducing the cost and complexity of manufacturing to improve patient access. In this review, we summarize the clinical lessons learned from the now substantial experience with commercial CAR T cells and clinical trials and discuss three waves shaping next-generation development: multi-engineered and logic-gated CAR T cells, rational combination strategies, and in vivo CAR T cell generation. By integrating clinical experience with emerging strategies, we highlight where CAR T cell therapy has succeeded, where current approaches remain insufficient, and how next-generation cell therapies may be designed to overcome these barriers.
    Keywords:  CAR T cell engineering; CAR T cell therapy; antigen escape; antigen selection; cancer immunotherapy; in vivo CAR T cell generation; logic gating; on-target off-tumor toxicity; therapeutic window
    DOI:  https://doi.org/10.1016/j.ccell.2026.09.005
  2. Crit Rev Oncog. 2026 ;31(1): 1-4
    Review Article: The Evolution and Future of Immunotherapy: The Promise of CAR T Cell-Derived Extracellular Vesicles.
    Anat Aharon, Anat Globerson Levin.
      CAR T cell therapy, pioneered by Prof. Zelig Eshhar, has transformed hematologic malignancies but faces significant barriers in solid tumors, including poor infiltration, toxicity, and cytokine release syndrome. This perspective explores CAR T cell-derived extracellular vesicles (CAR T EVs) as an emerging platform that extends Eshhar's vision by delivering CAR-mediated cytotoxicity with enhanced tumor penetration, physiological barrier, and reduced immunogenicity. EVs carry functional CARs as immunomodulatory cargo, enabling precise antigen targeting without cellular proliferation risks. Key advantages and challenges are reviewed. Building on Eshhar's foundational work, CAR T EVs represent a nanotechnology-immunotherapy alternative.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026063206
  3. Crit Rev Oncog. 2026 ;31(1): 51-66
    Review Article: Overcoming Antigen Expression Barriers in CAR-T Therapy for Solid Tumors.
    Owen R Moon, John S Bridgeman, Leyuan Bao.
      Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for hematologic malignancies, achieving deep and durable responses across multiple FDA approved products. This progress stems from foundational discoveries initiated by Zelig Eshhar, whose early demonstrations that T cells could be redirected using synthetic receptors laid the conceptual groundwork for modern CAR-T design. Despite these successes, translating CAR-T therapy into solid cancers remains challenging. Solid tumors present unique obstacles including antigen heterogeneity, immunosuppressive microenvironments, limited T cell trafficking, and multiple mechanisms of antigen escape. Case studies across key solid tumor targets such as mesothelin, interleukin 13 receptor alpha 2 (IL13Rα2), claudin 18.2 (CLDN18.2), glypican 3 (GPC3), epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), and ganglioside D2 (GD2) highlight both the promise of CAR-T therapy and the biological complexities that limit durable clinical benefit. To address these barriers, next generation engineering strategies incorporating multispecific targeting, adaptor platforms, and logic gated receptor circuits (OR, AND, NOT, and multi-layered designs) are being developed to enhance tumor specificity, mitigate on-target/off-tumor toxicity, and prevent antigen escape. Armored CAR-T cells capable of overcoming suppressive tumor microenvironments further expand therapeutic potential. Collectively, these advances signal a shift from single antigen targeting to programmable, modular T cell therapies capable of responding to the multifaceted challenges of solid tumors. As the field integrates synthetic biology innovations with lessons learned from decades of clinical practice, CAR-T therapy is poised for broader applicability across both hematologic and solid cancers, extending the legacy of Eshhar's pioneering work.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026064031
  4. JMIR Cancer. 2026 Oct 13. 12 e92253
    Cost-Effectiveness of AI-Powered Decentralized Production for Advanced Therapies in the Hospital-Generated Chimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma From a German Hospital Perspective: Early Health Technology Assessment Study.
    Iris W A Boot, Anna Louisa Weltin, Ysanne de Graaf, Hubertus J M Vrijhoef.
       BACKGROUND: Although effective, current chimeric antigen receptor T-cell (CAR-T) production methods-centralized, manual, and complex-are cost-intensive, time-consuming, and prone to variability. AIDPATH (AI-Powered Decentralized Production for Advanced Therapies in the Hospital) proposes a decentralized, automated alternative that integrates patient-specific data; optimizes resource use; and potentially improves cell viability, manufacturing efficiency, and patient outcomes.
    OBJECTIVE: The aim of this study was to compare CAR-T therapy produced by the AIDPATH platform to both ciltacabtagene autoleucel (cilta-cel) and standard of care (SoC) for patients with triple-class refractory multiple myeloma (MM) over a 40-year time horizon from the hospital perspective in Germany.
    METHODS: A partitioned survival model reflecting 3 health states (progression-free disease, progressed disease, and death) was used. The analysis used clinical trial data for cilta-cel, real-world data for SoC, and estimated parameters for AIDPATH due to the developmental status of the platform. The primary outcome was the incremental cost-effectiveness ratio; secondary outcomes included sensitivity and scenario analyses.
    RESULTS: On the basis of the model used in this analysis, AIDPATH was dominant compared to both cilta-cel and SoC. Most costs for CAR-T therapies were driven by acquisition and adverse events. Sensitivity analyses showed that the results were most influenced by discount rates and assumptions about progression-free survival. Scenario analyses, including reduced adverse events and shorter vein-to-vein times for AIDPATH, further supported its cost-effectiveness.
    CONCLUSIONS: This is the first study to assess the cost-effectiveness of a CAR-T product generated with AI support in Germany from the hospital perspective. AIDPATH was found to be a cost-effective alternative to both cilta-cel and SoC, making it a promising option for future implementation. Although further data are needed, this study provides valuable guidance for health care stakeholders, reimbursement discussions, and future research.
    Keywords:  AI manufacturing; CAR-T therapy; artificial intelligence manufacturing; automated decentralized manufacturing; chimeric antigen receptor T-cell therapy; cost-effectiveness analysis; early HTA; early health technology assessment; health economic modeling
    DOI:  https://doi.org/10.2196/92253
  5. Front Med (Lausanne). 2026 ;13 1894314
    GAN-enhanced digital twins for biomarker-guided cancer immunotherapy and adoptive cell therapy: a mini review.
    Jiayu Yang.
      Cancer immunotherapy and adoptive cell therapy have transformed modern oncology, yet durable benefits remain limited by tumor heterogeneity, immune escape mechanisms, biomarker variability, and the dynamic remodeling of the tumor immune microenvironment. Current biomarker strategies, including PD-L1 (programmed death-ligand 1) expression, microsatellite instability (MSI), tumor mutational burden (TMB), immune gene signatures, liquid biopsy measurements, and target antigen profiles, provide clinically useful information but are often static and insufficient to capture longitudinal tumor-immune-therapy interactions. Digital twin technology offers a computational paradigm for integrating multi-omics, immune profiling, clinical variables, imaging, and treatment-response data into patient-linked virtual models. Generative artificial intelligence, including generative adversarial networks (GANs), may enrich sparse biomarker-defined state spaces and support the simulation of underrepresented treatment response or toxicity trajectories. This mini review critically compares mechanistic quantitative systems pharmacology, spatial and agent-based modeling, data-driven prediction, and emerging digital twin approaches and proposes a platform-agnostic architecture that can be implemented in MATLAB/Simulink or other computational environments. The adoptive cell therapy scope focuses on chimeric antigen receptor T-cell (CAR-T), chimeric antigen receptor natural killer cell (CAR-NK), and T-cell receptor-engineered T-cell (TCR-T) therapies, with related principles applicable to tumor-infiltrating lymphocyte (TIL) therapy. We describe conditional and longitudinal GAN strategies, dynamic tumor-immune state modeling, biomarker integration, validation metrics, governance, and prospective implementation pathways. The proposed framework is conceptual and has not yet been clinically validated; synthetic data are treated as methodological support rather than clinical evidence. Its intended near-term uses are hypothesis generation, virtual-cohort enrichment, trial design, and uncertainty-aware decision support.
    Keywords:  adoptive cell therapy; cancer immunotherapy; digital twin; generative adversarial network; multimodal biomarkers; precision oncology; quantitative systems pharmacology
    DOI:  https://doi.org/10.3389/fmed.2026.1894314
  6. Transl Cancer Res. 2026 Sep 30. 15(9): 717
    Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review.
    Nannan Ma, Chunxiang Shang.
       Background and Objective: Lung cancer remains a leading cause of cancer-related mortality. Cellular immunotherapy has achieved major advances in hematologic malignancies, but translation to lung cancer is constrained by antigen heterogeneity, limited trafficking and persistence, an immunosuppressive tumor microenvironment (TME), manufacturing complexity, and on-target off-tumor toxicity. This narrative review summarizes current clinical evidence, major translational barriers, and future development strategies for cellular immunotherapy in lung cancer.
    Methods: PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched from database inception to 1 June 2026 using Medical Subject Headings (MeSH) and free-text terms. Evidence on chimeric antigen receptor T-cell (CAR-T), T-cell receptor-engineered T-cell (TCR-T), tumor-infiltrating lymphocyte (TIL), natural killer (NK), chimeric antigen receptor natural killer (CAR-NK), and cancer vaccine-based strategies was reviewed, with priority given to non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).
    Key Content and Findings: Most lung-cancer cellular therapy studies remain early phase. TIL therapy has demonstrated clinical activity in NSCLC, while EGFR, MSLN, CEA, MUC1, PD-L1, B7-H3, and DLL3 are representative targets under investigation for CAR-based approaches; NY-ESO-1 and KK-LC-1 are representative TCR-T targets. Major barriers include antigen escape, poor tumor infiltration, HLA restriction or loss, immunosuppressive signaling, cellular exhaustion, limited persistence, manufacturing burden, and treatment-related toxicity. Current optimization strategies include gene editing, chemokine-receptor engineering, armored or logic-gated receptors, safety switches, optimized lymphodepletion, and rational combinations with other anticancer therapies.
    Conclusions: Cellular immunotherapy is a promising but still developing strategy for lung cancer. Future studies should prioritize biomarker-guided patient selection, safer and more persistent cell products, scalable manufacturing, and prospective clinical validation of rational combination strategies.
    Keywords:  Lung cancer; cellular immunotherapy; chimeric antigen receptor T-cell therapy (CAR-T therapy); tumor microenvironment (TME); tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.21037/tcr-2026-1627
  7. Signal Transduct Target Ther. 2026 Oct 16. pii: 451. [Epub ahead of print]11(1):
    Next-generation natural killer cell therapy: bench to bedside and beyond.
    Aiqi Zhao, Jing Xu, Wenhai Deng, Minghuan Zhang, Yanping Shao, Yu Liu, Aibin Liang, Xiaobing Wang, Ting Niu, Wenbin Qian.
      Natural killer (NK) cells have emerged as central players in cancer immunotherapy, progressing from basic discovery to clinically validated platforms over five decades. This review synthesizes the evolving understanding of NK cell biology, including subset heterogeneity, epigenetic regulation, and metabolic control, and, as innovative focal points, intratumoral NK heterogeneity, epigenetic modulation, and intracellular immune checkpoints, forming the foundation for rational therapeutic engineering. We examine the clinical trajectory from unmodified adoptive transfer to cytokine-induced memory-like NK cells and, most transformatively, to chimeric antigen receptor (CAR)-NK cells. Landmark trials have established the remarkable efficacy and superior safety of CAR-NK cells in B-cell malignancies, with recent studies extending these benefits to autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis, demonstrating durable immune reset with a favorable safety profile. Despite these advances, solid tumors remain formidable challenges, hindered by antigen heterogeneity, physical barriers, and a metabolically hostile microenvironment. We therefore analyze next-generation engineering strategies that move beyond single modifications toward systems-level reprogramming, encompassing intrinsic enhancements (cytokine signaling, metabolic fitness, checkpoint disruption), extrinsic tumor microenvironment remodeling, and advanced delivery platforms. We further synthesize the practical dimensions of clinical translation by systematically examining key optimization parameters that will guide the path toward precision NK cell therapy. These include rational dosing and scheduling regimens, strategies to reduce lymphodepletion intensity, context-dependent persistence requirements across different disease indications and the emerging biomarker landscape.
    DOI:  https://doi.org/10.1038/s41392-026-02911-1
  8. Biologicals. 2026 Oct 10. pii: S1045-1056(26)00046-1. [Epub ahead of print]96 101918
    Sterility testing in the era of decentralised cell therapy: Challenges, innovations, and future directions.
    Athena Stathoulis, Dominic Fernandez, Christopher Doig, Salvatore Fiorenza.
       INTRODUCTION: Chimeric antigen receptor (CAR)-T cell therapies have transformed the treatment of haematological malignancies, yet patients with aggressive, time-sensitive disease remain vulnerable to manufacturing-related treatment delays. Current gold-standard sterility testing under United States Pharmacopoeia (USP) <71> requires a 14-day culture period that is structurally incompatible with the clinical timelines of short shelf-life cell therapy products, positioning sterility assurance as the principal bottleneck to decentralised CAR-T manufacturing. Rapid sterility testing methods have emerged as promising alternatives that may resolve this constraint and expand patient access to treatment.
    METHODS: We undertook a narrative review of the literature on sterility testing in cell therapy manufacturing to characterise current methodologies and the translational challenges of microbial detection in cell therapy products. Relevant publications were identified through searches of several biomedical databases, including MEDLINE, EMBASE, PubMed and Cochrane CENTRAL, supplemented by review of reference lists in relevant articles. Eligible studies reported original data relating to sterility testing in cell therapy products or addressed regulatory, infrastructural or procedural considerations relevant to GMP-compliant or decentralised manufacturing environments.
    DISCUSSION: ATP bioluminescence, solid phase cytometry, and PCR-based assays targeting conserved 16S/18S rRNA sequences have emerged as rapid alternatives to compendial methods, delivering substantially shorter turnaround times. However, four translational barriers continue to preclude their widespread integration. First, analytical validation requirements demand matrix-specific performance data generated under actual CAR-T manufacturing conditions. Second, the operational infrastructure demands of decentralised sites, spanning personnel training, equipment qualification, and documentation capacity, often makes such data difficult to generate. Third, regulatory acceptability remains inconsistent across jurisdictions with no harmonised pathway for alternative method approval. Fourth, clinical risk governance is hampered by the absence of standardised protocols for managing discordant results that would support conditional release decisions. In response, we propose a structured three-phase validation framework for the conditional release of CAR-T products using rapid sterility assays, progressing from analytical qualification through bridging and equivalency to conditional release implementation, with defined decision gates at each phase transition.
    CONCLUSION: Validating and integrating rapid sterility testing into decentralised CAR-T manufacturing workflows offers a credible route to shorter production lead times and broader access to CAR-T cell therapy. Significant barriers remain, however, most notably regulatory fragmentation and a paucity of real-world validation data that currently preclude widespread adoption. The three-phase validation framework proposed in this review provides a structured pathway for conditional release of CAR-T products using rapid sterility assays, progressing from analytical qualification through bridging and equivalency to conditional release implementation, with defined decision gates at each phase transition. Realising the full potential of this framework requires the field to treat regulatory harmonisation and prospective assay validation as jointly necessary conditions for equitable access to cell and gene therapy.
    Keywords:  CAR-T cells; Cell and gene therapy manufacturing; Decentralised manufacturing; Good manufacturing practice; Rapid microbial detection; Sterility testing
    DOI:  https://doi.org/10.1016/j.biologicals.2026.101918
  9. Cell Syst. 2026 Oct 14. pii: S2405-4712(26)00198-5. [Epub ahead of print] 101716
    CAR T cells from code to clinic: Framing modeling approaches with current translational research goals.
    Lucas E Sant'Anna, Rohita Roy, Janella C Schwab, Julian I Perez, Michaëlle N Mayalu.
      Chimeric antigen receptor (CAR) T cell therapy has transformed treatment of resistant cancers, yet it faces major limitations such as variable patient responses, relapse, and safety issues. Optimizing CAR T cell treatment regimens and genetic design could offer solutions to some of these problems, but the resulting design space is often too large to explore experimentally alone. Mathematical modeling-spanning ordinary differential equation (ODE), agent-based, statistical, and machine learning methods-provides a framework to link mechanistic understanding of CAR T cells to predictive design and clinical decision-making. Here, we present a perspective that organizes modeling approaches around key translational challenges in CAR T therapy, evaluating the strengths, limitations, and data gaps of current approaches. We outline a roadmap for clinicians and modelers alike, highlighting advances in machine learning, multiscale modeling, control theory, and alternative cell types as emerging opportunities in model-guided design of next-generation cell therapies.
    Keywords:  CAR T cell therapy; clinical translation; control theory; data-driven design; immune cell engineering; machine learning; mathematical modeling; multiscale modeling; pharmacodynamics; pharmacokinetics
    DOI:  https://doi.org/10.1016/j.cels.2026.101716
  10. Crit Rev Oncog. 2026 ;31(1): 35-49
    Review Article: The Extracellular Matrix as a Barrier for CAR-T Cell Therapy in Solid Tumors.
    Or-Yam Revach.
      Chimeric antigen receptor T (CAR-T) cell therapies, based on introducing a genetically modified T cell receptor to a patient's T cells, have transformed the treatment of hematological tumors. However, their efficacy in solid tumors is limited to date. Among the multiple barriers that shape CAR-T cell efficacy, including antigen heterogeneity, hypoxic tumor microenvironment (TME), and immunosuppressive cell populations, the altered extracellular matrix (ECM) has emerged as a dominant but understudied obstacle. In this review, we summarize the key ECM alterations characteristic of solid tumors and highlight the physical and molecular features that limit CAR-T cell function and promote exhaustion. We further discuss strategies to overcome these constraints and therapy resistance, as well as approaches to assess CAR-T therapy efficacy in clinically relevant models.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026063896
  11. Crit Rev Oncog. 2026 ;31(1): xv-xix
    Zelig Eshhar: The Pioneer Who Re-Engineered the T-Cells and Brought CAR-T into the World.
    Tova Waks.
      This article provides a personal and professional retrospective of the life and career of Professor Zelig Eshhar, a visionary immunologist whose work laid the foundation for Chimeric Antigen Receptor (CAR) T-cell therapy. Authored by Tova Waks, his long-time collaborator of 55 years.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026063205
  12. Cell Rep Med. 2026 Oct 16. pii: S2666-3791(26)00533-1. [Epub ahead of print] 103116
    NKG2D overexpression potentiates CAR-T cells through costimulation by tumor NKG2D ligands.
    Jiajia Li, Lu Han, Qi Zhu, Nan Liu, Hongyu Ma, Zhiqiang Wu, Yao Wang, Xin Lin, Jianshu Wei, Weidong Han.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, but durable efficacy remains limited by insufficient CAR-T cell persistence. Here, we show that activated CAR-T cells upregulate multiple NKG2D ligands (NKG2DLs), increasing their susceptibility to natural killer (NK) cell-mediated CAR-T cell cytotoxicity. To address this vulnerability, we engineer CAR-T cells to overexpress full-length NKG2D (CAR-NG). NKG2D overexpression reduces the surface accessibility of endogenous NKG2DLs without decreasing their total protein abundance. In parallel, engagement of tumor-expressed NKG2DLs in trans provides additional costimulatory signals, enhancing CAR-T cell activation and proliferation while attenuating exhaustion-associated phenotypes. In hematologic and solid tumor models, CAR-NG cells exhibit reduced susceptibility to NK-cell-mediated cytotoxicity, improved tumor control, increased in vivo expansion, deeper tumor infiltration, and no evident additional toxicity compared with conventional CAR-T cells. These findings identify NKG2D overexpression as an engineering strategy that enhances CAR-T antitumor activity primarily through tumor NKG2DL-dependent trans costimulation.
    Keywords:  CAR-T cells; NKG2D ligands; NKG2D overexpression; T cell persistence; trans costimulation
    DOI:  https://doi.org/10.1016/j.xcrm.2026.103116
  13. Front Immunol. 2026 ;17 1936815
    Clinical trial landscape and translational priorities for adoptive T-cell and NK-cell therapies in gynecologic malignancies.
    Qingyu Chen, Yuxin Zhu, Shilin Ye, Yaoyi Wang, Huilong Lin.
       Background: Adoptive T-cell and natural killer (NK)-cell therapies are expanding across solid tumors, but their registered development in gynecologic malignancies remains difficult to interpret because many studies use basket designs and registry records vary in detail.
    Methods: We conducted a cross-sectional analysis of therapeutic adoptive T-cell and NK-cell trial records identified from TrialTrove, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. Trials were classified into three mutually exclusive evidence-specificity groups: single gynecologic disease family specific, multiple gynecologic disease families only, and broader baskets including non-gynecologic cancers. We evaluated source sensitivity, target applicability, field-specific registry visibility, and the availability of posted registry safety results. A complementary registry-informed exploratory survey of 25 experts assessed translational barriers and development priorities using domain-specific 1-5 scales.
    Results: Among 442 unique records screened, 211 therapeutic trials met the eligibility criteria. Of these, 43 were restricted to a single gynecologic disease family, 2 included multiple gynecologic disease families only, and 166 were broader basket trials permitting enrollment of non-gynecologic malignancies. The public-registry-linked and public-search-captured sensitivity subsets included 200 and 141 records, respectively, with broadly similar structural patterns across datasets. The landscape was predominantly early phase, with 149 Phase I and 50 Phase I/II trials. CAR-T, TIL, and TCR-T were the leading modalities, accounting for 79, 60, and 42 trials, respectively. Only 20 records had posted registry results with an adverse-event module, indicating limited availability of registry-reported safety data. In the exploratory expert survey, an immunosuppressive tumor microenvironment and a lack of gynecologic-specific cohorts were identified as leading barriers, whereas ovarian cancer, TIL therapy, MSLN, target reporting, and registry completeness emerged as prominent development priorities.
    Conclusions: Registered cellular-therapy activity in gynecologic malignancies is broad but remains early phase, largely basket-derived, and unevenly visible in registry fields. Separating disease-specific trials from broader eligibility-only baskets, testing source sensitivity, and distinguishing modality biology from missing target reporting provide a more reproducible basis for future trial planning.
    Keywords:  CAR-T; TCR-T; adoptive cellular therapy; clinical trials; gynecologic malignancies; natural killer cells; registry-based landscape; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1936815
  14. Transplant Cell Ther. 2026 Oct 11. pii: S2666-6367(26)00800-6. [Epub ahead of print]
    Considerations for Improving Equity and Access to CAR-T Therapies.
    Eddie Hp Tan, Mickey Bc Koh.
      There are significant barriers to equitable access to cell therapies among which include the high costs of treatment, complex logistics from manufacture to bedside and the substantial economic gradients that exist between health systems of countries. Beyond the immediate issues of cost and safety balanced with efficacy, there exists a multifactorial interplay of factors which include patient and caregiver, provider and institutional, manufacturer and supply-chain, as well as regulatory or payer factors which all contribute to equity and access. With the continued evolution of advanced therapy offerings, a paradigm shift in thinking is required among policy makers, beyond the traditional drug product based regulatory frameworks and health systems. Four Key Drivers of the Paradigm shift: (1) New Manufacturing Models, (2) Technological Advancements, (3) Innovative Regulatory Approaches and (4) International Cooperation.
    Keywords:  CAR-T; Cell therapy; Chimeric antigen receptor T cell; Gene therapy; equitable access
    DOI:  https://doi.org/10.1016/j.jtct.2026.10.011
  15. iScience. 2026 Oct 16. 29(10): 117697
    Inhibitory receptor profiles for joint prediction of benefit and toxicity in immune checkpoint blockade.
    Xiaodong Wang, Di Xiong, Bingchen Duan, Gouping Ding, Yiping Huang, Qianqian Wang.
      Immune checkpoint blockade has transformed cancer therapy, but durable benefit is limited to a subset of patients and can be accompanied by immune-related adverse events. This Review evaluates inhibitory receptor profiles as candidate biomarkers for predicting both antitumor benefit and immune toxicity. We examine how receptor abundance, co-expression, cellular lineage, clonality, spatial context, and treatment-induced dynamics shape interpretation across tissue imaging, cytometry, bulk transcriptomics, single-cell multi-omics, and spatial profiling, with particular attention to organ-specific toxicity and time-dependent analytical bias. Current evidence supports context-dependent associations, especially for multi-receptor T-cell states and early on-treatment changes, but not universal thresholds or stand-alone clinical use. Because benefit and toxicity share pathways yet arise from partly distinct biological determinants, they should remain separate model outputs. We propose a staged path from mechanistic discovery to a locked minimal assay, external validation, and prospective evaluation of clinical utility.
    Keywords:  T cell exhaustion; immune checkpoint blockade; immune-related adverse events; inhibitory receptors; predictive biomarkers
    DOI:  https://doi.org/10.1016/j.isci.2026.117697
  16. Crit Rev Oncog. 2026 ;31(1): 5-21
    Review Article: Chimeric MHC Class I Receptors for Diverse Clinical Applications.
    Gideon Gross.
      Chimeric antigen receptors (CARs) are synthetic, modular receptors engineered to redirect T cells and other immune cells to recognize pre-selected antigens in an MHC-independent manner. CARs consist of an extracellular antigen-binding domain-typically an antibody single-chain variable fragment (scFv), a hinge region, a transmembrane domain, and intracellular signaling components. The modular CAR design facilitates the engraftment of diverse non-scFv binding moieties for redirecting immune cells toward non-conventional antigens or replacement of signaling elements according to the immune cell type and the desired function. A unique class of such antigens are the T-cell receptors (TCRs) of CD8+ T cells, expressed either by pathogenic T cells in transplantation and autoimmune diseases that need to be neutralized or, conversely, by antitumor T cells to be stimulated. The targeting of such TCRs is made possible by special CAR-like receptors, whose ectodomain comprises the antigenic epitopes recognized by the TCRs. In particular, expressing a chimeric MHC-I heavy chain or a membrane-attached form of the invariant β2-microglobulin light chain by CD8+ T cells or CD4+ regulatory T cells can be used to target alloreactive CD8+ T cells. Genetically linking a self-peptide to the N-terminus of either chain redirects these receptors to recognize pathogenic autoreactive CD8+ T cell clones, whereas a tumor-associated peptide turns them into the targeting unit of cell-based cancer vaccines when expressed by antigen-presenting cells with an appropriate endodomain. Here I describe the design of chimeric MHC-I receptors for these diverse applications, review preclinical studies examining their function and discuss their therapeutic potential.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026063496
  17. Biomarkers. 2026 Oct 13. 1-38
    Claudin 18.2: From a Tight Junction Protein to a Breakthrough Target in Solid Tumor Immunotherapy.
    Mohammad Bahrami, Masoud Hassanzadeh Makoui, Amir Bayat Bodaghi, Mansour Rajabi Vahid.
      Claudin 18.2 (CLDN18.2), a tight junction protein largely confined to normal gastric mucosa, is overexpressed and mislocalized on the surface of gastric, gastroesophageal, pancreatic, and other gastrointestinal cancers. This pattern has made CLDN18.2 a leading target in solid tumor immunotherapy. This review traces its path from a structural junctional component to a clinically relevant antigen and assesses the therapeutic platforms built around it. We discuss monoclonal antibodies, especially zolbetuximab, whose phase III SPOTLIGHT and GLOW trials improved survival in CLDN18.2-positive, HER2-negative gastric and gastroesophageal junction adenocarcinoma and led to regulatory approval. We then evaluate antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies, comparing their mechanisms, efficacy, toxicity, and resistance. We also examine the rationale for combining CLDN18.2-directed agents with immune checkpoint inhibitors, although clinical evidence for synergy remains indirect. Major challenges include antigen loss and heterogeneity, autophagy-mediated ADC resistance, on-target gastrointestinal toxicity, cytokine release syndrome, and unstandardized expression thresholds. Because optimal cutoffs differ by modality, patient selection should follow the intended therapeutic class rather than a universal biomarker score. Overall, CLDN18.2-directed therapy is a maturing precision oncology strategy; its impact will depend on randomized data, better biomarkers, and rational combinations.
    Keywords:  Chimeric Antigen Receptor T-Cell Immunotherapy; Claudin-18.2; Immunotherapy; Molecular Targeted Therapy; Stomach Neoplasms
    DOI:  https://doi.org/10.1080/1354750X.2026.2749578
  18. Int J Technol Assess Health Care. 2026 Oct 15. 42(1): e91
    Comparing harmonization in medicines regulation and health technology assessment in Europe: lessons for the EU HTA regulation.
    Francine Brinkhuis, Aukje K Mantel-Teeuwisse, Hubert G M Leufkens, Kirti Narsai, Wim G Goettsch, Hendrika A van den Ham.
       OBJECTIVES: The European Union (EU) has long pursued harmonization in medicines regulation and, more recently, in health technology assessment (HTA). The European Medicines Agency (EMA) and the EU HTA Regulation (EU HTAR) represent key milestones in these respective trajectories. This study compares the harmonization trajectories of EU medicines regulation and EU HTA to identify lessons relevant for EU HTAR implementation.
    METHODS: We used a multi-method qualitative approach combining a narrative literature review with online focus groups involving eighteen regulatory and policy experts. The review explored the historical development of harmonization in both policy areas. The focus-group analysis examined perspectives on collaboration, harmonization dynamics, and implementation.
    RESULTS: Both policy areas moved from national arrangements and voluntary cooperation toward more formal EU-level structures. Medicines regulation developed earlier and resulted in more centralized procedures and binding EU-wide authorization decisions. EU HTA retains greater national responsibility for value judgments, pricing, and reimbursement. The two areas also differ in the scope and standardization of assessments. In both trajectories, harmonization was shaped by trust, willingness to collaborate, capacity differences, and legal and procedural contexts. Participants emphasized the importance of stepwise implementation, work sharing, and sustained dialogue, while anticipating variation in national JCA uptake and impact.
    CONCLUSIONS: Experience from EU medicines regulation highlights the importance of building trust and adapting collaboration to differences in national maturity and priorities. Harmonization should develop gradually through learning and refinement across diverse legal and procedural contexts. These lessons may support EU HTAR implementation and further development.
    Keywords:  EU HTA regulation; harmonization; health technology assessment; medicines regulation; pharmaceutical policy
    DOI:  https://doi.org/10.1017/S0266462326104267
  19. Crit Rev Oncog. 2026 ;31(1): 23-33
    Review Article: Does CAR-T Cell Therapy of Solid Cancer Need the Activation of an Innate Immune Response?
    Markus Barden, Christoph Harrer, Hinrich Abken.
      CAR-T cells have shown efficacious in the treatment of hematologic malignancies; however, their efficacy towards solid tumors is so far limited by multiple challenges such as poor T cell infiltration, limited persistence, and immune suppression within the tumor tissue. On the other hand, tumor regression, especially of metastases, can spontaneously occur, which has long intrigued the scientific community. Spontaneous regression is thought to be associated with a more global immune response, triggered through the activation of both innate and adaptive immune cells. The viewpoint discusses strategies for combining CAR-T cell therapy with approaches stimulating innate immune responses to facilitate clearance of solid tumors. Currently explored approaches include vaccination, cytokine-driven activation, contact-dependent immune cell interactions, and pharmacological co-treatment, all aiming at reshaping the local environment through recruiting and activating innate immune cells together with CAR-T cells to form a more comprehensive anti-tumor response.
    DOI:  https://doi.org/10.1615/CritRevOncog.2026063886
  20. Cell Biomater. 2026 Aug 13. pii: 100558. [Epub ahead of print]
    Biomaterial-Enabled In vivo T Cell Engineering: A New Paradigm for Cell Therapy.
    Sharda Pandit, S Abbey Oliver, Emily Joe, Yevgeny Brudno.
      T cell therapies have transformed treatment for previously intractable diseases. However, their full potential remains constrained by reliance on ex vivo cell manipulations, which reduces cell quality, drives up manufacturing costs, and requires lengthy production times, ultimately reducing treatment efficacy and restricting patient access. Recent breakthroughs in biomaterials science, immunoengineering, and genetic editing have catalyzed a paradigm shift toward direct in vivo immune cell engineering using instructive biomaterials. These emerging strategies circumvent traditional limitations by dramatically reducing costs, eliminating manufacturing delays, and improving therapeutic outcomes through preservation of native cell states and functions. Key technological advances include highly specific targeted biomaterial-assisted gene delivery and instructive biomaterials that establish controlled microenvironments for precise immune cell programming and modulation. In this Perspective, we examine how biomaterials are redefining T cell therapies across a range of pathological contexts, from cancer to autoimmune disease. We analyze emerging breakthrough platforms, highlight their therapeutic potential, and discuss key challenges limiting clinical adoption. Looking ahead, we provide insights into future developments that could democratize access to these transformative immunotherapies.
    DOI:  https://doi.org/10.1016/j.celbio.2026.100558
  21. Transplant Cell Ther. 2026 Oct 11. pii: S2666-6367(26)00783-9. [Epub ahead of print]
    Advances in CAR-T and CAR-NK cell therapy in follicular lymphoma: a review.
    Sijia Yan, Wanying Liu, Mi Zhou, Yi Xiao.
      Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma and is characterized by prolonged survival but recurrent relapses. The unmet need is greatest among patients with high-risk disease, including progression of disease within 24 months of first-line immunochemotherapy (POD24), double-refractory disease, histologic transformation, and exposure to multiple previous lines of therapy. In pivotal single-arm studies enrolling heavily pretreated patients, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies produced overall response rates of 86-97% and complete response rates of 68-94%, with durable disease control in a substantial proportion of patients. However, autologous CAR-T therapy is limited by individualized manufacturing, the potential need for bridging therapy, intensive monitoring, unique toxicities, and restricted access outside specialized centers. This review summarizes the efficacy and safety of approved CAR-T products in relapsed/refractory FL, explains how differences in receptor architecture and costimulatory signaling may affect cellular kinetics and toxicity, and discusses emerging alternative targets, dual-target constructs, combination strategies, and CAR-natural killer (CAR-NK) cell platforms. CAR-NK cells represent a promising investigational off-the-shelf platform; however, current clinical evidence is derived predominantly from early-phase studies involving heterogeneous B-cell malignancies, with limited FL-specific data. Their efficacy, durability, safety, and scalability in FL therefore remain to be established in dedicated clinical studies.
    Keywords:  CAR NK cells, Cellular immunotherapy; CAR T-cell therapy; Follicular lymphoma; Relapsed/refractory lymphoma
    DOI:  https://doi.org/10.1016/j.jtct.2026.10.001
  22. J Hematol Oncol. 2026 Oct 16. pii: 85. [Epub ahead of print]19(1):
    CAR-T-centered sequential therapy: current status, challenges, and future clinical perspectives.
    Lucheng Zhou, Chengcheng Tian, Ruiqiang Du, Yizhao Chen, Zhihao Xu, Shuai Wang, Xinlei Chen, Haojie Zhang, Qianlei Wang, Qiang Cai, Jiajie Tu, Ning Lin.
      Over recent years, chimeric antigen receptor T-cell (CAR-T) therapy has markedly improved outcomes for patients with relapsed or refractory hematological malignancies. Nevertheless, a substantial proportion of patients still experience relapse or progression after treatment, driven by factors including antigen escape, suboptimal CAR-T cell expansion and persistence, functional exhaustion, and remodeling of the tumor microenvironment. In the context of managing patients who fail initial CAR-T therapy, CAR-T-centered sequential therapy has been increasingly investigated as a potential therapeutic approach. The selection of therapeutic targets and treatment approaches may be informed by resistance mechanisms, changes in target antigen expression, and disease progression patterns following prior treatment, with the aim of prolonging disease control and improving long-term outcomes. This review summarizes recent progress in CAR-T-centered sequential therapy, with particular emphasis on same-target retreatment, switching to different antigens, multi-target stepwise CAR-T regimens, and the sequential integration of CAR-T with hematopoietic stem cell transplantation, radiotherapy, immune checkpoint inhibitors, and other immunomodulatory approaches. We further discuss the biological rationale and clinical settings of these CAR-T-centered sequential approaches in the context of antigen escape, CAR-T cell functional decline, tumor clonal evolution, and immune microenvironment remodeling. Additionally, we discuss factors that may inform the selection of subsequent regimens, including the initial treatment response, antigen status at relapse, CAR-T cell persistence, and the patient's therapeutic window, as well as the clinical settings in which these sequential approaches have been explored.
    Keywords:  Antigen escape; CAR-T cell therapy; Hematologic neoplasms; Sequential treatment
    DOI:  https://doi.org/10.1186/s13045-026-01855-x
  23. Int J Technol Assess Health Care. 2026 Oct 15. 42(1): e89
    Restricted mean survival time ratio in oncology cost-effectiveness analysis: stability and data-driven support for treatment-effect waning modeling and survival extrapolation.
    Mingye Zhao, Hanqiao Shao, Taihang Shao, Yunong Jiang, Yunlin Jiang, Yuan Li, Hongshu Fang, Wenxi Tang.
       OBJECTIVES: We examined long-term treatment-effect patterns relevant to treatment effect waning (TEW) modeling in oncology health technology assessment (HTA), compared the dispersion and update stability of hazard ratios (HRs) and restricted mean survival time ratios (RMSTRs), and developed prediction models to support extrapolation model selection and TEW modeling.
    METHODS: Using the FDA Hematology/Oncology Approvals Database, we identified phase II/III randomized controlled trials (2006-2025) with updates. We included overall survival (OS) and other time-to-event end points (non-OS). We conducted 2/3/4/5-year landmark analyses to estimate post-landmark HRs and RMSTRs, summarized by event-weighted medians and dispersion (coefficient of quartile relative dispersion, CQR). Update-related change was quantified using updated-to-initial ratios. We predicted longer-term RMSTR using elastic-net regression with nested cross-validation and split-conformal 90 percent prediction intervals.
    RESULTS: We analyzed 168 trials (270 contrasts; 150 OS, 120 non-OS). Across landmark analyses at 2, 3, 4, and 5 years, RMSTR was consistently less dispersed than HR for both OS and non-OS end points, while post-landmark HRs generally remained < 1. Update ratios were more stable for RMSTR than HR. Initial and updated RMSTR were strongly correlated (OS r = .87; non-OS r = .82). Parsimonious regularized models accurately predicted updated RMSTR, with conformal prediction intervals achieving 91 percent and 96 percent coverage for OS and non-OS.
    CONCLUSIONS: Reliance on current HR-based TEW modeling practices alone may be insufficient to fully characterize long-term treatment-effect uncertainty. RMSTR was consistently less dispersed than HR and predictable from early trial data, providing an anchor for extrapolation model selection and TEW uncertainty analysis in oncology economic evaluations.
    Keywords:  cost-effectiveness analysis; hazard ratio; oncology; restricted mean survival time; treatment effect waning
    DOI:  https://doi.org/10.1017/S026646232610422X
  24. Cells. 2026 Oct 03. pii: 1809. [Epub ahead of print]15(19):
    Antigen-Presentation Competence in Gynecologic Cancers: Mechanisms, Evidence and Translational Priorities.
    Zihao Xu, Yifan Liu, Jun Xu, Mengxin Xiong.
      Immune-checkpoint biomarkers in gynecologic cancers primarily estimate antigenic potential or characterize an inhibited immune response. However, they do not establish whether malignant cells are visible to antigen-specific lymphocytes. We define antigen-presentation competence as the capacity of the tumor-immune ecosystem to generate antigenic peptides, display them through functional human leukocyte antigen molecules, prime cognate T cells through professional antigen-presenting cells, and permit recognition of malignant cells by effector lymphocytes. Recurrent defects have been reported at each step in cervical, endometrial, and ovarian cancers, but the evidence is not equally mature across these diseases. Cervical studies emphasize human papillomavirus-associated immune selection and antigen-processing machinery abnormalities; endometrial cancer provides relatively direct treatment-linked evidence for major histocompatibility complex class I and interferon-pathway defects; and ovarian cancer offers direct immunopeptidomic and multiregion evidence that antigen availability, presentation, and immune recognition can diverge. Taken together, the literature makes antigen-presentation competence a testable functional framework. It does not yet justify a biomarker or clinical score. Prospective work will need spatial and longitudinal measurements of tumor presentation, dendritic-cell priming, and T-cell recognition. A key test is whether these measurements improve prediction beyond mismatch repair, polymerase epsilon, programmed death-ligand 1, and tumor mutational burden.
    Keywords:  HLA class I; antigen presentation; biomarker; cDC1; gynecologic cancer; immune escape; immune-checkpoint inhibition; immunopeptidomics
    DOI:  https://doi.org/10.3390/cells15191809
  25. J Am Pharm Assoc (2003). 2026 Oct 13. pii: S1544-3191(26)00531-5. [Epub ahead of print] 103546
    Mapping pharmacist roles across the chimeric antigen receptor T-cell therapy care continuum: A scoping review.
    Sunil Shrestha, Nabin Pathak, Ajaya Acharya, Shreya Dhungana, Sanjeev Sharma Kattel, Santusta Adhikari, Simit Sapkota.
       BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy represents a transformative but operationally demanding treatment modality, requiring rigorous coordination across clinical, regulatory, and logistical domains. While pharmacists are widely acknowledged as integral members of CAR-T programs, the full breadth and impact of their contributions have not been systematically characterized.
    METHODS: A scoping review was conducted in accordance with the Arksey and O'Malley framework and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines, with the protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO). Multiple electronic databases were searched, with an initial search conducted to July 2025 and an updated search subsequently extending coverage through 2026. Eligible sources included original studies, narrative reviews, practice guidelines, consensus documents, commentaries, book chapters, and conference proceedings describing pharmacist involvement in CAR-T therapy. Data were extracted using a standardized charting form and synthesized descriptively.
    RESULTS: Fifteen sources out of 859 studies published between 2020 and 2026 were included. The evidence base was heterogeneous and predominantly descriptive, comprising narrative reviews, expert commentaries, guidance and consensus documents, original observational or process evaluation studies, a book chapter, and a conceptual framework. Pharmacists were reported to contribute across the entire CAR-T care pathway, encompassing program development and governance, electronic prescribing systems, medication management, product ordering and chain-of-identity traceability, supportive care and toxicity preparedness, patient education, pharmacovigilance, regulatory and financial stewardship, and quality improvement initiatives. Observational evidence indicated that pharmacist-led process interventions may reduce system-level safety risks, particularly within medication-use processes and identity traceability, and may contribute to shorter treatment timelines and expanded outpatient continuity of care. However, standardized clinical and economic outcome data remained limited across the included literature.
    CONCLUSIONS: Pharmacists fulfilled a critical, multifaceted role in the safe, effective delivery of CAR-T therapy, consistently acting as stewards of medication safety, product traceability, and regulatory compliance. The current evidence base, while informative, lacks prospective and comparative studies evaluating pharmacist-specific interventions against standard care. Future research should prioritize the development of standardized role definitions and the robust measurement of clinical, operational, and economic outcomes as CAR-T therapy continues to expand into broader practice settings.
    Keywords:  CAR-T; Cellular therapy; Chimeric antigen receptor T-cell therapy; Hospital pharmacy; Medication safety; Multidisciplinary care; Pharmacist; Scoping review
    DOI:  https://doi.org/10.1016/j.japh.2026.103546
  26. Trends Pharmacol Sci. 2026 Oct 16. pii: S0165-6147(26)00253-1. [Epub ahead of print]
    Engineering monocytes and macrophages for therapeutic control.
    Yunzhu Chen, Christine E Brown, Yanhong Shi, Mingye Feng.
      Engineered monocytes and macrophages are emerging as therapeutic platforms for eliminating pathological targets, remodeling diseased tissues, and coordinating local immune responses. Early clinical studies support their feasibility, but target recognition alone does not ensure sustained function after tissue entry. Recent advances in myeloid-adapted receptors, context-responsive circuits, checkpoint and metabolic engineering, in vivo mRNA delivery, and stem-cell-derived platforms have expanded the strategies available to improve tissue tracking, control cellular plasticity, and sustain effector capacity. Previous reviews have commonly organized the field by disease, target, or platform. Here, we examine engineered monocyte and macrophage therapies as integrated pharmacological systems structured across four coupled layers-sensing, signal integration, actuation, and delivery-and discuss how their coordination determines tissue exposure, functional durability, and pharmacodynamic readouts across therapeutic settings.
    Keywords:  cell therapy; chimeric antigen receptor; delivery; engineered monocytes and macrophages; induced pluripotent stem cells (iPSCs); sensing and signal integration
    DOI:  https://doi.org/10.1016/j.tips.2026.09.009
  27. FEBS J. 2026 Oct 13.
    A guide to studying tumour-T-cell interactions using in vitro coculture assays.
    Nooshin Khoshdoozmasouleh, Conor J Kearney.
      T cells are central mediators of antitumour immunity and are the cellular basis of many successful cancer immunotherapies, including immune checkpoint blockade, T-cell receptor (TCR)-engineered therapies and chimeric antigen receptor (CAR) T cells. However, clinical responses remain variable, and many tumours evade or resist T-cell-mediated control. Understanding how T cells recognise tumour cells, deliver cytotoxic signals, produce inflammatory cytokines and shape tumour cell fate is therefore essential for improving modern immunotherapies. In vitro tumour T-cell coculture systems provide a powerful experimental framework for dissecting these processes under controlled conditions. They allow investigators to manipulate antigen specificity, HLA/MHC restriction, tumour genotype, T-cell activation state, cytokine exposure and drug-mediated perturbation in ways that are difficult to achieve in vivo. However, these systems require careful design, because assay outcomes are strongly influenced by tumour model, antigen expression, effector-to-target ratio, assay duration and readout. This guide provides a practical framework for studying tumour T-cell interactions in vitro, with a focus on CD8+ T-cell-mediated tumour recognition and killing. It discusses commonly used mouse and human antigen-specific models, how antigen expression and presentation can be experimentally controlled, T-cell activation and coculture conditions, cytotoxicity assays, immune synapse imaging, competition assays, cytokine-mediated bystander killing, transcriptional profiling, CRISPR perturbation strategies, therapeutic testing and patient-derived models. The aim is to help researchers choose the most appropriate model, experimental setup and readout for the biological question being asked and to avoid common interpretive pitfalls when studying tumour immune sensitivity, resistance and therapeutic response.
    Keywords:  CRISPR screening; T‐cell cytotoxicity; cancer immunotherapy; cytokine‐mediated killing; tumour immune evasion; tumour–T‐cell coculture
    DOI:  https://doi.org/10.1111/febs.70765
  28. Drug Discov Today. 2026 Oct 15. pii: S1359-6446(26)00239-4. [Epub ahead of print] 104834
    Advancing a drug-development program is not the same as de-risking it.
    Mileidys Perez-Alea.
      Drug-development programs are often called de-risked after accumulating data, publications, financing or regulatory milestones. These signals may establish activity, credibility or readiness, but not necessarily a reduction in consequential uncertainty. Accumulation alone does not make an asset de-risked; de-risking is a claim that evidence has reduced uncertainty relevant to a decision. Such a claim requires evidence that is reliable, relevant to the choice ahead and available before that choice becomes difficult to reverse. Three oncology histories illustrate how evidence can support progression, narrow an indication or arrive too late. This Editorial proposes a shared uncertainty record to make that reasoning explicit across development.
    Keywords:  de-risking; decision-making; drug development; evidence; oncology; translational research
    DOI:  https://doi.org/10.1016/j.drudis.2026.104834
  29. Clin Lymphoma Myeloma Leuk. 2026 Sep 30. pii: S2152-2650(26)03983-2. [Epub ahead of print]
    Cardiovascular Toxicities of Contemporary Cancer Immunotherapies: A Narrative Review of Immune Checkpoint Inhibitors, Bispecific T-Cell Engagers, and CAR-T Cell Therapies.
    Jean El Cheikh, Bahaa El Deen Wehbeh, Ali Tarhini, Ralf Mansour, Georgio Sayde, Nicole Charbel, Katia Kautaich, Ibrahim Hasan, Marwan M Refaat.
      Immune checkpoint inhibitors (ICIs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies have produced durable responses across different hematologic malignancies, but each class carries cardiovascular liabilities that differ fundamentally in mechanism, incidence, timing, and mortality risk. A structured narrative review of PubMed/MEDLINE and EMBASE from inception through March 2026 was performed, supplemented by pharmacovigilance data from FAERS and WHO VigiBase, to review and synthesize the available evidence on cardiovascular toxicity and provide a structured comparison of incidence, mechanisms, clinical presentation, outcomes, and monitoring strategies to guide clinical practice. ICI-associated myocarditis is rare (0.06%-1.14%) but carries a case fatality rate approaching 50%, a lethality amplified by combination regimens and obscured by preserved left ventricular ejection fraction in approximately half of presentations. BiTEs may occupy a mechanistically intermediate position: cardiovascular adverse events are reported in 8% to 20% of pharmacovigilance cases, and 83% of these arise without documented concurrent cytokine release syndrome (CRS), implying that their immunopathological profile lies closer to ICI than to CAR-T injury. Bispecific agents are not a homogeneous class: blinatumomab, teclistamab, talquetamab, and elranatamab differ in construct, target antigen, disease setting, CRS frequency, and reported cardiovascular phenotype, and agent-level effects cannot presently be separated from population-level ones. CAR-T cell therapy produces cardiovascular events in up to 19% to 26% of patients, predominantly through IL-6-driven, CRS-coupled hemodynamic injury, with left ventricular dysfunction resolving in the majority following CRS management. Across all 3 classes, foundational clinical trials incorporated no routine cardiac monitoring, current surveillance practices are heterogeneous, and no prospective head-to-head comparative data exist. Each immune therapy class poses a qualitatively distinct cardiac threat at a different point in the treatment course. Risk-adapted surveillance extending beyond the CRS window appears prudent for BiTEs, although this reflects extrapolation rather than validated evidence; serologic and imaging monitoring regardless of systemic symptoms remains essential for ICI recipients; and CRS-guided early intervention is the cornerstone of CAR-T cardiotoxicity management. This review aims to provide clinicians with a comprehensive overview of the cardiovascular toxicities associated with these modern therapies.
    Keywords:  Cardio-oncology; Cardiotoxicity; Cardiovascular adverse events; Cytokine release syndrome; Myocarditis
    DOI:  https://doi.org/10.1016/j.clml.2026.09.019
  30. Cell Stem Cell. 2026 Oct 13. pii: S1934-5909(26)00348-6. [Epub ahead of print]
    Rapid CAR-T manufacturing with low-intensity priming enhances CAR-T cell fitness and limits inflammatory programming in a phase 1 study.
    Zhi Yang, Shiqi Li, Linling Wang, Yunyan Li, Huailong Xu, Yu Li, Lin Liu, Zhongtao Yuan, Yingzi Zhang, Lihua Zhang, Yingnian Chen, Qianzhen Zhang, Junjie Shen, Meiling Wang, Wei Zhu, Xiao He, Youcheng Wang, Yancheng Dong, Sanbin Wang, Cheng Qian.
      Conventional chimeric antigen receptor (CAR)-T manufacturing requires prolonged ex vivo activation and expansion, which may compromise T cell fitness and promote inflammatory differentiation. Here, we developed PrimeCAR, a 2-day manufacturing strategy combining low-intensity anti-CD3 priming with IL-7 and IL-21. Compared with conventionally manufactured CAR-T cells, PrimeCAR products exhibited a distinct transcriptional state characterized by preserved stemness-associated programs and a PrimeCAR-enriched primed naive T cell (Tn)-like state. Following antigen stimulation, PrimeCAR cells preferentially engaged proliferative programs while limiting exhaustion-associated regulators and inflammatory mediators. Functionally, PrimeCAR cells demonstrated enhanced expansion, persistence, and durable antitumor activity in xenograft models. In investigator-initiated phase I studies of relapsed or refractory B cell acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma, PrimeCAR showed encouraging clinical activity with a favorable safety profile. Together, these findings demonstrate that rapid manufacturing with controlled early T cell priming selectively restrains inflammatory programming while preserving CAR-T cell fitness, providing a practical strategy for improving CAR-T manufacturing and therapeutic performance.
    Keywords:  CAR-T cell fitness; CD19 CAR; T cell activation; acute lymphoblastic leukemia; chimeric antigen receptor T cell; inflammatory programming; low-intensity priming; non-Hodgkin’s lymphoma; primed Tn-like cell state; rapid manufacturing
    DOI:  https://doi.org/10.1016/j.stem.2026.09.006
  31. Eur J Haematol. 2026 Oct 16.
    Chimeric Antigen Receptor T-Cell Therapy in T Cell/Histiocyte-Rich Large B-Cell Lymphoma: A Systematic Review and Meta-Analysis.
    Stefan Koeck, Michael Leisch, Bernd Schöpf, Josia Fauser, Normann Steiner, Nina Worel, Gianfranco Pocobelli, Thomas Melchardt.
      T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare subtype of B-cell non-Hodgkin lymphoma with an aggressive clinical course and poor prognosis in the case of relapsed or refractory (r/r) disease. Recently, anti-CD19 chimeric antigen-receptor (CAR) T-cell therapy has been approved for the treatment of large B-cell lymphoma (LBCL), but subgroup-specific outcomes in these patients have never been reported. Therefore, only limited retrospective data on the safety and efficacy of CAR T-cell therapy in r/r THRLBCL is available. To comprehensively evaluate outcomes of CAR T-cell recipients with r/r THRLBCL, we performed a systematic literature review (SLR) and meta-analysis (MA). The SLR identified seven studies including 157 patients with r/r THRLBCL. Pooled overall response rates and complete remission rates were 48.3% and 30.4%, respectively. Median progression-free survival was 3.4 months, with a 12-month rate of 29.1% and median overall survival was 15.0 months, with a 12-month rate of 57.4%. Low- and high-grade cytokine release syndrome occurred in 68.3% and 4.5% of patients while low- and high-grade immune effector cell-associated neurotoxicity syndrome was seen in 23.1% and 12.9% of the patients. Overall, no unexpected safety signals were identified in r/r THRLBCL patients receiving CAR T-cell therapy but durable responses were only achieved in a subset of patients.
    Keywords:  T‐cell/histiocyte‐rich large B‐cell lymphoma; chimeric antigen‐receptor (CAR) T‐cell therapy; large b‐cell lymphoma; meta‐analysis; systematic review
    DOI:  https://doi.org/10.1111/ejh.70340
  32. JCO Glob Oncol. 2026 Oct;12(10): e2600217
    Leveraging Real-World Evidence to Drive Advances in Oncology Care in the Asia-Pacific Region: Recommendations From the Asia-Pacific Oncology Drug Development Consortium Working Group.
    Herbert H Loong, Pankaj Kumar Panda, Ben Tran, Toshio Shimizu, Pei Jye Voon, Frederic Ivan Leong Ting, Takafumi Koyama, Daphne Day, K Arnold Chan, Grace L Wong, Daniel S W Tan.
      In an era of rapid technological advancements, the Asia-Pacific (APAC) region stands at the forefront of health care innovation, leveraging real-world evidence (RWE) to drive transformative changes. RWE, derived from real-world data such as electronic health records and patient registries, provides actionable insights that supplement clinical trial data, thus enhancing clinical decision making and policy formulation. The utilization of RWE has become crucial, especially in addressing the diverse health care needs of the APAC region. Despite the potential, APAC faces significant challenges, including heterogeneous data collection methodologies, limited technological infrastructure, and regulatory disparities. To overcome these barriers, collaborative efforts among governments, health care institutions, and industry partners are essential. The methodology of this study involved the collaboration of a group of experts to assess the current state of RWE utilization, explore challenges and opportunities, and synthesize recommendations for harmonizing RWE practices. The APAC Oncology Drug Development Consortium Working Group recommends harmonizing data standards, fostering collaborative partnerships, and promoting policy innovations to facilitate the effective use of RWE. By focusing on these areas, APAC can enhance data quality, aiding health technology assessment, improve health care delivery and decision making, and achieve better patient outcomes. The successful integration of RWE into decision-making processes will require a unified approach to data standards, robust quality assurance measures, and a commitment to ethical data-sharing practices. As the health care landscape continues to evolve, embracing RWE offers a promising pathway to accelerate therapeutic innovations and improve public health across the region.
    DOI:  https://doi.org/10.1200/GO-26-00217
  33. Res Sq. 2026 Oct 04. pii: rs.3.rs-10808000. [Epub ahead of print]
    Functional Exhaustion Limits CAR-NK Therapy in Glioblastoma but Can Be Mitigated by Early Repeated Dosing.
    Kajal Chaudhry, Nethaji Muniraj, Haili Lang, Ashley Geiger, Gage Paul, Ehsan Dowlati, Danielle Sohai, Joshua Terao, Sridevi Yadavilli, Carlos Sanchez, Eric Yvon, Christopher Lazaraski, Eugene Hwang, Matthias Holdhoff, Barbara Savoldo, Conrad Russell Cruz, Catherine Bollard.
      With the commercial success of Chimeric Antigen Receptor T (CAR-T) cell therapies in the blood cancer setting, there are increasing numbers of clinical trials evaluating this treatment modality in patients with solid tumors, including brain tumors. Allogeneic CAR-natural killer (NK) cell therapy offers an attractive "off-the-shelf" option using the CAR platform. However, this approach remains comparatively untested clinically, with only one published clinical trial to date in patients with central nervous system (CNS) tumors. Building on our prior in vitro characterization of allogeneic B7H3-CAR-NK for brain tumors, we compared B7H3/CD28z CAR-NK and CAR-T cells in an aggressive adult Glioblastoma Multiforme (GBM) model in vitro and in an orthotopic murine xenograft system. CAR-NK cells killed GBM targets more rapidly than CAR-T cells in vitro, and secreted higher levels of IFN-γ. However, in vivo, CAR-T cells controlled tumor growth and prolonged survival while CAR-NK cells failed to restrict tumor outgrowth despite confirmed tumor infiltration and persistence. Neither B7H3 antigen upregulation on NK cells nor trogocytosis-driven fratricide accounted for this discrepancy. Instead, we discovered that CAR-NK cells lost cytolytic activity, proliferative capacity, and cytokine secretion after multiple rounds of tumor challenge. This coincided with a downregulation of activating receptors and upregulation of inhibitory receptors. In contrast, CAR-T cells retained their cytolytic activity through four rounds of tumor challenge. While negating the consequences of tumor-induced suppression (by abrogating TGF-β signaling and increasing IL15 signaling), restored in vitro serial killing capacity and reduced in vivo tumor burden, these engineering strategies were insufficient to enhance overall survival. In contrast, administering multiple doses of NK cell products early did confer a survival benefit in preclinical models, suggesting that the CAR-NK cell platform may be more effective when utilized clinically in the adjuvant setting for patients with high-risk brain tumors such as GBM.
    DOI:  https://doi.org/10.21203/rs.3.rs-10808000/v1
  34. Blood Immunol Cell Ther. 2026 Sep;2(3): 100065
    Glucocorticoid-induced TNF receptor ligand-dependent B-cell expansion of regulatory T cells as an immune cell therapy strategy.
    Cody J Gurski, Mohamed Khalil, Kelli C Sommers, Angela K Beltrame, Bonnie N Dittel.
      B-cell-based immune cell therapies represent a potential strategy for restoring immune tolerance by expanding regulatory T cells (Tregs). CD4+Foxp3+ Tregs are essential for maintaining immune homeostasis and represent an attractive therapeutic target. However, clinically established strategies to safely and durably expand endogenous Tregs remain lacking. We previously identified IgDlow/- B cells as a splenic B-cell subset that promotes Treg expansion through a glucocorticoid-induced TNF receptor ligand (GITRL)-dependent mechanism, whereas other B cell populations do not. In B-cell-specific GITRL transgenic mice, Treg numbers are significantly increased, and the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, is attenuated. To evaluate the translational potential of this pathway as a hematopoietic immune cell therapy, we transplanted wild-type recipients with bone marrow from GITRL transgenic donors. After hematopoietic reconstitution, GITRL expression was selectively increased on B cells. This resulted in the expansion of endogenous Tregs and a corresponding increase in the proportion of Tregs within the CD4+ T-cell compartment, with near-complete suppression of EAE. These findings demonstrate that enhancing GITRL expression within the hematopoietic B-cell compartment provides a tractable strategy for expanding endogenous Tregs and augmenting Treg-mediated immune suppression, establishing a framework for developing B-cell-based immune cell therapies capable of durable immune suppression for inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.bict.2026.100065
  35. Int J Mol Sci. 2026 Sep 23. pii: 8489. [Epub ahead of print]27(19):
    Artificial Intelligence as a Catalyst for Novel Therapeutic Opportunities in Precision Oncology.
    Kostas A Papavassiliou, Amalia A Sofianidi, Angeliki Margoni, Athanasios G Papavassiliou.
      Artificial intelligence (AI) is reshaping molecular oncology by making complex biological data tractable and by extending the reach of precision drug discovery. Its emerging value is particularly evident at the interface of immunoengineering and targeted therapy, where computational models can help prioritize tumor-selective antigens, predict neoantigen immunogenicity, optimize engineered receptors, support antibody and antibody-drug conjugate design, guide small-molecule discovery, refine genome-editing strategies, and anticipate treatment response. Across these applications, the central promise is not automation for its own sake, but a wider therapeutic window in which tumor control is increased while off-target toxicity is reduced. Yet the translational gap remains substantial. Many models are still preclinical, external validation is limited, and clinical implementation remains uncommon. This Commentary follows representative methods across a therapeutic continuum that now extends from target discovery and therapeutic engineering to imaging, liquid biopsy, resistance forecasting, combination selection, and drug repurposing. We argue that clinical value will depend on closed-loop workflows in which multimodal predictions are experimentally validated, externally tested, and longitudinally updated to guide the next therapeutic decision.
    Keywords:  artificial intelligence; deep learning; drug discovery; immunoengineering; machine learning; precision oncology
    DOI:  https://doi.org/10.3390/ijms27198489
  36. Crit Rev Oncol Hematol. 2026 Oct 12. pii: S1040-8428(26)00529-9. [Epub ahead of print] 105642
    Rewiring the Tumor-Immune Ecosystem: Extracellular Vesicles in the Next Era of Cancer Immunotherapy.
    Ahmed Reda Bahr, Youssef Basem, Abdelrahman Alaa, Maria Tamer, Amira Basem, Mariam Hossam El-Deen, Esraa M Halawa.
      Cancer immunotherapy has transformed oncology by enabling immune-mediated tumor elimination; however, durable responses remain limited, particularly in solid tumors due to antigen heterogeneity, immunosuppressive tumor microenvironment, and adaptive resistance mechanisms. To overcome these barriers, therapeutic paradigms are expanding from single-agent interventions toward programmable cellular and acellular platforms. This review examines recent advances in CAR-T, CAR-NK, and TCR-engineered cell therapies alongside key resistance mechanisms. In parallel, we evaluate the dual biological role of extracellular vesicles (EVs) as mediators of immune evasion and as engineered delivery tools. Rather than presenting multimodal integration as an inherently superior solution, we critically evaluate the trade-offs of combining engineered cells, EVs, checkpoint blockade, oncolytic viruses, and targeted agents, focusing on therapeutic synergy versus cumulative toxicity and biomanufacturing complexity. Collectively, we propose that future cancer immunotherapy will rely on multi-modal, adaptive, and systems-level engineering approaches capable of dynamically reshaping the tumor-immune ecosystem to achieve sustained tumor regression and durable overall survival.
    Keywords:  CAR-NK cells; CAR-T cells; Cancer immunotherapy; extracellular vesicles (EVs); immune evasion; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105642
  37. Front Oncol. 2026 ;16 1932372
    Efficacy and safety of immunotherapy in pediatric malignant brain tumors: a systematic review and exploratory meta-analysis.
    Tomasz Tykocki.
       Background: Immunotherapy for pediatric brain tumors has expanded rapidly, yet its effects on survival and neurologic safety remain unclear. A systematic review and meta-analysis was conducted to quantify efficacy and toxicity across immunotherapy modalities.
    Methods: Following PRISMA 2020 guidelines, prospective pediatric immunotherapy studies were identified. Random-effects meta-analyses were performed using vaccine-based immunotherapy as the reference. Primary endpoints were overall survival (OS) and 12-month overall survival (OS12); grade ≥3 neurotoxicity was the primary safety outcome. Meta-regression and sensitivity analyses explored modality-specific effects.
    Results: Twenty studies were included. Median OS ranged from 3.6 months in heavily pretreated recurrent cohorts to 17.8 months in selected intratumoral oncolytic virus trials, while OS12 ranged from 8-13% to 75%. Compared with vaccines, non-vaccine immunotherapy did not improve OS (pooled HR 1.14, 95% CI 0.99-1.31; I² 43%) or OS12 (HR 1.13, 95% CI 0.95-1.34; I² 65%). Subgroup analyses showed comparable OS for CAR-T therapies (OS HR 1.09, 95% CI 0.89-1.34) and checkpoint/systemic therapies (OS HR 1.14, 95% CI 0.96-1.36), or oncolytic/viral therapies (OS HR 1.51, 95% CI 0.81-2.84). Severe neurotoxicity differed substantially by modality. No grade ≥3 neurotoxicity occurred in vaccine studies. In contrast, pooled non-vaccine therapies showed a markedly increased risk (OR 19.66, 95% CI 6.78-57.02; I² 60%). CAR-T therapies (OR 57.95, 95% CI 16.15-207.98) and oncolytic/viral approaches (OR 69.41, 95% CI 17.00-283.33) had the highest risk, whereas checkpoint/systemic therapy showed a lower, non-significant increase (OR 2.26, 95% CI 0.77-6.60).
    Conclusions: Across pediatric immunotherapy trials, survival outcomes were comparable to vaccine-based approaches, but neurotoxicity varied markedly by modality. Cellular and oncolytic therapies carry a substantial neurologic risk that must be balanced against uncertain survival benefit in future trial designs.
    Keywords:  CAR-T; immunotherapy; neurotoxicity; overall survival; pediatric brain tumors
    DOI:  https://doi.org/10.3389/fonc.2026.1932372
  38. Cancers (Basel). 2026 Oct 05. pii: 3213. [Epub ahead of print]18(19):
    Bone Marrow Adipocytes in Multiple Myeloma: Emerging Immunometabolic Interactions and Implications for Immunotherapy.
    Adriana Roque, Artur Paiva, Raquel Seiça, Catarina Geraldes.
      Immunotherapy has revolutionized the treatment of multiple myeloma (MM), but durable immune control remains limited, increasing interest in how the bone marrow (BM) microenvironment influences antitumor immunity. BM adipocytes (BMAds) are increasingly recognized as metabolically active components of the BM. This review summarizes the current evidence linking BMAds to myeloma cell survival and immune cell function, particularly T cell activity. It also discusses their potential relevance to monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy. Preclinical studies have shown that myeloma-associated BMAds undergo lipid depletion and acquire inflammatory and senescence-associated secretory features. BM lipid exposure is associated with impaired CD8+ T-cell metabolic fitness, whereas leptin receptor activation suppresses invariant natural killer T-cell anti-myeloma activity. Evidence concerning conventional natural killer cells and other immune compartments remains limited. Available clinical evidence is predominantly cross-sectional and therefore does not establish a direct role for BMAds in resistance to current immunotherapies or clarify whether they influence therapeutic target availability or function as clinically relevant bystander targets. Patient- and treatment-related factors, including aging and obesity, may further reshape the adipocytic-stromal and immune landscape of the marrow, potentially modifying local responses to immunotherapy. Future studies combining patient-derived multicellular models with spatial and longitudinal approaches should determine how BMAd-associated metabolic, inflammatory, and adipokine signaling affect immune control and treatment outcomes in MM and whether these processes can be therapeutically modulated.
    Keywords:  CAR T cell therapy; T-cell dysfunction; bispecific antibodies; bone marrow adipocytes; bone marrow microenvironment; immunometabolism; lipid metabolism; monoclonal antibodies; multiple myeloma; natural killer cells
    DOI:  https://doi.org/10.3390/cancers18193213
  39. Expert Rev Vaccines. 2026 Dec;25(1): 2746121
    Virus-like particle vaccines: from antigen architecture to antigen presentation and adaptive immune responses.
    Zihan Zhang, Huiwen Zheng, Longding Liu.
       INTRODUCTION: Virus-like particles (VLPs) mimic key structural features of native viruses while lacking a replication-competent viral genome, combining favorable safety with multivalent antigen presentation and strong immunogenicity. Yet, how VLP design influences the quality and persistence of adaptive immunity remains incompletely understood.
    AREAS COVERED: This review examines relevant literature identified through targeted searches on recent advances in VLP engineering, with emphasis on particle architecture, antigen-display strategies, and structural determinants of immune recognition. We discuss how VLPs facilitate antigen presentation by antigen-presenting cells and shape CD4+ and CD8+ T-cell responses, immune memory, and T follicular helper cell-B-cell interactions within germinal centers. Emerging approaches linking VLP design with humoral and cellular immunity are also considered.
    EXPERT OPINION: The next generation of VLP vaccines will require a transition from empirical enhancement of immunogenicity toward precision engineering of immune responses. A major challenge is to establish robust and transferable structure-immunity relationships while addressing manufacturing feasibility, quality control, potency assessment, and product comparability. Advances in computational protein design, structural biology, and high-dimensional immune profiling are expected to enable increasingly quantitative and mechanism-based optimization of VLP platforms. However, fully predictive control over human immune responses will remain a complex challenge.
    Keywords:  Adaptive immunity; antigen display; antigen presentation; vaccine design; virus-like particles
    DOI:  https://doi.org/10.1080/14760584.2026.2746121
  40. Cancers (Basel). 2026 Sep 29. pii: 3158. [Epub ahead of print]18(19):
    Single-Cell and Multi-Omics Profiling of the Multiple Myeloma Immune Niche: From Bone Marrow Architecture and Metabolic Reprogramming to Immunotherapy Response.
    Katia Beider, Olga Ostrovsky, Arnon Nagler.
      Multiple myeloma (MM) is increasingly understood as a spatially organized and dynamically evolving disease, in which malignant plasma-cell behavior is shaped by local immune, stromal, vascular, and metabolic contexts. Single-cell, spatial, and multi-omic technologies have resolved tumor-cell heterogeneity, bone marrow niche remodeling, immune dysfunction, and therapy-induced selection at unprecedented resolution, yet an integrated synthesis linking marrow architecture, extramedullary dissemination, circulating tumor cells, metabolic reprogramming, chimeric antigen receptor T (CAR-T) cell and T-cell-redirecting immunotherapy, and stem-cell transplantation remains lacking. Here, we review how malignant subclones occupy distinct marrow regions, focal lesions, and extramedullary sites with different transcriptional, antigenic, immune-interactive, and metabolic states. We discuss how spatial transcriptomics and multiplexed imaging reveal immune exclusion, stromal support, oxidative and glycolytic niches, and region-specific antigen heterogeneity. We further examine how circulating tumor cells serve as liquid readouts of tumor burden, high-risk genomics, and clonal evolution. Emphasis is placed on CAR T-cell and T-cell engager therapies, where response and resistance depend on antigen retention, effector-cell fitness, clonal T-cell expansion, myeloid suppression, and spatial accessibility. Finally, we consider autologous hematopoietic stem-cell transplantation as a clinical model of cytoreduction, lymphodepletion, and incomplete immune reconstitution. We propose that MM progression and relapse should be interpreted through an integrated spatial-temporal framework, in which therapeutic outcome reflects the interaction between malignant plasma-cell plasticity, immune competence, stromal persistence, metabolic adaptation, and residual disease localization.
    Keywords:  bone marrow microenvironment; immune niche; immunotherapy; metabolic reprogramming; multi-omics; multiple myeloma; single-cell RNA sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.3390/cancers18193158
  41. Front Immunol. 2026 ;17 1965459
    Case Report: CD20/BCMA bispecific CAR-T therapy for progressive multiple sclerosis.
    Zhenfen Ling, Xia Liu, Wensi Li, Qingguo Wang, Nu Tan, Xueying Ding, Yunyi Zan, Youyao Gu, Yuan Qian, Xiaobing Luo, Thule Trinh, Yanfeng Li, Xiaoteng Lv, Minna Wang, Qian Tan, Kevin Zhu, Chengxiao Zheng, Xin Yao, Judy Zhu, Jiaqi Huang, Yihong Yao, Nan Shen.
      Refractory secondary progressive multiple sclerosis (SPMS) remains an area of unmet need, particularly once disability continues to accumulate despite multiple disease-modifying therapies. Two SPMS patients are reported with C-CAR168 treatment, a bispecific CD20/BCMA CAR-T product, achieving 12- and 6-month drug-free remission. Patient 001 (EDSS 4.0→3.0) showed improvement of oculomotor dysfunction, ataxia, and cognitive impairment. Patient 002 (EDSS 6.5→6.0) demonstrated halted lower-limb progression and relieved bowel/bladder dysfunction. C-CAR168 infiltrated into the cerebrospinal fluid (CSF), persistently depleted pathogenic B-lineage cells and CD20dim T cells, and normalized inflammatory markers with an overall favorable safety profile. This first-in-human experience supports bispecific CAR-T as a promising immune-reprogramming strategy for refractory SPMS.
    Keywords:  CAR-T therapy; CD20/BCMA; case report; drug-free remission; secondary progressive multiple sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1965459
  42. Front Immunol. 2026 ;17 1993921
    Editorial: The functional plasticity of innate immune cells.
    Filipe Rodolfo Moreira Borges Oliveira, Jacqueline Alves Leite, Luiz Henrique Agra Cavalcante-Silva.
      
    Keywords:  HIV; NK cell; dendritic cell; iNKT cell; innate lymphoid cell; macrophage; neutrophil; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1993921
  43. Sci China Life Sci. 2026 Oct 12.
    Current understanding and new promises of umbilical cord blood in emerging clinical applications.
    Xinyu Feng, Yuxuan Liu, Sha Hao, Tao Cheng, Linping Hu.
      Umbilical cord blood (UCB) has become an important resource for regenerative medicine owing to its unique cellular composition, immune immaturity, and abundance of bioactive factors. Although UCB was initially applied in hematopoietic stem cell transplantation, accumulating evidence indicates that its diverse cellular and paracrine components possess broad regenerative potential. Beyond conventional hematopoietic stem cell transplantation, substantial progress has expanded the therapeutic scope of UCB to immune cell-based therapies, the treatment of genetic and metabolic disorders, and tissue repair. In this review, we focus on the biological characteristics of the key cellular and noncellular components of UCB and analyze how these properties support tissue repair, immunomodulation, and regeneration across multiple organ systems. We further summarize recent technological advances, including cell engineering, gene modification, and manufacturing technologies, that have enhanced the scalability and therapeutic potential of UCB-derived products. In addition, we highlight current challenges that limit their widespread clinical application. This review aims to provide a framework for optimizing UCB-based therapies and accelerating their clinical translation. Optimizing UCB collection, processing, and application strategies may further unlock its therapeutic potential, thereby improving clinical efficacy and expanding its applicability to a broader range of diseases.
    Keywords:  cell therapy; clinical applications; gene editing; hematopoietic stem cell; immune cell; regenerative medicine; umbilical cord blood
    DOI:  https://doi.org/10.1007/s11427-026-3460-2
  44. J Hematol Oncol. 2026 Oct 16. pii: 87. [Epub ahead of print]19(1):
    The advances and challenges of mRNA-LNP application in fields of hematology and oncology therapeutics.
    Yuan Wang, You Ge, Yu Chen, Yongfeng Yang, Junwei Li.
      The rapidly global deployment of COVID-19 mRNA-LNP vaccines established the clinical feasibility of combining RNA medicine with LNP delivery systems, transforming a long-standing experimental concept into a scalable therapeutic modality, previously considered impossible. Currently, the value of mRNA-LNPs has been expanding from infectious disease vaccines to cancer immunotherapy, personalized neoantigen vaccination, in vivo immune-cell engineering, protein replacement therapy, mRNA-encoded biologics and genome editing, with particular relevance to hematology and oncology. However, in hematologic and oncologic settings, therapeutic success is constrained by biological barriers that less prominent in prophylactic vaccination. Systemically administered LNPs are strongly influenced by hepatic sequestration, protein corona formation and mononuclear-phagocyte clearance; solid tumors additionally present heterogeneous vasculature, variable enhanced permeability and retention, dense extracellular matrix, elevated interstitial pressure and limited intratumoral diffusion. Hematologic applications face a different set of constraints, including access to spleen and bone marrow, selective delivery to T cells, NK cells and hematopoietic stem and progenitor cells (HSPCs), and preservation of the normal marrow niche. In this Review, we therefore discuss the molecular and principles of formulation that underpin mRNA-LNP performance in hematology and oncology, including mRNA engineering, lipid nanoparticle architecture, intracellular trafficking and selective organ targeting(SORT) delivery strategies, oncology applications spanning neoantigen vaccines, tumor-microenvironment reprogramming, mRNA-encoded biologics, gene editing and combination therapy; and hematology applications including in vivo CAR-T, CAR-NK and HSPC engineering. We further consider how inefficient extrahepatic delivery, limited endosomal escape, context-dependent reactogenicity, repeat-dosing constraints and the manufacturing complexity of individualized products continue to limit broader clinical translation. Emerging strategies, including artificial-intelligence-guided RNA and lipid design, self-amplifying RNA, circular RNA and next-generation thermostable formulations, may help address these application limitations in the fields of hematology and oncology.
    Keywords:  CAR-NK; Cancer immunotherapy; HSPC; Hematology; In vivo CAR-T; Lipid nanoparticles; Oncology; Targeted delivery; mRNA therapeutics
    DOI:  https://doi.org/10.1186/s13045-026-01857-9
  45. Front Oncol. 2026 ;16 1919105
    Advances in γδ T cell-mediated immune surveillance in cervical cancer.
    Jinlei Wang, Xiujun Xu, Qiang Li.
      Cervical cancer is one of the most common malignancies of the female reproductive system worldwide, and its development is closely associated with persistent infection with high-risk human papillomavirus (HPV). γδ T cells, as key effector cells bridging innate and adaptive immunity, exert unique and complex regulatory functions in tumor immune surveillance. However, the distribution patterns, functional polarization states, and antitumor mechanisms of distinct γδ T-cell subsets within the cervical cancer microenvironment have not yet been systematically elucidated, and the impact of HPV infection on the functional remodeling of γδ T-cell subsets remains controversial. This review summarizes the distribution characteristics and functional polarization states of the major γδ T-cell subsets, including Vδ1, Vδ2, and Vδ3 T cells, in the cervical cancer microenvironment. We further discuss the molecular mechanisms through which these subsets participate in immune surveillance via T-cell receptor (TCR) signaling, NKG2D-mediated recognition, Fas/FasL signaling, and cytokine secretion, and examine the regulatory effects of HPV infection on γδ T-cell subset remodeling. In addition, recent preclinical advances in γδ T-cell subset-based adoptive immunotherapy and combination strategies involving immune checkpoint blockade in cervical cancer are reviewed. Overall, this review aims to provide a theoretical basis and new perspectives for optimizing immunotherapeutic targets and developing individualized treatment strategies for cervical cancer.
    Keywords:  HPV; adoptive immunotherapy; cervical cancer; immune surveillance; immunotherapy; γδ T cells
    DOI:  https://doi.org/10.3389/fonc.2026.1919105
  46. Crit Rev Oncol Hematol. 2026 Oct 10. pii: S1040-8428(26)00530-5. [Epub ahead of print]228 105643
    Stromal-myeloid-lymphoid crosstalk in immune evasion and immunotherapy resistance in solid tumors.
    Badar Raza, Muhammad Usama, Qingshuang Cai, Zeenia Iqbal, Shanming Ji.
      Despite the remarkable advances in cancer immunotherapy, immune evasion, relapse, and immunotherapy resistance remain major challenges in the fight against solid tumors. These limitations cannot be fully attributed to tumor-intrinsic changes; the interplay between stromal, myeloid, and lymphoid (SML) compartments in the tumor microenvironment (TME) strongly influences tumor response. This review summarizes the current understanding of SML crosstalk and how multicellular interactions control immune exclusion, suppression and immunotherapy resistance. We provide a narrative overview of the recent literature to discuss the spatial organization and functional states of stromal, myeloid, and lymphoid populations and the mechanisms involving chemokine-mediated trafficking, cytokine signaling, extracellular matrix remodeling, antigen presentation defects, metabolic competition, hypoxia, and immune checkpoint pathways. The evidence suggests that SML crosstalk creates interconnected regulatory circuits in which stromal remodeling fosters myeloid suppression and lymphoid dysfunction, which in turn increases tumor resistance to therapy. These networks are involved in primary and acquired resistance to immune checkpoint blockade and resistance to adoptive cell therapy, cancer vaccines and oncolytic virus therapy. Still, the evidence is limited by significant tumor heterogeneity, reliance on preclinical studies, and insufficient spatial and longitudinal validation as well as by the lack of standardization of biomarkers predictive of treatment outcomes. Future studies should focus on spatial multi-omics, functional experimental models and prospective clinical studies to delineate causal SML interactions and develop clinically relevant biomarkers. A more comprehensive understanding of SML ecosystem dynamics could provide a basis for more accurate patient stratification and appropriate combination therapies in cancer immunotherapy.
    Keywords:  Immune evasion; Immunotherapy resistance; Spatial multi-omics integration; Stromal-myeloid-lymphoid crosstalk; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105643
  47. Blood. 2026 Oct 15. 148(16): 2085
    Cilta-cel CAR T-cell expansion and neurotoxicity.
      
    DOI:  https://doi.org/10.1182/blood.2026036298
  48. Mol Biol Rep. 2026 Oct 16. pii: 1742. [Epub ahead of print]53(1):
    Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions.
    Gülfem Erbil, Damla Aykora, Metehan Uzun.
      Neurodegenerative diseases remain largely untreatable at the disease-modifying level, with currently approved therapies providing primarily symptomatic benefits. Small interfering RNA (siRNA) has emerged as a promising therapeutic modality because of its ability to selectively silence disease-associated genes. However, a major obstacle to clinical translation is not the gene-silencing mechanism itself, but the efficient delivery of therapeutic siRNAs to target cells within the central nervous system.This review examines the barriers that limit siRNA-based therapies for neurodegenerative diseases. We adopt a barrier-oriented framework that follows the sequential challenges encountered during siRNA delivery, including extracellular instability, unfavorable pharmacokinetics, immune recognition, limited transport across the blood-brain barrier, inefficient cellular internalization, and endosomal entrapment. Rather than cataloguing available delivery systems, we evaluate how nanocarrier engineering strategies have been developed to address these barriers and assess their impact on delivery. Evidence from Alzheimer's disease, Parkinson's disease, and Huntington's disease is synthesized to distinguish shared limitations from disease-specific challenges and to evaluate the translational performance of lipid-based nanoparticles, polymeric nanocarriers, engineered exosomes, and hybrid platforms.Available evidence indicates that delivery platforms can improve specific aspects of siRNA transport but have not consistently overcome the sequential biological barriers required for therapy. Although nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking, and gene-silencing efficiency in preclinical models, manufacturing scalability, biological heterogeneity, long-term safety, reproducibility, and regulatory feasibility remain important barriers to clinical translation. Future progress will likely depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release, and scalable manufacturing within clinical platforms.
    Keywords:  Blood-Brain Barrier; Drug Delivery Systems; Exosomes; Nanotechnology; Neurodegenerative Diseases; Small Interfering RNA
    DOI:  https://doi.org/10.1007/s11033-026-12937-x
  49. Sci Immunol. 2026 Oct 16. 11(124): eaec9553
    Glycome remodeling programs pathogenic γδ T17 cell responses in autoimmunity.
    Beatriz Santos-Pereira, Rafaela Nogueira, Yohannes Tafesse, Ariana Correia-Silva, Eduarda Leite-Gomes, Guillem Sanchez Sanchez, Xavier Luppens, Lyndsay E A Young, Bruno Cavadas, Carlos Vasconcelos, Daniela Oliveira, Ana Lé, Joana Torres, Ana Campar, João F Serodio, António Marinho, José D Alves, Tiago Torres, Richard R Drake, David Vermijlen, Inês Alves, Salomé S Pinho.
      Glycans play fundamental roles in T cell biology; however, the glycome landscape of γδ T cells remains to be unlocked. Despite the growing importance of γδ T cells in host defense, tissue homeostasis, and diseases, the glycosylation mechanisms guiding their activation, commitment, and function remain poorly defined. By performing single-cell RNA sequencing, we revealed that type 3/γδ T17/interleukin-17A (IL-17A)-committed γδ T cells rely on (N-acetylglucosaminyltransferase 1) MGAT1-MGAT5-mediated branched N-glycosylation. We further demonstrated that the absence of branched N-glycans on γδ T cells acts as a peripheral signal, driving an IL-17A-pro-inflammatory phenotype, alongside a shift to a Vγ4+ subset and the imprinting of innate-like properties. This altered glycoform of type 3 γδ T cells was shown to induce severe psoriasis. γδ T cells from patients with autoimmune and inflammatory diseases exhibited a deficiency in branched N-glycans. Glycan supplementation can reprogram γδ T cells toward a less-pathogenic state, highlighting N-glycans as a previously unrecognized immune checkpoint for γδ T cells.
    DOI:  https://doi.org/10.1126/sciimmunol.aec9553
  50. J Nurs Manag. 2026 ;2026(1): e3645510
    Remote Patient Monitoring in Hospital at Home: Bibliometric Analysis of the Field and Scoping Review of Nursing Practice.
    Tian Liu, Ying Hua, Kejun Sun, Jingjing Shi, Pan Li.
       AIM: To map the research landscape of remote patient monitoring-enabled hospital at home (RPM-HaH) and delineate the core domains of nursing practice within this care model.
    BACKGROUND: RPM-HaH has emerged as a key strategy to alleviate hospital capacity pressures driven by population ageing and rising multimorbidity. Despite its clinical viability, the structural positioning and substantive practice of nursing within this model remain poorly defined.
    METHODS: A two-stage integrative design was employed. Stage one involved a bibliometric analysis of literature indexed in Web of Science, Scopus, PubMed and CINAHL (January 2015-October 2025) to examine publication trends, collaboration networks, journal distributions and keyword co-occurrences. Stage two conducted a scoping review guided by the PRISMA-ScR and SALSA frameworks within this literature body, utilizing thematic synthesis to identify core nursing practice domains.
    RESULTS: Across 389 included publications, research output accelerated post-2019, predominantly led by the United States and the United Kingdom. While keyword analysis suggested that nursing-related terms were underrepresented in the RPM-HaH literature, the scoping review identified four core cognitive domains of nursing practice: (1) clinical risk recognition and assessment, (2) data interpretation and meaning-making, (3) prioritization and resource coordination and (4) patient empowerment and safety accountability.
    CONCLUSIONS: Bibliometric findings indicate that nursing remains underrepresented despite its operational centrality, likely reflecting research indexing conventions rather than a lack of substantive value. The scoping review also identifies coherent cognitive practice domains that clarify nursing's substantive contributions. These findings collectively demonstrate a structural-substantive mismatch, emphasizing the need for explicitly defined roles, integrated service delivery and theoretically grounded frameworks to inform clinical decision-making in digitally enabled care.
    IMPLICATIONS FOR NURSING MANAGEMENT: Nurse leaders should align competency frameworks with these four cognitive domains while advocating for formal recognition of nursing roles in regulatory standards and quality metrics. Continuing education programmes must expand beyond technical device operation to foster remote clinical reasoning and interprofessional coordination.
    Keywords:  bibliometric analysis; digital health; hospital at home; nursing practice; remote patient monitoring; scoping review
    DOI:  https://doi.org/10.1155/jonm/3645510
  51. Cancer Res. 2026 Oct 15.
    Antiviral T cells doing double-duty to fight cancer.
    Nicole H Hirsh, Joshua D Brody.
      The exquisite antigen specificity of T cells is one foundation of modern cancer immunotherapy. The therapeutic efficacy of checkpoint blockade, cancer vaccines, and engineered T-cell therapies, all appear to depend on T cells capable of recognizing specific antigens displayed by tumor cells. In a recent issue of Nature Immunology, Smith and colleagues challenge this paradigm by demonstrating that local activation of virus-specific memory T cells can eliminate tumors without direct tumor-cell recognition. Instead, activated T cells initiate a multicellular inflammatory response involving IFNγ, TNF, nitric oxide and recruited myeloid cells that collectively induce tumor-cell death. These findings separate the antigen specificity required for T-cell activation from that required for tumor killing and expand the role of T cells from direct cytotoxic effectors to organizers of a broader antitumor response. Together, these findings broaden the potential scope of T-cell-mediated antitumor immunity beyond the constraints of direct tumor-antigen recognition.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-4373
  52. Ann Hematol. 2026 Aug 08. pii: 456. [Epub ahead of print]105(11):
    BCMA CAR T-cell therapy in a patient with heavily pretreated relapsed/refractory POEMS Syndrome: a case report.
    Hongxiao Han, Danqing Zhao, Anan Li, Kaini Shen, Lu Zhang, Jian Li.
      B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T-cell) therapy is an established treatment for relapsed/refractory multiple myeloma. However, its application in POEMS syndrome remains largely unreported, despite overlapping pathogenesis involving plasma cell dyscrasia. Herein, we present a woman in her 30s with heavily pretreated relapsed/refractory POEMS syndrome who received equecabtagene autoleucel, a fully human anti-BCMA CAR T-cell product. The patient achieved a complete vascular endothelial growth factor (VEGF) response by day 14 post-infusion, with sustained remission through 12 months of follow-up. Clinical improvements included resolution of heart failure, pulmonary hypertension, and renal dysfunction, along with marked neurological recovery, enabling the patient to return to normal daily activities and occupational functioning, a status that persisted through the 16-month follow-up. Treatment-related toxicities comprised Grade 2 cytokine release syndrome and persistent hypogammaglobulinemia, without severe infectious complications. No delayed neurotoxicity or secondary malignancies were observed. This case provides evidence that BCMA CAR T-cell therapy is a safe and efficacious option for patients with relapsed/refractory POEMS syndrome.
    Keywords:  BCMA CAR T-cell Therapy; Equecabtagene autoleucel; Hypogammaglobulinemia; ICATH; Relapsed/refractory POEMS syndrome
    DOI:  https://doi.org/10.1007/s00277-026-07224-5
  53. Stat Med. 2026 Oct;45(23-24): e70758
    Using Joint Models in Phase I Dose-Finding Designs in Oncology: Considerations for Frequentist Approaches.
    Xijin Chen, Pavel Mozgunov, Richard D Baird, Thomas Jaki.
      Dose-finding trials for oncology studies are traditionally designed to assess safety in the early stages of drug development. With the rise of molecularly targeted therapies and immuno-oncology compounds, biomarker-driven approaches are increasingly importance. In this article, we propose a novel approach to dose-finding that incorporates biomarkers which predict for the subsequent development of clinical toxicity. The proposed joint model framework, which incorporates repeated biomarker measurements, is compared to the likelihood-based continual reassessment method (CRM) using only binary toxicity data, across various dose-toxicity relationship scenarios. Our findings highlight a critical limitation of likelihood-based approaches in early-phase dose-finding studies with small sample sizes: estimation challenges that have been previously overlooked in the phase I dose-escalation setting. We explore potential remedies to address these challenges and emphasize the appropriate use of likelihood-based methods. Simulation results demonstrate that the proposed joint model framework, by integrating biomarker information, can alleviate estimation problems in the likelihood-based CRM and improve the proportion of correct selection. However, we highlight that the inherent data limitations in early phase dose-finding studies remain a significant challenge that cannot be fully overcome in the frequentist framework.
    Keywords:  CRM likelihood; biomarker information; existence of MLE; factorization; mixed outcomes; separation condition
    DOI:  https://doi.org/10.1002/sim.70758
  54. Cureus. 2026 Sep;18(9): e116199
    Comprehensive Molecular Profiling for Precision Diagnostics: Integrating Genomic, Proteomic, and Epigenetic Landscapes in Human Pathology.
    Anandraj Vaithy K, Apoorv Shukla, Ajay Bhengra, Rakesh Venuturumilli, Falak Aara, Jigar Gusani.
      Comprehensive molecular characterization may enhance diagnostic assessment in complex human diseases by capturing biological heterogeneity beyond conventional single-layer approaches. This review examines the integration of genomic, proteomic, and epigenetic profiling for precision diagnostics and clinical interpretation. Major advances include comprehensive genomic characterization, high-throughput proteomic profiling, clinically informative epigenetic biomarkers, machine-learning-assisted data integration, and single-cell and spatial multiomics for resolving cellular and tissue-level heterogeneity. Evidence across diverse disease models indicates that integrated molecular data may enhance biomarker identification and provide additional information for disease classification, prognostic assessment, and prediction of therapeutic response; however, comparative measures of diagnostic performance are not consistently available. Proteomic and epigenetic information provides functional and regulatory context to genomic alterations, enabling a more complete representation of disease mechanisms. Current barriers include heterogeneous data formats, batch effects, missing data, limited standardization, high computational and financial requirements, privacy and regulatory concerns, and insufficient clinical validation. Future priorities should focus on harmonized analytical standards, reproducible pipelines, scalable computational infrastructure, improved model interpretability, robust clinical validation, and stronger interdisciplinary collaboration across oncology, rare genetic disorders, neurodegenerative disease, and other clinically heterogeneous conditions in routine practice. Integrative molecular profiling therefore represents a major direction for next-generation diagnostics, with its potential clinical value depending on analytical validation, clinical validity and utility, reproducible implementation, and prospective comparison with established diagnostic pathways.
    Keywords:  biomarkers; epigenomics; genomics; multiomics; proteomics
    DOI:  https://doi.org/10.7759/cureus.116199
  55. Eur J Dent Educ. 2026 Oct 10.
    AI-Driven Feedback on Bitewing Radiographic Technique: A Comparative Study of Large Language Models.
    Katharina Alves Rabelo, Laura Swinckles, Eduardo Delamare, Zhuoran Duan, Elvis Trinh, Yongpei Ma, Jinman Kim, Vesna Miletic.
       INTRODUCTION: Large language models (LLMs) can enhance learning engagement and accessibility, though their performance in dentistry is inconsistent. Bitewing radiographs are critical for caries detection but prone to diagnostic errors from operator positioning. This study compared the performance of four LLMs with reasoning capabilities, GPT o1, GPT o3-mini, Gemini 2.0 Flash and Grok 3, in generating scenario-specific educational feedback from a structured textual format of bitewing radiographs.
    MATERIALS AND METHODS: Ten positioning error scenarios were created by DMFR specialists. LLMs were evaluated using an original prompt (OP) and an engineered prompt (EP), resulting in a 4 × 2 LLM-by-prompt design. Each LLM was tested via its model-specific access mode: API or web interface. Eighty outputs were assessed by two DMFR specialists for detail, content, clarity and relevance using a 5-point Likert scale. Ordinal category-level scores were analysed using a cumulative link mixed-effects model, with LLM, prompt type, scenario group, assessment category and LLM × prompt as fixed effects, and scenario as a random intercept.
    RESULTS: The LLM-prompt interaction was significant, indicating prompt engineering affected models differently. GPT o3-mini had significantly lower odds of higher scores than Gemini 2.0 Flash, while EP reduced Grok 3 performance. Positioning error type influenced performance, with significant model-dependent differences across scenario groups. No significant LLM-assessment category interaction was observed, suggesting model differences did not vary across assessment categories.
    CONCLUSION: LLM-generated feedback varied by model, prompt design and positioning error type, but not consistently across assessment categories. Outputs require validation, model-specific prompt testing and specialist review before implementation.
    Keywords:  artificial intelligence; bitewings; chatbots; dental education; dental radiology; large language models
    DOI:  https://doi.org/10.1111/eje.70325
  56. Lancet Reg Health Eur. 2026 Dec;71 101876
    Empowering regulatory science for medical devices in Europe.
    Alan G Fraser, Robert A Byrne, Elisabeth M C Dequeker, Per Kjærsgaard-Andersen, Sanja Kolaček, Tom Melvin, Rob G H H Nelissen, Piotr Szymański, Elizabeth Macintyre.
      From clinical and ethical perspectives, the need for scientific evidence establishing safety and efficacy of high-risk therapeutic medical devices, and for transparency of that evidence, is similar to new drugs-but requirements for devices and drugs have developed quite differently. The first European system for evaluating new devices applied a framework that had been developed for industrial products. Despite reforms the same flawed structure persists, as a fundamental obstacle to the uniform application of clinical standards, adherence to the principles of open science, and flexibility to respond to innovations. In this Viewpoint, we summarise how the regulatory system evolved and review how it needs to change, for the assessment and approval both of implantable devices and of laboratory diagnostic tests. There are too few clinically-qualified regulators within the EU governing institutions, so substantial investment is needed to boost scientific expertise within a central coordinating unit. Clinicians and scientists must support these changes by developing shared principles with regulators. Some colleagues within each medical speciality should develop expertise in 'regulatory science'.
    Keywords:  European union; Expert panels; Medical device regulations; Regulatory science
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101876
  57. Front Immunol. 2026 ;17 1939256
    Trained immunity in cancer immunotherapy and vaccine development: mechanisms, evidence gaps, and translational opportunities.
    Lian Yang, Jianfeng Liu, Shufei Zhang, Yong He, Jiaxu Chen, Donghui Tan.
      Breakthroughs in cancer immunotherapy have been overwhelmingly driven by advances in adaptive immunity, leaving the therapeutic potential of innate immunity largely untapped, a gap in the current treatment paradigm. Trained immunity, defined by the durable, mitotically maintained metabolic and epigenetic memory that innate immune cells acquire after transient stimulation, offers a new approach to addressing this deficit. Here we survey the triggering signals, cellular heterogeneity, and molecular circuitry that govern trained immunity within the tumor microenvironment. We dissect its dualistic character: the mechanistic basis by which trained immunity can either restrain or promote tumor progression, and what this ambivalence means for the design of next-generation immunotherapies. These insights inform a growing pipeline of trained-immunity-based cancer vaccines, which we categorize into four engineered platforms, recombinant BCG, β-glucan nanoformulations, lipid nanoparticle (LNP)-mRNA bifunctional vaccines, and commensal-derived adjuvants. We further propose that vaccine efficacy may depend in part on host immune context, and outline stratification strategies and dosing schedules that may need to be adjusted according to individual immune status, pending clinical validation. In aggregate, evidence from human bladder cancer, preclinical tumor models, and non-tumor trained immunity studies suggests that trained immunity could elevate innate immunity from a supporting role toward an independent therapeutic axis, although most of its direct cancer applications remain at the preclinical or conceptual stage.
    Keywords:  cancer immunotherapy; cancer vaccine; innate immunity; metabolic reprogramming; trained immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1939256
  58. Int J Mol Sci. 2026 Sep 24. pii: 8511. [Epub ahead of print]27(19):
    Special Issue "Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies, 3rd Edition".
    Bernhard Biersack.
      In recent years, there has been some impressive progress made in cancer research in terms of sophisticated new small-molecule drugs, particularly targeted drugs, and of immune, cell, and gene therapies, which have saved and prolonged the lives of many cancer patients [...].
    DOI:  https://doi.org/10.3390/ijms27198511
  59. Cancer Cell. 2026 Oct 12. pii: S1535-6108(26)00397-1. [Epub ahead of print]44(10): 1916-1917
    Microbial cues for a stem-like lymphoid niche.
    Ming Kuang.
      While tertiary lymphoid structures (TLSs) broadly correlate with immunotherapy efficacy, their functional heterogeneity can translate into divergent clinical outcomes. In this issue of Cancer Cell, Hu et al. uncover a microbiota-orchestrated stem-like lymphoid niche in which CD70+ ILC2s sustain progenitor exhausted T cells, and their findings redefine the functional organization underlying TLS-associated antitumor immunity.
    DOI:  https://doi.org/10.1016/j.ccell.2026.08.020
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