bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–10–11
53 papers selected by
Luca Bolliger, lxBio
  1. Microbiota-derived metabolic priming of CAR-T cell fitness: a translational framework for next-generation cell therapy.
  2. Updates in CAR-T and TCR-T therapy for solid tumors from the 2026 ASCO Annual Meeting.
  3. Automating chimeric antigen receptor T-cell manufacturing across distinct platforms delivers similar cell quality, phenotype and function.
  4. When too late is too late: timing of CAR T-cell therapy in SLE & lupus nephritis.
  5. Antigen-experienced NK-T cells: integrating new insights and exploring therapeutic potential in cancer immunotherapy.
  6. Precision targeting and alternative effector cells: Revolutionizing CAR-based therapy for T-cell malignancies.
  7. In vivo CAR-T cell generation: a production-rate framework linking vector and cellular pharmacology.
  8. Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies.
  9. Next-generation immune cell engagers for B cell depletion in autoimmune diseases.
  10. Targeted delivery platforms for in vivo immune cell engineering: emerging strategies for cancer immunotherapy.
  11. Engineering CAR-T cell therapies for digestive tract cancer: advances, challenges, and strategies to overcome tumor heterogeneity and immunosuppressive barriers.
  12. BCMA-Targeted Immunotherapy in Early Relapsed/Refractory Multiple Myeloma: Mechanisms, Clinical Evidence, and Practical Management.
  13. Chimeric antigen receptor-macrophages: A new paradigm for cell therapy.
  14. γδ T Cells in Cancer Immunotherapy, 2000-2025: A Bibliometric Analysis and Clinical-Trial Evidence Map.
  15. Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet.
  16. The safety and efficacy of chimeric antigen receptor-T cell therapy in solid malignancies: a systematic review and meta-analysis.
  17. Rationale and Design of the CARdio-Tox Study: A Prospective Evaluation of Cardiovascular Toxicity in Patients Receiving Chimeric Antigen Receptor-T (CAR-T) Cell Therapy.
  18. Bridging the gap in cell and gene therapy: addressing operational and financial barriers to achieve sustainable access.
  19. Integrated T-cell enrichment, static transduction, and expansion in gas-permeable bioreactors for adoptive cell therapy.
  20. KPNA2-Mediated MYC Nuclear Import Enhances CAR-T Cell Memory and Potentiates Antitumor Efficacy.
  21. From specialized centers to community care: expanding the reach of CAR T-cell therapy.
  22. [The risk and management strategies for second primary tumor after CAR-T cell therapy].
  23. Acute myelopathy following chimeric antigen receptor (CAR) T cell therapy: an unusual diagnostic challenge.
  24. EXPRESS: Immune Effector Cell-Associated Neurotoxicity Syndrome in Hematological Malignancy Patients Treated with CAR-T Cell: A Systematic Review.
  25. A regulatory gap: addressing visible particle control in cell and gene therapies through a risk-based framework.
  26. Methodological Challenges and Preferred Approaches for the Economic Evaluation of CAR T Therapies: Evidence Review and Expert Consensus from NICE Appraisals.
  27. Clonal hematopoiesis of indeterminate potential and cancer immunotherapy: a host-intrinsic immune-inflammatory modifier of treatment efficacy and toxicity.
  28. CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy.
  29. CAR T‑Cell Therapy as a Bridging Strategy to Second Transplant in Relapsed B‑Cell ALL.
  30. Human T cell engineering via serial delivery of mRNA encapsulated within lipid nanoparticles.
  31. The European cancer landscape: A focused review of epidemiology, prevention, inequalities and innovation.
  32. Artificial intelligence for precision gene therapy: emerging technologies, clinical applications, and future directions.
  33. The Price of a Cure: Luxturna and the Economic Dilemmas of Precision Medicine.
  34. Five decades of gene therapy innovation and regulation in the US and EU: a historical analysis.
  35. Therapeutic engineering of the IL-18-IL-18BP axis for precision cancer immunotherapy.
  36. Entering the Age of Specificity in T Cell Immunity.
  37. Affinity and costimulatory architecture-associated toxicity in mesothelin-targeted TCR-mimetic CAR-T cells.
  38. Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors.
  39. Mapping the Alignment Between the Portuguese Pharmacotherapeutic Assessment Methodology and EU Joint Clinical Assessment Guidance.
  40. Decentralized CAR T-Cell Manufacturing in Southeast Asia: A Hub-and-Spoke Model for Therapeutic Equity.
  41. T cell immunomonitoring: a comparative analysis of traditional and novel methods to quantify and characterize human antigen-specific T cells.
  42. BOIN12-PFS: A Bayesian Optimal Interval Phase I/II Design Incorporating Progression-Free Survival Endpoint.
  43. Nurse Practitioner-Led Antibiotic Stewardship for Febrile Chimeric Antigen Receptor T-Cell Recipients.
  44. Organelle-Targeted Nanocarriers for Cancer Therapy: Design Principles, Intracellular Trafficking, and Translational Barriers in Precision Drug Delivery.
  45. Automated Production of Gene-Edited CAR-T Cells for People Living with HIV.
  46. CAR T cells for autoimmune diseases: 2026 update of the EBMT-ISCT-JACIE practice harmonisation and consensus recommendations.
  47. Targeting innate immunity in cancer: mechanistic foundations, therapeutic vaccination, and clinical translation.
  48. Priorities and Implementation Barriers in End-to-End Digital Transformation in the Pharmaceutical Industry: Sequential Mixed Methods Analysis.
  49. Blockchain for Digital Health Governance: Evidence Gap Map and Scoping Review.
  50. Unsupervised identification of low-frequency antigen-specific TCRs using distance-based anomaly scoring.
  51. Recent advances in Tumor microenvironment-responsive pro-antibody to overcome on-target, off-Tumor toxicity.
  52. Methods in Systematic Reviews of Health Economic Evaluations in Submissions to Health Technology Assessment Agencies: How Systematic Are They, and Does This Matter?
  53. Efficient Privacy-Preserving Medical Cross-Silo Federated Learning.
  1. Front Immunol. 2026 ;17 1953443
    Microbiota-derived metabolic priming of CAR-T cell fitness: a translational framework for next-generation cell therapy.
    Simone Melchiorri, Ignazio Castagliuolo.
      Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet durable responses remain inconsistent and clinically significant toxicities persist. Emerging evidence identifies the gut microbiota as an extratumoral determinant of CAR-T efficacy, persistence, and toxicity. However, taxonomic signatures associated with clinical outcomes show limited reproducibility and are influenced by antibiotics, geography, diet, and methodological heterogeneity. Building on prior reviews addressing microbiome-CAR-T associations and CAR-T-cell immunometabolism separately, here we synthesize clinical, translational, and preclinical evidence into an integrated, metabolome-centered framework spanning the full CAR-T treatment and manufacturing trajectory. Broad-spectrum antibiotic exposure disrupts microbial metabolic output, depleting short-chain fatty acids, indole derivatives, and other bioactive metabolites, and has been associated with inferior clinical outcomes in several cohorts, although these associations are heterogeneous and may be confounded by baseline disease severity, systemic inflammation, and infection-related factors. Experimental studies further indicate that butyrate, valerate, inosine, indoles, and succinate modulate mitochondrial fitness, memory differentiation, epigenetic programming, cytotoxicity, and exhaustion through interconnected metabolic and receptor-mediated pathways. We propose that the gut microbiota acts as a distributed metabolic organ whose collective output shapes CAR-T-cell fitness and therapeutic response. This framework supports the development of metabolite-based biomarkers and therapeutic strategies, including microbiota-conscious antibiotic stewardship, ecosystem restoration, dietary or metabolite-based interventions, and ex vivo metabolic conditioning during CAR-T manufacturing. Shifting from descriptive microbiome profiling to functional metabolomics may improve both prediction and optimization of CAR-T therapy.
    Keywords:  CAR-T cell therapy; gut microbiota; immunometabolism; microbial metabolomics; microbiota-derived metabolites; short-chain fatty acids
    DOI:  https://doi.org/10.3389/fimmu.2026.1953443
  2. J Hematol Oncol. 2026 Oct 07. pii: 82. [Epub ahead of print]19(1):
    Updates in CAR-T and TCR-T therapy for solid tumors from the 2026 ASCO Annual Meeting.
    Oriol Mirallas, Ecaterina E Dumbrava.
      Adoptive cellular therapies (ACT) have reshaped the treatment landscape of hematologic malignancies and are increasingly being explored in solid tumors. Key approaches include chimeric antigen receptor T-cell (CAR-T) therapy, which targets tumor-associated surface antigens in an HLA-independent manner, and T-cell receptor-engineered T-cell (TCR-T) therapy, which enables recognition of intracellular tumor antigens presented by major histocompatibility complex molecules. However, the application of CAR-T and TCR-T in solid tumors remains limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, manufacturing complexity, and safety concerns related to on-target/off-tumor effects and cytokine-mediated toxicities. The American Society for Clinical Oncology (ASCO) Annual Meeting is a key platform for the presentation of cutting-edge clinical data, and in this brief correspondence, we summarize the principal early-phase clinical trials with CAR-T and TCR-T for solid tumors reported at the 2026 meeting.
    Keywords:  ASCO; Adoptive cellular therapies (ACT); Chimeric antigen receptor T-cell (CAR-T); Clinical trials; T-cell receptor–engineered T-cell (TCR-T)
    DOI:  https://doi.org/10.1186/s13045-026-01852-0
  3. Cytotherapy. 2026 Aug 05. pii: S1465-3249(26)00939-4. [Epub ahead of print]28(12): 102978
    Automating chimeric antigen receptor T-cell manufacturing across distinct platforms delivers similar cell quality, phenotype and function.
    Eu Han Lee, Meredith Safford, Terri Staab, Min Sung Park, Mack Ryan, Despina Pleitez, Alex Sargent.
       BACKGROUND AIMS: Manufacturing chimeric antigen receptor (CAR) T cell therapies is complex and costly, and automation holds tremendous promise to improve access to these life-saving treatments.
    METHODS: Here, we compared two end-to-end automated CAR T-cell manufacturing platforms, the CliniMACS Prodigy and the Sefia system, using identical reagents, stimulation conditions, culture duration, perfusion rate and donor starting material to assess how platform design affects critical product attributes.
    RESULTS: With identical CD4 and CD8 magnetic isolation reagents, both systems produced similar T-cell yields, with exceptionally high purity and comparable phenotype. During culture, total cell yield differed between platforms, reflecting differences in culture volume; however, expansion rate, population doubling time, transduction efficiency and CAR T-cell yield were not significantly different. The resulting CAR T cells also showed comparable phenotype, exhaustion profiles and in vitro tumor-killing activity. These similar outcomes may be explained by shared media perfusion rates and convergent metabolic profiles, because cell-specific glucose consumption and cell-specific lactate production were similar by the end of culture.
    CONCLUSIONS: Collectively, these findings show that distinct automated platforms can generate CAR T-cell products with remarkably similar quality and function when process conditions are aligned. More broadly, they highlight the potential of automation and in-line analytics to standardize CAR T cell manufacturing and improve product consistency from cell collection to patient infusion.
    Keywords:  CAR T cell; T cell; automation; cell therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102978
  4. Front Immunol. 2026 ;17 1914091
    When too late is too late: timing of CAR T-cell therapy in SLE & lupus nephritis.
    Saira Sheikh, Shaun Jackson, Vimal Derebail, Natalie Grover, Astia Allenzara.
      CAR T-cell therapy has demonstrated the capacity to induce deep, drug-free remissions in patients with severe, refractory systemic lupus erythematosus (SLE), including those with lupus nephritis (LN). These observations challenge long-standing assumptions about the reversibility of autoimmune disease and raise a critical question: whether CAR T-cell therapy should remain a therapy of last resort or if trials could investigate use earlier in the disease course, when its disease-modifying potential may be greatest. When CAR T-cell therapy is administered late in the disease course, its true biologic effect may therefore be underestimated, and clinical nonresponse may be misattributed to lack of therapeutic activity rather than to persistent damage and fibrosis. CAR T-cell therapy is still experimental and undergoing investigation as a treatment option in autoimmune diseases. Given the potential for a durable disease-free, drug free remission, we propose investigating use of CAR T-cell therapy in early severe SLE. We highlight CAR T-cell therapy in SLE and LN with a brief discussion of risks and benefits from the evidence to date. The current positioning as a refractory/salvage therapy late in the treatment algorithm may limit its impact for patients with SLE at high risk of irreversible organ damage.
    Keywords:  cell therapy; chimeric antigen receptor (CAR T); clinical trials; lupus (SLE); lupus nephritis; treatment
    DOI:  https://doi.org/10.3389/fimmu.2026.1914091
  5. Front Immunol. 2026 ;17 1877232
    Antigen-experienced NK-T cells: integrating new insights and exploring therapeutic potential in cancer immunotherapy.
    Shunichiro Kuramitsu, Masasuke Ohno, Mitsugu Fujita.
      Conventional CD8+ T cells can acquire natural killer (NK) cell receptors upon persistent antigen exposure, forming antigen-experienced NK-T (AENK-T) cells. Their dual-state plasticity within the tumor immune microenvironment determines cancer immunotherapy outcomes. This narrative review synthesizes recent transcriptomic, epigenomic, and functional data to define the trajectory, regulation, and therapeutic relevance of AENK-T cells. The analysis establishes a "temporal hierarchy" differentiating AENK-T cells from innate-like T cells: activating NK receptors (NKG2C, NKG2D) emerge early, while inhibitory receptors (NKG2A, killer-cell immunoglobulin-like receptors, KLRB1) accumulate under sustained stimulation. Mechanistically, BCL11B downregulation and the T-bet-Zeb2 axis stabilize a cytotoxic Effector AENK-T state. Conversely, the TOX-LAG-3 loop and SOX4-ID3 axis drive transition into a suppressive Exhausted AENK-T state, mirroring terminal exhaustion. The tumor immune microenvironment accelerates this shift via hypoxia, metabolic competition, and TGF-β, contrasting with chronic infection models. Translating these findings, an evaluation of emerging strategies, such as NKG2A blockade, biomarker-guided patient selection, and next-generation chimeric antigen receptor (CAR)-T cell engineering, suggests that temporally informed approaches targeting the AENK-T trajectory may overcome current immune checkpoint therapy limitations.
    Keywords:  T cell exhaustion; antigen-experienced NK-T (AENK-T) cells; chimeric antigen receptor (CAR)-T cells; immune checkpoint blockade; innate-like T cells; natural killer cell receptors; tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.3389/fimmu.2026.1877232
  6. Clin Exp Immunol. 2026 Oct 06. pii: uxag060. [Epub ahead of print]
    Precision targeting and alternative effector cells: Revolutionizing CAR-based therapy for T-cell malignancies.
    Yingtong Chen, Shuang Gao, Shuozi Liu, Ping Yang, Hongmei Jing.
      T-cell malignancies are highly heterogeneous and associated with high relapse rate and poor prognosis. While chimeric antigen receptor-T (CAR-T) cell therapy has achieved remarkable success in relapsed or refractory B-cell malignancies, its application in T-cell malignancies remains limited. Key challenges include shared surface antigen expression among CAR-T cells, normal T cells, and malignant T cells, leading to fratricide and T-cell aplasia, and the risk of tumor cell contamination during CAR-T manufacturing. This review summarizes recent advances in CAR-based therapies for T-cell malignancies, focusing on clinical translation barriers, emerging solutions, and future directions. We highlight promising target antigens under preclinical and clinical investigation, as well as alternative effector platforms, including natural killer (NK) cells, NKT cells, γδ T cells, and macrophages, that hold potential as next-generation CAR-expressing cellular therapeutics.
    Keywords:  Cell therapy; Chimeric antigen receptor (CAR); Fratricide; T-cell aplasia; T-cell malignancies
    DOI:  https://doi.org/10.1093/cei/uxag060
  7. Front Immunol. 2026 ;17 1939127
    In vivo CAR-T cell generation: a production-rate framework linking vector and cellular pharmacology.
    Jing Hu, Dandan Zhu, Shanliang Zheng.
      In vivo CAR-T cell generation is advancing rapidly within gene and cell therapy, but it is often framed as an "in-body" version of ex vivo CAR-T-a view that obscures fundamental pharmacological differences. We propose that in vivo CAR-T is better understood as a vector-to-cell pharmacological transition, in which vector pharmacology directly shapes cellular pharmacology: vector dose is only the administered input, whereas therapeutic cellular exposure is hypothesized to depend jointly on the rate, duration, and functional quality of CAR-T cells generated within the patient. Three generation-phase constraints - niche competition without lymphodepletion, founding-state lock-in, and antigen-encounter timing mismatch - define this transition and inform platform-indication matching. We develop this as a testable organizing hypothesis rather than a validated pharmacokinetic model, specifying which quantities are observed, which are inferred, and which are derived, together with four falsifiable predictions and the measurements required to evaluate them. "Production rate × functional window" is retained as a mnemonic for the two axes involved - the kinetics and duration of cellular generation, and the functional quality of the cells generated - rather than as an arithmetic product.
    Keywords:  T-cell engineering; cancer immunotherapy; cellular pharmacology; gene delivery; in vivo CAR-T; lipid nanoparticle; production-rate framework; vector pharmacology
    DOI:  https://doi.org/10.3389/fimmu.2026.1939127
  8. Front Mol Biosci. 2026 ;13 1955532
    Therapeutic reprogramming of natural killer cells for solid tumors: expanding frontiers into rare and ultra-rare malignancies.
    Francesca Rosato, James W Hodge.
      Rare and ultra-rare solid tumors collectively account for approximately one-quarter of all cancer diagnoses yet remain associated with poor clinical outcomes. Delayed diagnosis, limited biological characterization, few therapeutic options, and the logistical challenges of conducting adequately powered clinical trials underscore the potential for adaptable cellular immunotherapies that can be applied across diverse tumor histologies. Natural killer (NK) cells have emerged as a promising platform for adoptive cell therapy because of their ability to recognize and eliminate malignant cells independently of major histocompatibility complex restriction, their favorable safety profile, and their suitability for standardized allogeneic, off-the-shelf manufacturing. This review examines the progression of NK cell-based therapies from their biological and therapeutic foundations in solid tumors to their emerging application in rare and ultra-rare malignancies. Recent advances in NK cell engineering are enabling multifunctional cell products designed to enhance tumor recognition, trafficking, persistence, and resistance to the immunosuppressive tumor microenvironment. We also review emerging clinical evidence demonstrating the feasibility and safety of these approaches while highlighting the major biological and translational barriers that continue to limit durable responses. Building on these advances, attention is given to the unique challenges of rare and ultra-rare cancers, where small patient populations, tumor heterogeneity, limited therapeutic targets, and logistical constraints pose unique challenges to conventional drug and cellular therapy development. Finally, we discuss how scalable off-the-shelf manufacturing, rational combination strategies, innovative clinical trial designs, and next-generation technologies, including multiplex gene editing, armored NK cells, and in vivo engineering, may facilitate this translation. Collectively, progress in NK cell therapy across solid tumors provides a framework for extending increasingly adaptable and scalable immunotherapeutic platforms to rare and ultra-rare malignancies, with the potential to expand treatment opportunities for patient populations that have historically had limited therapeutic options.
    Keywords:  adoptive cell therapy; chimeric antigen receptor; clinical trials; immunotherapy; natural killer cells; rare tumors; solid tumors
    DOI:  https://doi.org/10.3389/fmolb.2026.1955532
  9. Nat Rev Drug Discov. 2026 Oct 07.
    Next-generation immune cell engagers for B cell depletion in autoimmune diseases.
    Yakai Fu, Bruno Robert, Samuel Bitoun, Pierre Martineau, Maximilian F Konig, Jerome Avouac, George C Tsokos, Shuang Ye, Marc Scherlinger.
      Immune cell engagers (ICEs) offer a promising approach for achieving deep depletion of pathogenic B cell populations in systemic autoimmune diseases. Their modular design enables the recruitment of T cells, natural killer cells, γδ T cells or myeloid cells to eliminate B cells, plasmablasts and long-lived plasma cells. Use of ICEs in haematological malignancies has established the therapeutic potential of targeting the lineage antigens of B cells and plasma cells, and informed understanding of resistance, treatment-associated toxicity and incomplete target-cell depletion. However, applications in autoimmune diseases present distinct challenges, including disease-specific B cell heterogeneity, pharmacokinetic limitations, effector-cell dysfunction and the risk of cytokine release syndrome. Despite these challenges, early clinical reports using CD19-directed and B cell maturation antigen-directed T cell engagers have shown sustained improvements in several systemic autoimmune diseases. In this Review, we discuss the principles guiding ICE development for autoimmune diseases, including target selection, engager architecture, effector-cell recruitment and safety. We also consider emerging strategies, including CD8-biased T cell engagement, co-stimulatory multispecific formats, and natural killer or γδ T cell recruitment, to improve safety and durability of response. ICEs could ultimately provide an off-the-shelf alternative to chimeric antigen receptor T cell therapies, enabling sustained immune reprogramming in patients with refractory autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41573-026-01534-z
  10. Front Pharmacol. 2026 ;17 1936688
    Targeted delivery platforms for in vivo immune cell engineering: emerging strategies for cancer immunotherapy.
    Hari Krishnareddy Rachamala, Sandeep Atla, Ramcharan Singh Angom.
      Cancer immunotherapy is a transformative technology allowing for the elimination of malignant cells through immune system stimulation; however, the large-scale clinical application of adoptive cellular therapy technologies is limited due to difficulties in ex vivo immune cell engineering, high costs, and complicated manufacturing process. Recently, in vivo immune cell engineering was discovered as an emerging approach that allows for the genetic reprogramming of immune cells in patients, thus circumventing many problems inherent to traditional cellular therapy technologies. Breakthroughs in targeted drug delivery systems such as cell-penetrating peptides, antibody- and receptor-mediated delivery approaches, lipid nanoparticles (LNPs), polymeric drug carriers, and biomimetic delivery systems allow for the more effective selective delivery of messenger RNA (mRNA), clustered regularly interspaced short palindromic repeats (CRISPR)/Cas gene editing systems, proteins, and other types of cargo to the target immune cells. In vivo immune cell engineering allows for the efficient generation of chimeric antigen receptor T-cells (CAR-T), CAR- natural killer (NK) cells, engineered macrophages, dendritic cells, and other immune cell types; moreover, transient and permanent immune reprogramming is achievable via vivo technologies. The present review discusses the biological barriers limiting immune cell-targeted delivery, including biodistribution, cellular uptake, intracellular transport, and endosomal escape of delivered drugs, and reviews the latest advancements in targeted delivery technologies addressing these obstacles. We also address the latest applications of in vivo immune cell engineering in hematological malignancies and solid tumors, including mRNA therapeutics, CRISPR-based genome editing, and advanced programmable immunotherapy technologies. Furthermore, we discuss unresolved issues related to the specificity of targeting, efficiency of drug delivery, safety of treatment, manufacturing processes, and regulation of in vivo immune engineering technologies and outline future opportunities arising from the integration of nanomedicine, synthetic biology, genome engineering, and artificial intelligence-assisted materials science.
    Keywords:  In vivo immune cell engineering; cancer immunotherapy; chimeric antigen receptor (CAR) therapy; lipid nanoparticles; mRNA therapeutics; targeted delivery
    DOI:  https://doi.org/10.3389/fphar.2026.1936688
  11. Neoplasia. 2026 Oct 08. pii: S1476-5586(26)00107-7. [Epub ahead of print]82 101375
    Engineering CAR-T cell therapies for digestive tract cancer: advances, challenges, and strategies to overcome tumor heterogeneity and immunosuppressive barriers.
    Qiaoyan Qu, Jintan Xiao, Bingjian Zhao, Peng Gu.
      CAR-T therapy yields remarkable clinical efficacy against hematological malignancies, yet its translation to solid tumors, particularly gastrointestinal cancers, is impeded by multiple bottlenecks including antigen heterogeneity, immunosuppressive tumor microenvironments and metabolic inhibition. This review systematically summarizes coping strategies for these barriers. Claudin-18.2, B7-H3 and c-Met represent attractive therapeutic targets eliciting tumor-specific cytotoxicity in gastric, colorectal and esophageal cancers. Structural modifications such as dual-targeted CARs, cytokine-expressing constructs and logic-gated receptors improve antigen specificity and mitigate off-tumor toxicity. Combination regimens with radiotherapy, immune checkpoint inhibitors and TME-modulating agents synergistically boost CAR-T infiltration, persistence and effector activity. Unresolved hurdles still involve antigen loss, production scalability and inconsistent clinical responses, which may be tackled by γδT-based platforms, synthetic biology and universal CAR designs. Adopting a challenge-solution paradigm, this review integrates cutting-edge clinical data to objectively dissect CAR-T progress in digestive tract malignancies and proposes a systematic optimization roadmap for future translational development.
    Keywords:  Antigen-specific targeting; CAR-T therapy; Combinatorial immunotherapy; Digestive tract cancer; Tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.neo.2026.101375
  12. Eur J Haematol. 2026 Oct 07.
    BCMA-Targeted Immunotherapy in Early Relapsed/Refractory Multiple Myeloma: Mechanisms, Clinical Evidence, and Practical Management.
    Massimo Martino, Erica Bilardi, Martina Pitea, Gaetana Porto, Giorgia Policastro, Giovanna Utano, Laura Giordano, Giulia Santoro, Jessyca Germano, Caterina Alati.
       BACKGROUND: B-cell maturation antigen (BCMA), a plasma cell-restricted member of the tumor necrosis factor receptor superfamily, has emerged as the premier immunotherapeutic target in Multiple Myeloma (MM).
    METHODS: We performed a comprehensive, comparative review of pivotal Phase II and III clinical trials of BCMA-directed therapies, including the antibody-drug conjugate (ADC) belantamab mafodotin (belamaf), bispecific antibodies (BsAbs), and BCMA-directed chimeric antigen receptor T-cell (CAR-T) products, with explicit attention to balanced, platform-by-platform comparison of efficacy, durability, toxicity, and sequencing evidence rather than emphasis on a single agent.
    RESULTS: BCMA-directed therapies deliver unprecedented benefit in early relapse settings. DREAMM-7 established belamaf plus bortezomib-dexamethasone (BVd) as a new reference point, and DREAMM-8 showed benefit for belamaf plus pomalidomide-dexamethasone (BPd), although both regimens achieved comparatively modest MRD-negativity rates (24.7% and pending, respectively) relative to CAR-T and emerging BsAb combinations, and depth of response requires further maturation. MajesTEC-3 showed teclistamab plus daratumumab achieved a 36-month PFS rate of 83.4%, compared with 29.7% for daratumumab-based triplets. CARTITUDE-4 showed ciltacabtagene autoleucel produced a median PFS not reached, compared with 11.8 months with standard of care in lenalidomide-refractory patients with 1-3 prior lines, with MRD-negativity of 60.6%. Sequencing data indicate an asymmetric effect: CAR-T efficacy is substantially compromised by prior BCMA-directed BsAb exposure, whereas BsAbs largely retain meaningful activity after prior BCMA-directed CAR-T.
    CONCLUSIONS: BCMA-directed therapies are rapidly redefining early R/R MM treatment. Optimal sequencing, management of class-specific toxicities-including immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), enterocolitis (IEC-EC), and hematotoxicity (ICAHT), in addition to CRS and ICANS-and inclusion in current guidelines require hematologists to develop competency across ADC, BsAb, and CAR-T platforms. Future directions include advancing BCMA therapies into frontline settings, next-generation and in vivo/allogeneic CAR-T approaches, and exploring novel combination strategies.
    Keywords:  BCMA; CAR T‐cell therapy; antibody‐drug conjugate; belantamab mafodotin; bispecific antibodies; immune effector cell toxicity; multiple myeloma; relapsed/refractory; sequencing
    DOI:  https://doi.org/10.1111/ejh.70328
  13. Bioeng Transl Med. 2026 Sep;11(5): e70157
    Chimeric antigen receptor-macrophages: A new paradigm for cell therapy.
    Heng Wang, Yaling Li, Yiwei Shi, Yun Zhou, Guoping Zheng.
      Chimeric antigen receptor (CAR) technology has propelled CAR-T cells to transformative success in hematologic malignancies, yet translation to solid tumors remains limited, motivating exploration of alternative CAR-engineered immune effectors. Macrophages, sentinels of the innate immune system, are abundantly recruited to solid tumors, making them compelling candidates. Preclinical studies show that CAR-engineered macrophages (CAR-M) exhibit precise tumor homing, potent antigen-directed phagocytosis, and the capacity to remodel immunosuppressive tumor microenvironments (TMEs). Notably, early-phase clinical investigations indicate a favorable safety profile, strengthening confidence in their therapeutic potential against solid cancers. In this review, we synthesize design principles for CAR-M constructs, with a particular focus on emerging engineering strategies for next-generation CAR-M. We further discuss their applications in oncology and emerging non-oncologic indications, and summarize the current clinical trial landscape. We further propose a "4S framework" (specificity, switchability, synergy, and safety) to guide next-generation CAR-M development. Collectively, these advances support CAR-M as a new paradigm for cancer therapy and beyond.
    Keywords:  CAR‐M; chimeric antigen receptor; fibrosis; inflammation; macrophages; solid tumor
    DOI:  https://doi.org/10.1002/btm2.70157
  14. Crit Rev Oncol Hematol. 2026 Oct 06. pii: S1040-8428(26)00523-8. [Epub ahead of print] 105636
    γδ T Cells in Cancer Immunotherapy, 2000-2025: A Bibliometric Analysis and Clinical-Trial Evidence Map.
    Yuheng Wang, Yuanzhi He, Jiayu Xu, Yujia Wang, Hengjie Su, Yarong Zhang, Jiadi Lv, Hui Chen, Jing Wang.
      γδ T cells are promising cancer-immunotherapy effectors because they recognize tumors without major histocompatibility complex (MHC) restriction and carry low graft-versus-host-disease risk in allogeneic settings, yet few bibliometric studies have integrated immunotherapy-specific research trends with clinical-trial mapping and translational-gap analysis. We characterized the global research output, intellectual foundations, emerging frontiers, and clinical translation of γδ T cells in cancer immunotherapy (2000-2025) by combining bibliometric analysis of 3,273 Web of Science publications (bibliometrix, VOSviewer, CiteSpace), a Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR)-guided evidence map of 26 interventional cancer trials (ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform [WHO ICTRP], regional registries), and an integrative step linking bibliometric hotspots to the pipeline. Annual output grew from 18 (2000) to 418 (2024) publications (compound annual growth rate [CAGR], 14.0%) across three phases; China (33.1%) and the United States (27.3%) led production. Co-citation analysis identified five intellectual pillars: phosphoantigen recognition, subset heterogeneity, clinical adoptive transfer, tumor-microenvironment suppression, and engineered γδ T therapy. Chimeric antigen receptor-engineered γδ T cells (CAR-γδ T cells), allogeneic platforms, and single-cell RNA sequencing were the leading 2022-2025 frontier terms. Trials shifted toward allogeneic cell sources; early-phase studies consistently met safety and feasibility endpoints, but monotherapy efficacy was modest. The LAVA-051 and LAVA-1207 programs were discontinued for disclosed business or internal-benchmark reasons, whereas allogeneic CAR-Vδ1 therapy (ADI-001) produced the most encouraging early signals before oncology reprioritization in 2024. Three persistent translational gaps-single-cell/T-cell receptor (TCR) profiling, metabolic reprogramming, and γδT17 biology-frame a proposed roadmap to convert bibliometric hotspots into mechanism-guided γδ T-cell cancer immunotherapy.
    Keywords:  CAR-γδ T cells; bibliometric analysis; cancer immunotherapy; clinical trials; γδ T cells
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105636
  15. Nat Rev Cancer. 2026 Oct 07.
    Boosting CAR T cell efficacy in cancer with metabolic insights from design to diet.
    Jessica Morgan, Sarah MacPherson, Julian J Lum.
      Chimeric antigen receptor (CAR) T cell therapy has advanced the treatment of haematological cancers, but faces challenges achieving durable responses, particularly in solid tumours. Metabolism is a major determinant of CAR T cell fitness, persistence and function. The choice of co-stimulatory domain induces distinct metabolic profiles within the CAR T cell, making it crucial to consider engineering approaches that favour T cell metabolic phenotypes conducive to sustained antitumour activity. Likewise, variations in manufacturing platforms and expansion conditions, including nutrient composition, lead to distinct metabolic and functional profiles, yet the metabolic parameters in manufacturing protocols for clinical studies remain largely unstandardized. Beyond intrinsic cellular engineering, host metabolism exerts a sizeable influence on therapeutic outcome. Diet-based interventions offer a clinically accessible and scalable way to modulate systemic metabolism, which may in turn enhance CAR T cell efficacy. In this Review, we examine how metabolism integrates with CAR design, cell production and host conditioning. We highlight opportunities to leverage diet as a promising, underexplored avenue towards overcoming current barriers in treating solid tumours with CAR T cell therapy. Integrating metabolic and dietary strategies may unlock the potential for durable, effective CAR T cell therapy.
    DOI:  https://doi.org/10.1038/s41568-026-00984-2
  16. Front Immunol. 2026 ;17 1957437
    The safety and efficacy of chimeric antigen receptor-T cell therapy in solid malignancies: a systematic review and meta-analysis.
    Kunpeng Wang, Lian Li, Zhangneng Yu, Dong Li, Jinting Jiang, Zhicheng Guo, Liang Wang, Hua Zhang, Liangliang Xu, Ming Zhang.
       Introduction: Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematologic malignancies, prompting its exploration in solid tumors. This systematic review and meta-analysis aimed to evaluate the safety and feasibility of CAR-T therapy for solid tumor treatment.
    Methods: We systematically searched PubMed, Cochrane Library, Embase, and Web of Science from database inception to June 1, 2026, for clinical studies evaluating CAR-T therapy in solid tumors. Primary outcomes included the incidence of any-grade and grade ≥3 adverse events (AEs); secondary outcomes were the overall response rate (ORR) and disease control rate (DCR). This review adhered to PRISMA guidelines and was registered with PROSPERO (CRD42024549048).
    Results: 52 studies with 712 patients were enrolled in our study. Lymphopenia (70%, grade≥3: 48%) was the most common adverse event. The pooled ORR and DCR were 13% (95%CI: 11-16%) and 63% (95%CI: 59-67%), respectively. Subgroup analysis indicated that the incidence of hematologic toxicity was significantly higher in patients who had received lymphodepletion, and intravenous delivery was associated with a higher risk of several AEs. Patients who had undergone lymphodepletion (LD) achieved higher ORR (p = 0.0002) and DCR (p = 0.0083). In comparison to regional delivery, intravenous infusion was associated with higher ORR (p = 0.0345).
    Conclusion: CAR-T therapy demonstrates an acceptable safety profile for solid tumors. While lymphodepletion and intravenous delivery correlate with higher ORR and DCR, they also increase adverse event risks. Balancing therapeutic benefits and safety concerns therefore remains a critical consideration for clinical practice.
    Keywords:  CAR-T therapy; adverse events; efficacy; immunotherapy; meta-analysis; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2026.1957437
  17. J Cardiovasc Pharmacol. 2026 Oct 07.
    Rationale and Design of the CARdio-Tox Study: A Prospective Evaluation of Cardiovascular Toxicity in Patients Receiving Chimeric Antigen Receptor-T (CAR-T) Cell Therapy.
    Massimiliano Camilli, Michela Ortenzi, Ludovica Leo, Marcello Viscovo, Eugenio Galli, Priscilla Lamendola, Ludovica Amore, Stefan Hohaus, Simona Sica, Filippo Crea, Francesco Burzotta, Giorgio Minotti, Antonella Lombardo.
      Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as an innovative treatment of haematologic malignancies; however, its use is frequently complicated by Cytokine Release Syndrome (CRS), an increasingly recognized driver of cancer therapy-related cardiovascular toxicity (CTR-CVT) able to provoke a wide spectrum of manifestations, from paucysimptomatic and reversible effects to potentially fatal cardiovascular damage. The 2022 European Society of Cardiology (ESC) guidelines on cardio-oncology highlighted the need for systematic cardiovascular assessment in patients receiving CAR-T therapy, yet specific monitoring protocols are lacking at this point in time. The CARdio-Tox study was conceived to address this surveillance gap, testing the hypothesis that acute systemic inflammation, particularly mediated by high levels of interleukin (IL)-1 and IL-6 pathways, might represent the key determinant of early myocardial dysfunction. The primary endpoint of this protocol is to assess the incidence of acute CTR-cardiac dysfunction (CTRCD) occurring within 7 and 30 days after CAR-T cell infusion. Key secondary endpoints include the assessment of the relationship between CTRCD occurrence and CRS diagnosis and grade, as well as the association of inflammatory biomarkers increase with cardiac imaging and/or serum biomarker abnormalities. Data collection will continue over 30 days to assess middle and long-term cardiovascular toxicity. Despite its single-center design, the CARdio-Tox results might provide clinically relevant insights into early cardiovascular effects of CAR-T cell administration, identify key risk factors for CTR-CVT and support more tailored, pathophysiology-driven monitoring strategies in this rapidly evolving field.
    Keywords:  CAR-T cell therapy; cardio-oncology; cardiovascular surveillance; cytokine release syndrome; risk stratification
    DOI:  https://doi.org/10.1097/FJC.0000000000001886
  18. J Comp Eff Res. 2026 Oct 07. e260075
    Bridging the gap in cell and gene therapy: addressing operational and financial barriers to achieve sustainable access.
    Gary L Simmons, Robert E Richards, Ivan M Borrello, Mylove Mortel, Joe DePinto, Elias C Pittos.
      Cell and gene therapies (CGTs) represent a major transformation in modern medicine, offering the potential for cure in patients with serious and treatment-refractory diseases. However, despite this promise, real-world delivery remains highly constrained. This white paper synthesizes insights from a multidisciplinary advisory council of 21 healthcare professionals involved in CGT delivery, together with the authors' collective experience, to examine operational and financial barriers from a provider perspective and to identify strategies to support sustainable expansion of CGT programs across diverse care settings. While clinical management of CGTs has become increasingly standardized, operational and financial barriers continue to impede broader implementation. Product onboarding can often be a complex process, as treatment sites must navigate manufacturer-specific site qualification processes, quality standards, and compliance requirements that can result in significant administrative burden. At the same time, reimbursement processes remain complex and variable across payers, with high upfront costs and inconsistent coverage and reimbursement models that can contribute to institutional financial risk and treatment delays. Drawing on provider experiences and advisory council discussions, this white paper identifies opportunities to improve the sustainability and scalability of CGT delivery. Key priorities include greater standardization of manufacturer onboarding and contracting processes, improved reimbursement predictability, and enhanced alignment among manufacturers, providers, and payers. Addressing these challenges may help reduce administrative burden, mitigate financial risk, and support streamlined implementation of CGTs across both academic and community settings.
    Keywords:  CAR T-cell therapy; cell and gene therapy; financial risk; operational complexity; reimbursement; site onboarding
    DOI:  https://doi.org/10.57264/cer-2026-0075
  19. Cytotherapy. 2026 Jul 29. pii: S1465-3249(26)00931-X. [Epub ahead of print]28(12): 102970
    Integrated T-cell enrichment, static transduction, and expansion in gas-permeable bioreactors for adoptive cell therapy.
    Nikolaos Gkitsas-Long, Aidan J Retherford, Carely Fowler, Dorota D Klysz, Andrew Scheffler, Dan Fick, Janette Mata Alcazar, Annie K Brown, Casey Carr, Michelle Monje, Steven A Feldman, Crystal L Mackall, Ramya H Tunuguntla.
       BACKGROUND AIMS: Broader access to autologous chimeric antigen receptor (CAR) T-cell therapy is limited by costly, device-bound manufacturing workflows and reliance on dedicated instrumentation for discrete unit operations, including T-cell enrichment and culture. These constraints affect academic, decentralized and high-throughput centralized manufacturing programs. We developed a closed-system CAR T-cell manufacturing workflow centered on a gas-permeable G-Rex bioreactor platform that enables direct in-vessel CD4⁺/CD8⁺ T-cell enrichment, static viral transduction and expansion without requiring a separate standalone enrichment device or spinoculation hardware.
    METHODS: Key unit operations of a G-Rex-based GD2 CAR T-cell manufacturing process were optimized, including RetroNectin-mediated static retroviral transduction, coating concentration and timing, and media-exchange strategy. T-cell phenotype and functional potency were characterized longitudinally throughout the 7-day culture period. The optimized workflow was translated to a manufacturing-scale G-Rex 100M-CS process incorporating a newly developed, previously unpublished method for direct in-vessel CD4⁺/CD8⁺ magnetic enrichment using detachable beads and a prototype SepaRex magnetic base. At-scale products from three healthy donors were assessed for enrichment performance, transduction efficiency, expansion, viability, phenotype, cytokine secretion and tumor-cell killing, and benchmarked against historical products manufactured using a clinically validated CliniMACS Prodigy-based GD2 CAR T-cell process.
    RESULTS: Retronectin-coated G-Rex cultures supported efficient static retroviral transduction without spinoculation, and media exchange between 24 and 96 h post-transduction did not significantly affect final yield or viability. Direct in-vessel CD4⁺/CD8⁺ enrichment achieved 61.6 ± 8.6% recovery and 87.2 ± 7.9% purity. At manufacturing scale, the integrated workflow generated GD2 CAR T cells with 62.3 ± 5.1% transduction efficiency, 26.8 ± 4.7-fold expansion, >94% viability and >96% CD3⁺ T-cell purity. Final products retained central memory features, secreted cytokines and mediated cytotoxicity against GD2-expressing tumor targets, with manufacturing performance comparable to the historical Prodigy-based process.
    CONCLUSIONSS: This closed, scalable and cost-conscious G-Rex-based workflow integrates T-cell enrichment, activation, static viral transduction and expansion within a single bioreactor-centered process. By eliminating dedicated enrichment instrumentation and reducing reliance on highly automated, device-bound culture systems, this bioreactor-centered platform may support flexible CAR T-cell manufacturing across academic, decentralized, and high-throughput centralized settings.
    Keywords:  CAR T cells in-vessel enrichment; retronectin; scalable cell therapy manufacturing; static transduction
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102970
  20. Blood. 2026 Oct 08. pii: blood.2026034296. [Epub ahead of print]
    KPNA2-Mediated MYC Nuclear Import Enhances CAR-T Cell Memory and Potentiates Antitumor Efficacy.
    Shi Han, Delin Kong, Chen Yang, Fang Ye, Juan Yue, Kexin Wang, Haiqiong Zheng, Zhuomao Mo, Xinghua Liang, Kejia Hu, Jianyu Wang, Penglei Jiang, Xia Li, Meng Zhang, Xiangjun Zeng, Yijin Chen, Lin Yang, Yanyan Wang, Mi Shao, Pengxu Qian, Yongxian Hu, He Huang, Dongrui Wang.
      Chimeric antigen receptor (CAR)-T cell therapy demonstrates remarkable clinical efficacy, yet limited persistence and functional exhaustion impede durable responses. While memory-like phenotypes are associated with sustained CAR-T function and improved clinical outcomes, the underlying molecular mechanisms of CAR-T cell memory maintenance remain incompletely defined and we still lack actionable strategy to sufficiently promote CAR-T cell memory formation. Here, we identified that Karyopherin Subunit Alpha 2 (KPNA2)-mediated MYC nuclear import robustly enhanced CAR-T cell memory and antitumor function. In clinical CAR-T cell products, KPNA2 expression and MYC pathway activation are correlated with superior therapeutic potency. Overexpressing MYC showed negligible effect on CAR-T cell function due to insufficient nuclear import; in contrast, incorporating KPNA2 in CAR-T cells facilitated MYC nuclear import, augmented memory formation, enhanced cytotoxicity and antitumor activity both in vitro and in vivo. Such functional improvement was not associated with risks of transformation in KPNA2-overexpressing CAR-T cells. Mechanistically, our integrated transcriptomic and epigenomic analyses revealed that KPNA2 increased MYC occupancy at memory-associated gene loci, upregulating T cell memory programs. Furthermore, virtual drug screening identified the small molecule TMS which potentiates KPNA2-MYC interaction. TMS treatment of CAR-T cells enhanced MYC nuclear accumulation, promoted memory-oriented transcriptional profiles, and improved antitumor potency in preclinical models. These findings established KPNA2-MYC interaction as a pivotal mechanism governing CAR-T cell memory formation, providing genetic and pharmacological strategies to advance therapeutic T cell design and manufacturing.
    DOI:  https://doi.org/10.1182/blood.2026034296
  21. Blood. 2026 Oct 08. 148(15): 1855-1857
    From specialized centers to community care: expanding the reach of CAR T-cell therapy.
    Helen E Heslop.
      
    DOI:  https://doi.org/10.1182/blood.2026035567
  22. Zhonghua Xue Ye Xue Za Zhi. 2026 Aug 14. 47(8): 818-824
    [The risk and management strategies for second primary tumor after CAR-T cell therapy].
    R N Li, W Y Wang, F Yang, L L Zhang, J Shi.
      Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of refractory hematologic malignancies, but its long-term safety has become an increasing concern. Secondary primary malignancies (SPM) following CAR-T-cell therapy have emerged as a growing focus of clinical and translational research. Evidence to date suggests that the incidence of different types of SPMs vary, with a two-year cumulative incidence ranging from approximately 0.08% to 8% and a median time to onset of 9.7 to 26.4 months, predominantly involving myeloid malignancies such as myelodysplastic syndromes and acute myeloid leukemia, while solid tumors and rare T-cell lymphomas have also been reported. CAR transgenes have been detected in only a minority of T-cell lymphoma cases. The mechanisms involved vector-related genomic integration risks, genotoxic stress from prior chemotherapy or hematopoietic stem cell transplantation, immune dysregulation, and clonal hematopoietic expansion. Future research may focus on developing safer gene-editing technologies, moving CAR-T-cell therapy to earlier treatment lines to reduce cumulative toxicity from prior therapies, implementing genetic risk screening before treatment, and establishing long-term systematic monitoring after therapy. By optimizing full-process management, the risk of SPM can be minimized, thereby improving the long-term safety of CAR-T-cell therapy while maintaining its therapeutic efficacy.
    DOI:  https://doi.org/10.3760/cma.j.cn121090-20260118-00036
  23. Intensive Care Med. 2026 Oct 08.
    Acute myelopathy following chimeric antigen receptor (CAR) T cell therapy: an unusual diagnostic challenge.
    Antoine Bois, Corentin Provost, Justine Decroocq, Sarah Benghanem.
      
    DOI:  https://doi.org/10.1007/s00134-026-08617-w
  24. J Investig Med. 2026 Oct 07. 10815589261497365
    EXPRESS: Immune Effector Cell-Associated Neurotoxicity Syndrome in Hematological Malignancy Patients Treated with CAR-T Cell: A Systematic Review.
    Kareem Latif, Jasmine Cha, Robert Niihara, Jerry Qi, Mohammad Dastjerdi, Mojtaba Akhtari.
       BACKGROUND: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a clinically significant complication of chimeric antigen receptor T-cell (CAR-T) therapy, with reported incidence varying across products and indications. However, the overall and product-specific risks of ICANS have not been comprehensively quantified. The aim of this study was to determine the pooled incidence of any-grade and severe (grade ≥3) ICANS across FDA-approved CAR-T products used in hematologic malignancies.
    METHODS: We performed a meta-analysis of prospective and retrospective studies evaluating six FDA-approved CAR-T products (axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, idecabtagene vicleucel, and ciltacabtagene autoleucel). The primary endpoint was incidence of any-grade ICANS; the secondary endpoint was incidence of grade ≥3 ICANS. Pooled incidence proportions were calculated using random-effects models. Heterogeneity was assessed using Cochran's Q and I2 statistics.
    RESULTS: Sixty analytic cohorts including 8,411 patients were analyzed. The pooled random-effects incidence of any-grade ICANS was 29.7% (95% CI, 24.3%-35.5%), and grade ≥3 ICANS occurred in 9.9% (95% CI, 7.4%-12.8%). Heterogeneity remained substantial for any-grade ICANS (Q=1822.40; I2=96.76%; τ2=0.22) and grade ≥3 ICANS (Q=965.44; I2=93.89%; τ2=0.11).Incidence varied markedly by product, with highest rates observed in CD28-based CD19 CAR-T therapies (axicabtagene ciloleucel and brexucabtagene autoleucel) and lower rates in 4-1BB-based CD19 and BCMA-targeted therapies.
    CONCLUSIONS: Approximately one in four CAR-T recipients develop ICANS, with nearly one in ten experiencing severe neurotoxicity. Risk varies significantly by product, supporting the need for product-specific risk stratification, monitoring strategies, and toxicity mitigation approaches.
    Keywords:  Hematologic Diseases
    DOI:  https://doi.org/10.1177/10815589261497365
  25. Cytotherapy. 2026 Jun 15. pii: S1465-3249(26)00890-X. [Epub ahead of print]28(12): 102929
    A regulatory gap: addressing visible particle control in cell and gene therapies through a risk-based framework.
    Manufacturing Materials Safety & Technology Working Group (formerly the Particulate Working Group) Within the ISCT Process Development & Manufacturing Committee
      Visible particulate matter is a critical quality attribute in injectable drug products; however, current regulatory standards provide limited guidance for addressing the specific challenges of Cell-Based Advanced Therapies (CT), where conventional inspection and rejection criteria may be incompatible with manufacturing and clinical constraints. Autologous and small-batch therapies often lack manufacturing redundancy, making the rejection of a single unit potentially equivalent to losing an opportunity to provide a life-saving treatment. To address this gap, we present a risk-based framework for evaluating and controlling particulate risk in CT, focusing on how particulate sources, process conditions, and control strategies can be characterized and improved early in development while incorporating benefit-risk considerations unique to these therapeutic modalities. Grounded in principles from international quality and regulatory publications, the proposed Visible Particulate Risk Assessment Matrix guides developers and manufacturers in assessing and managing particulate risk by integrating factors such as particle type and origin, characterization sufficiency, route and administration context, clinical urgency and therapeutic alternatives, system performance and controls, and lot replacement feasibility.
    Keywords:  autologous cell therapy; benefit-risk assessment; contamination control strategy; parenteral products; quality risk management; visible particulate matter
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102929
  26. Pharmacoeconomics. 2026 Oct 09.
    Methodological Challenges and Preferred Approaches for the Economic Evaluation of CAR T Therapies: Evidence Review and Expert Consensus from NICE Appraisals.
    Mehdi Yousefi, Amin Mehrabian, Maeve A O'Reilly, Claire Roddie, Peter Auguste, Dawn Lee, Jo Parsons, Daniel Gallacher.
       BACKGROUND: Chimeric antigen receptor T cell (CAR T) therapies pose challenges for economic evaluation because of complex treatment pathways and uncertainty around long-term outcomes. Within health technology assessment (HTA) bodies such as the National Institute for Health and Care Excellence (NICE), these features have led to recurring methodological debates.
    OBJECTIVES: To identify methodological challenges specific to the HTA of CAR T therapies within NICE technology appraisals and to develop Delphi-informed recommendations to support more consistent modelling practice.
    METHODS: A three-phase mixed-methods study was conducted. Phase 1 involved qualitative content analysis of published NICE appraisals of CAR T therapies to identify methodological issues and solutions. Phase 2 used a modified Delphi to determine which issues were specific to CAR T therapies and to agree upon preferred methodological approaches. Phase 3 involved clinical sense-checking of the preferred methodological approaches.
    RESULTS: Phase 1 reviewed nine NICE appraisals, identifying 16 issues around survival modelling, cure assumptions, costing and long-term outcomes. Ten issues were specified in relation to CAR T. Phase 2 identified one further relevant issue. The preferred approaches included modelling from leukapheresis (85%), applying cure assumptions consistently across treatment arms (95%) and applying modest utility decrements for long-term survivors (94%). For delivery costs, 61% preferred the most recent NHS England CAR T tariff with targeted supplements, while 28% preferred the most transparent tariff choice, indicating less uniform agreement. UK-specific real-world data were preferred to inform assumptions on treatment delivery, resource use and subsequent therapies. Phase 3 provided a clinical sense-check of these preferred approaches and identified important additional considerations for future appraisals.
    CONCLUSIONS: Methodological challenges in the economic evaluation of CAR T therapies recur across NICE appraisals and materially influence cost-effectiveness results. Drawing on evidence from NICE appraisals combined with Delphi findings and clinical sense-checking, this study provides practical recommendations relating to model start-point, cure modelling and long-term survivor utility decrements supporting more consistent and transparent economic evaluation within the NICE framework.
    DOI:  https://doi.org/10.1007/s40273-026-01673-6
  27. Front Oncol. 2026 ;16 1966718
    Clonal hematopoiesis of indeterminate potential and cancer immunotherapy: a host-intrinsic immune-inflammatory modifier of treatment efficacy and toxicity.
    Longjun Huang, Jiahao Sheng, Luyang Chi, Yehan Xu, Yun Wang.
      Clonal hematopoiesis of indeterminate potential (CHIP), the age-related expansion of hematopoietic stem cells carrying leukemia-associated somatic mutations, is common in patients with cancer and is increasingly detected during tumor-only genomic profiling and cell-free DNA sequencing. In this narrative review, we assess epidemiological, mechanistic, and clinical evidence at the interface between CHIP and cancer immunotherapy using a three-level hierarchy: established inflammatory biology, suspected effects on antitumor immunity, and unresolved direct human causality. We also map the evidence by driver gene, clone size, tumor type, treatment modality, and detection context. Immunotherapy-specific data are concentrated in TET2-mutant CHIP; associations for DNMT3A and ASXL1 are weaker, and direct JAK2 data are absent. Clinical ICI cohorts report favorable TET2-associated efficacy signals and no evidence that checkpoint blockade selects CH clones. Separate studies associate CHIP with ICI myocarditis and with severe cytokine release syndrome, prolonged hematologic toxicity, and TP53-mutant clonal expansion after CAR T-cell therapy. These findings remain observational and context dependent. Current evidence does not support CHIP-guided treatment selection. Prospective, standardized studies are needed to determine whether specific CHIP phenotypes predict efficacy, toxicity, or neither.
    Keywords:  biomarkers; causality; chimeric antigen receptor T cells; clonal hematopoiesis of indeterminate potential; immune checkpoint inhibitors; immune-related adverse events; inflammation; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1966718
  28. Front Immunol. 2026 ;17 1901504
    CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy.
    Alice Vitali, Jennie Padlo, Carlotta Caramel, Lena Andersch, Laura M Hartmann, Jonas Kath, Laura Grunewald, Silke Schwiebert, Anika Winkler, Efrosiinia Talalai, Tabea Biereder, Judith Wienke, Jan J Molenaar, Michael Launspach, Catharina Delebinski, Anton Kern, Kathy Astrahantseff, Dimitrios L Wagner, Gerald Willimsky, Angelika Eggert, Thomas Blankenstein, Kathleen Anders, Annette Künkele.
       Background: T cell receptor (TCR)-engineered T cells target antigens presented on major histocompatibility complex (MHC) class I molecules. MHC class I expression is often low in childhood tumors such as neuroblastoma but can be stimulated by interferon gamma (IFNγ). Chimeric antigen receptor (CAR) T cell effector function, including IFNγ production, is MHC class I-independent.
    Aim: We aimed to enhance neuroblastoma immunotherapy by combining CAR- and TCR-engineered T cells. Our strategy exploits CAR T cell-derived effector molecules, including IFNγ, to increase tumor cell MHC class I expression and thereby enhance subsequent TCR T cell activity.
    Methods: IFNγ-mediated induction and persistence of MHC class I expression were analyzed in neuroblastoma cell lines by flow cytometry. Primary human T cells were engineered to express either a high-affinity TCR targeting the cancer testis antigen NY-ESO-1 or an L1CAM-targeted CAR. Cytotoxic activity of CAR and TCR T cells, applied alone or sequentially, was quantified against LAN-1 neuroblastoma cells using IncuCyte-based real-time killing assays. To model heterogeneous antigen expression, mixed tumor populations containing L1CAM-positive and CRISPR/Cas9-generated L1CAM-knockout cells were analyzed. In vivo MHC class I upregulation was assessed in a human tumor xenograft model following treatment with human L1CAM-CAR T cells and in a syngeneic tumor model following treatment with GD2-CAR T cells.
    Results: NY-ESO-1 TCR T cells alone showed limited cytotoxicity against LAN-1 cells in vitro, whereas L1CAM-CAR T cell pretreatment increased MHC class I expression and enhanced subsequent TCR-mediated killing. In tumor cells with heterogeneous CAR antigen expression, CAR T cell recognition of antigen-positive cells induced HLA-A*02 upregulation across the tumor population, enabling subsequent NY-ESO-1 TCR T cell recognition of cells not directly recognized by CAR T cells. Exploratory in vivo analyses further showed increased tumor MHC class I expression following CAR T cell treatment, providing preliminary evidence of CAR T cell-mediated inflammatory priming in vivo.
    Conclusion: Sequential CAR- and TCR-engineered T cell therapy may help overcome limitations imposed by low MHC class I and heterogeneous antigen expression in neuroblastoma, supporting further investigation of this combinatorial strategy.
    Keywords:  MHC class I low; T cell therapy; TCR T cell resistance; antigen loss; neuroblastoma; tumor heterogeneity
    DOI:  https://doi.org/10.3389/fimmu.2026.1901504
  29. Transplant Cell Ther. 2026 Oct 03. pii: S2666-6367(26)00778-5. [Epub ahead of print]
    CAR T‑Cell Therapy as a Bridging Strategy to Second Transplant in Relapsed B‑Cell ALL.
    Vaibhav Agrawal, Haoyue Shan, Monzr Al Malki, Amandeep Salhotra, Ahmed Aribi, Paul Koller, Karamjeet Sandhu, Salman Otoukesh, Haris Ali, Hoda Pourhassan, Andrew Artz, Tamer Othman, Yazeed Samara, Len Farol, Anthony Stein, Ryotaro Nakamura, Guido Marcucci, Vinod Pullarkat, Stephen Forman, Ibrahim Aldoss.
       BACKGROUND: A second allogeneic transplant (HSCT2) may offer cure for selected patients with acute lymphoblastic leukemia (ALL) relapsing after first transplant (HSCT1), however, outcomes have historically been poor, largely driven by high incidence of subsequent relapse. Chimeric antigen receptor (CAR) T‑cell therapy induces deep and durable remissions in relapsed/refractory (R/R) ALL, yet its role as a bridge to HSCT2 remains under studied. Consolidation with transplant after CAR-T therapy may enhance post‑HSCT2 disease control and improve outcomes.
    OBJECTIVES: To compare HSCT2 outcomes according to bridging therapy strategies, with a particular focus on CAR T‑cell therapy versus non‑CAR bridging approaches.
    STUDY DESIGN: This is a single‑center retrospective analysis of adult patients with relapsed B‑cell ALL after a HSCT1 who subsequently underwent a HSCT2 in complete remission (CR) at City of Hope.
    RESULTS: Among 55 adults with relapsed B‑ALL who underwent HSCT2, the median age was 32, with a median of 4 prior lines of therapies. The median time from HSCT1 to relapse was 425 days, and over half of patients proceeded to HSCT2 in ≥CR3. Salvage therapy included CAR T‑cell therapy in 23 patients (42%), blinatumomab in 12 (22%), inotuzumab ozogamicin in 12 (22%), and other regimens in 8 (15%). Baseline patients and disease characteristics were not significantly different between those receiving CAR T and other salvage approaches. Patients receiving CAR T-cell therapy before HSCT2 had significantly improved 2-year progression free survival (PFS) (67.6% vs. 31.4%, p= 0.003) and overall survival (OS) (77.3% vs. 51.6%, p= 0.021) compared with other salvage therapies, respectively. Cumulative incidence of relapse was significantly lower in patients who received CAR T‑cell therapy before HSCT2 (p=0.01), while non-relapse mortality was similar between the two groups (p=0.43). In multivariable analysis, CAR T-cell therapy remained independently associated with superior PFS (HR 0.26; 95% CI, 0.10-0.62; p < 0.001) and OS (HR 0.33; 95% CI, 0.13-0.81; p = 0.026). A longer interval from HSCT1 to relapse (>475 days) also predicted improved OS (HR 0.42; 95% CI, 0.18-0.96; p = 0.04), while older age showed a trend toward inferior OS (HR 2.17; 95% CI, 0.97-4.89; p = 0.054).
    CONCLUSION: Our study supports CAR T-cell therapy as an effective bridging strategy to HSCT2 in selected patients with relapsed B-ALL, associated with improved post HSCT2 survival outcomes and reducing relapse. Careful optimization of patient selection and timing of transplant remains critical to maximize long-term outcomes.
    Keywords:  B-cell ALL; CAR T-cell therapy; hematopoietic stem cell transplantation; relapse post-transplant
    DOI:  https://doi.org/10.1016/j.jtct.2026.09.048
  30. Mol Ther Nucleic Acids. 2026 Dec 08. 37(4): 103081
    Human T cell engineering via serial delivery of mRNA encapsulated within lipid nanoparticles.
    Apoorva Ramamurthy, Giulia Scimonelli, William L Murphy, Krishanu Saha.
      Human T cells modified with nucleic acids constitute a powerful and emerging therapeutic modality for cancer, autoimmune disorders, and aging-related diseases. However, delivering nucleic acids, such as mRNA encoding synthetic receptors, transcription factors, cytokines, or genome editors to T cells can be challenging, as nucleic acids can unintentionally reduce viable T cell yield and function, particularly when delivered sequentially ex vivo. To address this challenge, we evaluated the efficiency of serial non-viral delivery of synthetic mRNA encapsulated within lipid nanoparticles (LNPs) incorporating cationic lipid, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), and fusogenic helper lipid, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). DOTAP/DOPE-containing LNPs delivered mRNA more efficiently than a clinically benchmarked 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-containing LNP formulation, resulting in significantly higher protein expression in primary human T cells. Furthermore, DOTAP/DOPE-LNP delivery resulted in 100% higher yield of live cells compared to electroporation, an advantage that compounded over serial rounds, with LNP-treated cultures maintaining substantially more viable cells through all four transfections. Additionally, serial transfection of mRNAs encoding a therapeutically relevant chimeric antigen receptor (CAR) payload produced functional CAR T cells. These results demonstrate that LNPs can be a viable platform for serial and iterative T cell engineering using multiple mRNA payloads, providing an alternative to electroporation for the engineering of therapeutic T cells.
    Keywords:  CAR T cell engineering; DOPE; DOTAP; LNP; MT: Delivery Strategies; T cells; cell therapy manufacturing; electroporation; mRNA delivery; non viral gene delivery
    DOI:  https://doi.org/10.1016/j.omtn.2026.103081
  31. Int J Biol Markers. 2026 Jan-Dec;41:41 3936155261492332
    The European cancer landscape: A focused review of epidemiology, prevention, inequalities and innovation.
    Christoph Schatz, Daria Maria Filippini, Johannes Haybaeck.
      This review provides a focused overview of the current cancer landscape in Europe, addressing epidemiological trends, cancer-related costs, prevention and early detection, inequalities in access to care, and the implementation of therapeutic innovation. Recent studies from major European institutions were selected to illustrate key developments. Cancer incidence, mortality, direct and indirect costs vary substantially across countries, although comparisons remain limited by differences in geographical areas included, data collection, registration systems, and methodological approaches. The available evidence highlights the need for more standardized cancer data, greater investment in prevention, equitable implementation of screening programmes, broader access to multidisciplinary care, advanced diagnostic tools, clinical trials, and precision oncology. European funding programmes and collaborative networks may contribute to these objectives by promoting shared research infrastructures and cooperation.
    Keywords:  Cancer; Cancer 2025; Cancer sites; Current European Cancer Landscape; Europe; European Union; Financial costs
    DOI:  https://doi.org/10.1177/03936155261492332
  32. Front Genet. 2026 ;17 1940629
    Artificial intelligence for precision gene therapy: emerging technologies, clinical applications, and future directions.
    Govinder Flora, Abhinay Thakur.
      Artificial Intelligence (AI) is revolutionizing gene therapy from an empirical and iterative process to a predictive, data-driven and increasingly intelligent therapeutic development approach. This review covers the application of AI extensively throughout the gene therapy development process, from target therapeutic discovery, identification of disease genes, variant interpretation, integration of multi-omics data, optimization of CRISPR, engineering of the vector, prediction of immunogenicity, manufacturing, and clinical development and post-marketing surveillance. The role of machine learning, deep learning, foundation models, generative AI and digital twins for advancing therapeutic design, boosting vector performance, manufacturing optimization, patient stratification and enabling precision medicine is discussed. Lastly, we provide directions for future research and highlight the need for close multidisciplinary cooperation between computational scientists, biologists, clinicians, industry, and regulatory agencies to facilitate the development of safe, effective and personalized genetic medicines responsibly.
    Keywords:  CRISPR; artificial intelligence; biomanufacturing; gene therapy; genomics
    DOI:  https://doi.org/10.3389/fgene.2026.1940629
  33. J Law Med Ethics. 2026 Oct 07. 1-4
    The Price of a Cure: Luxturna and the Economic Dilemmas of Precision Medicine.
    Alex Tabarrok.
      The $850,000 price for the gene therapy Luxturna is often framed as a story of private profiteering from publicly funded science. This paper challenges that narrative. Pharmaceuticals are a hit-driven industry: most projects fail, so the few successes must earn revenues well in excess of their own direct costs if the portfolio as a whole is to attract investment. Precision medicine intensifies this logic through two core economic challenges: (1) the "sticker shock" of one-time cures, which compress decades of value into a single payment, creating a financing problem more than a value problem; and (2) the "targeting dilemma," in which precisely targeting drugs to smaller patient groups shrinks the market, requiring higher rewards per treated patient to maintain incentives to innovate. Rather than simply controlling prices, the paper proposes a policy toolkit that includes amortizing payments over time, bundling diagnostics with drugs and insurance, and streamlining regulation to lower development costs. The aim is to preserve innovation while expanding patient access.
    Keywords:  Luxturna; drug pricing; gene therapy; health insurance; pharmaceutical innovation; precision medicine; research and development
    DOI:  https://doi.org/10.1017/jme.2026.10294
  34. Mol Ther. 2026 Oct 09. pii: S1525-0016(26)00867-1. [Epub ahead of print]
    Five decades of gene therapy innovation and regulation in the US and EU: a historical analysis.
    Thomas Wessel van de Voort, Jarno Hoekman, Elisabeth Henrica Maria Moors, Lourens Theo Bloem.
      The development of gene therapy is characterized by expectations of patient benefits, but challenges persist, including rapid technological change and, typically, small target populations. This has thus far resulted in relatively few gene therapies reaching the market and benefiting patients. Regulation plays a central role in shaping how these challenges are addressed and how gene therapies reach patients. This study investigated how gene therapy regulatory regimes have developed in the US and EU between 1973 and 2025, and how gene therapy regulation events contributing to regulatory regime building have shaped gene therapy innovation outcomes. We conducted a scoping review of scientific literature and expert interviews, which together characterized all authorized gene therapies in the US and EU. We constructed and validated timelines of gene therapy regulation events in these regimes. Interviewees attributed observed differences in the timelines to factors specific to gene therapy regulation and to the broader medicines regulatory system. Regulatory leadership in gene therapy has shifted repeatedly between the US and the EU, reflecting differences in how each jurisdiction responds to scientific and technological uncertainty, societal risks and needs, and commercial pressure.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.10.009
  35. Life Sci. 2026 Oct 06. pii: S0024-3205(26)00532-1. [Epub ahead of print] 124723
    Therapeutic engineering of the IL-18-IL-18BP axis for precision cancer immunotherapy.
    Yan Chen, Meiji Chen, Mingyue Zhang, Ge Shan, Zheng Xiang, Zhinan Yin.
      Interleukin-18 (IL-18) is a pleiotropic cytokine that promotes interferon-γ (IFN-γ) production and cytotoxicity in natural killer (NK) and T cells, but its antitumor activity is limited by ligand maturation and release, IL-18-binding protein (IL-18BP) sequestration, IL-18 receptor (IL-18R) abundance and signaling competence, exposure kinetics, and the tumor microenvironment. This regulatory network may explain the limited and heterogeneous objective responses observed in early clinical studies of recombinant human IL-18 (rhIL-18). Here, we review strategies for engineering the IL-18-IL-18BP axis for cancer immunotherapy, including decoy-resistant IL-18 (DR-18) variants, IL-18R agonists and mimetics, oncolytic virus (OV)-mediated delivery, IL-18-armored adoptive cell therapies (ACT), membrane-tethered IL-18, and combinations with immune checkpoint blockade (ICB). Preclinical studies support intratumoral immune activation and tumor control, whereas early clinical studies of IL-18-armored cellular therapies highlight cytokine release syndrome (CRS), prolonged cytopenias, and systemic inflammation as major safety concerns. Accordingly, clinical development should evaluate target engagement, antitumor activity, and safety as distinct dimensions, integrating free and IL-18BP-bound IL-18, IL-18R expression, downstream signaling competence in effector cells, spatial immune contexture, and inflammatory toxicity. Conditional or tumor-restricted activation, controllable expression, and exposure profiles matched to tumor biology may be required to establish a clinically manageable therapeutic window for IL-18-based immunotherapy.
    Keywords:  Cancer immunotherapy; Cytokine engineering; IL-18; IL-18BP
    DOI:  https://doi.org/10.1016/j.lfs.2026.124723
  36. Immunol Rev. 2026 Oct;343(1): e70184
    Entering the Age of Specificity in T Cell Immunity.
    Paul G Thomas.
      The discovery of MHC restriction, the resolution of peptide-MHC structure, and the identification of the T cell receptor gene quickly centered epitope-level specificity as a core concern of T cell biology. Epitope mapping culminated in functional peptide-based stimulation assays and tetramer staining, which together provide exquisite resolution of individual responses. Despite these tools, quantitative assessment of epitope-resolved responses in complex human infections and tumors has rarely been applied at scale. As a result, no epitope-aware correlates of protection or risk have been established for major infections, and most human T cell profiling still occurs at the level of representative epitopes or bulk assays. In this review, I propose that variation in specificity, defined as distinct epitope-level responses across individuals, represents a largely untested critical element in our assessment of anti-pathogen and antitumor immunity. Advances in TCR repertoire profiling and reverse epitope discovery now make formal tests of this hypothesis tractable, and I discuss approaches to determine the extent to which epitope variation underlies the noise and variation of human immune phenotypes.
    Keywords:  T cell; biology; computational biology; epitope; epitope mapping; immune correlates; immune system; major histocompatibility complex; viral infection
    DOI:  https://doi.org/10.1111/imr.70184
  37. Front Immunol. 2026 ;17 1947351
    Affinity and costimulatory architecture-associated toxicity in mesothelin-targeted TCR-mimetic CAR-T cells.
    Wei Du, Siqi Li, Shaomei Gan, Chen Wang, Rui Lu, Wenbin Yu, Jie Lin, Xidai Long, Fang Tang, Enxiu Wang.
       Introduction: TCR-mimetic CAR-T combines antibody-based targeting with physiological TCR signaling, yet suboptimal co-stimulation and safety risks remain key barriers for solid tumor therapy. The prevailing assumption that stronger co-stimulation yields superior efficacy has not been systematically tested in TCR-mimetic CAR-T architectures.
    Methods: We developed a Mesothelin-targeted scFv-CD3ϵ TCR-mimetic CAR-T platform and systematically compared co-stimulatory modules-4-1BB, BRM-truncated 4-1BBΔBRM, and the 80BB chimera-alongside CD3ζ overexpression. To define the requirements for toxicity, we generated a series of control constructs and compared SS1 versus MOR-based scFvs targeting the same antigen, which differ in their binding properties including affinity.
    Results: The optimized SS1-ϵζ-80BB TCR-mimetic CAR-T exhibited potent anti-tumor activity but unexpectedly induced dose-dependent lethal toxicity. Systematic controls identified the intact 80BB chimera as the construct associated with lethality. Deleting the 4-1BB intracellular domain, rerouting the 4-1BB intracellular domain to an antigen-dependent format, or replacing SS1 with MOR each abrogated toxicity while preserving anti-tumor efficacy. The SS1-ϵζ-80BB architecture was associated with excessive T-cell expansion and multi-organ infiltration while the MOR-ϵζ-80BB architecture was moderate.
    Discussion: These observations suggest that the mode of co-stimulatory configuration, rather than its mere presence, influences safety outcomes in TCR-mimetic CAR-T cells. Modifying either the affinity-related properties or the 80BB-based architecture preserved efficacy while reducing toxicity, providing potential design considerations for affinity selection and co-stimulator design in the mesothelin-targeted TCR-mimetic CAR-T platform.
    Keywords:  4-1BB; CAR-T toxicity; TCR-mimetic CAR-T; antibody affinity; mesothelin
    DOI:  https://doi.org/10.3389/fimmu.2026.1947351
  38. Front Immunol. 2026 ;17 1944643
    Immune signatures of common exposures through co-occurrence of T-cell receptors in tens of thousands of donors.
    Damon H May, Steven Woodhouse, Matthew T Noakes, Kathryn Doroschak, Rebecca Elyanow, Amanda J Moore, Edward J Osborne, Brad Greenfield, Tim Hayes, Ruth Taniguchi, Zheng Yang, John R Grino, Rachel Byron, Jamie Oaks, Haiyin Chen-Harris, Anna Sherwood, Julia Greissl, Bryan Howie, Mark Klinger, Harlan S Robins.
       Background: Memory T cells are records of clonal expansion from prior immune exposures such as infections, vaccines and chronic diseases. Some of the receptors of these expanded T cell clones in a typical immune repertoire are highly public (present in many individuals) because they respond to the same peptide from a prevalent immune exposure, presented by the same Human Leukocyte Antigen (HLA) allele. Only a tiny fraction of public T-cell receptor β sequences (TCRs) have known associations with exposures or specific peptides.
    Methods: We mined the TCR repertoires of tens of thousands of donors to define "ECOclusters" (Exposure Co-Occurrence clusters): clusters of public TCRs that tend to occur in the same donors. First, we built models to infer donor HLA type from the TCR repertoire, then associated public TCRs with HLA alleles. Next, we derived co-occurrence clusters of TCRs responding to antigens presented by the same HLA allele, then combined those clusters by co-occurrence across HLA alleles. Each such cross-HLA ECOcluster putatively represents a public TCR signature of a single exposure.
    Results: We constructed sensitive, specific models to predict the presence of 220 HLA alleles from TCR repertoires and clustered 8,618,285 HLA allele-associated TCRs to define 11,058 ECOclusters. Using serologically labeled repertoires, we identified ECOclusters associated with HSV-1, HSV-2, EBV, Parvovirus, Toxoplasma gondii, Cytomegalovirus (CMV) and SARS-CoV-2, and constructed sensitive, specific classifiers of exposure. We explore the 50,217 TCRs in the CMV ECOcluster in detail, including diagnostic performance of each HLA-associated component and intersection with public TCR databases. ECOclusters represent a step toward deciphering the ledger of immune exposure history encoded by the T-cell repertoire.
    Keywords:  Cytomegalovirus; T cell receptor; T cells; TCR repertoire; TCR-seq; machine learning
    DOI:  https://doi.org/10.3389/fimmu.2026.1944643
  39. Ther Innov Regul Sci. 2026 Oct 07.
    Mapping the Alignment Between the Portuguese Pharmacotherapeutic Assessment Methodology and EU Joint Clinical Assessment Guidance.
    Ricardo Amaral, Diogo Mendes, Carlos Alves, António Donato, Cristina Lopes, Vasco Conde, Francisco Batel Marques.
       BACKGROUND: Regulation (EU) 2021/2282 on health technology assessment (HTA) entered into force on January 11, 2022 and became applicable on January 12, 2025, introducing Joint Clinical Assessments (JCAs) focused on relative clinical effectiveness and safety to support national HTA processes. This study assessed the alignment of Portugal's pharmacotherapeutic assessment methodology (version 3.0, 2022) in force within the National HTA System (SiNATS) with EU JCA guidance.
    METHODS: Five domains were analyzed: quantitative evidence synthesis; multiple hypothesis testing and complementary analyses; outcome measures; clinical study validity; and scoping. Methodological topics and subtopics were extracted from both sources and compared item by item to determine whether they were present in both methodologies (concordant or divergent) or in only one. Descriptive statistics were used to summarize findings.
    RESULTS: Most differences reflected information gaps in Portugal's methodology rather than conflicting methodological principles. Across domains, subtopics present in only one methodology accounted for 43.1% of items in quantitative evidence synthesis, 56.2% in multiple hypothesis testing and complementary analyses, 72.2% in outcome measures, 61.1% in clinical study validity, and 58.3% in scoping; most of these were addressed only in EU JCA guidance. Where subtopics overlapped, agreement was high (71.4%-100%), and remaining divergences mainly concerned terminology and approaches to complementary analyses.
    CONCLUSION: Portugal's guidance is broadly consistent with the EU JCA framework where content is shared, but targeted updates are needed, particularly for outcomes, scoping, evidence validity appraisal, and multiplicity reporting, to maximize the direct usability of JCA reports within SiNATS as the Regulation is progressively implemented.
    Keywords:  EU HTA Regulation; Health Technology Assessment (HTA); Joint Clinical Assessment (JCA); Joint Scientific Consultation (JSC); Relative Effectiveness Assessment (REA)
    DOI:  https://doi.org/10.1007/s43441-026-01057-0
  40. Pediatr Blood Cancer. 2026 Oct 07. e70749
    Decentralized CAR T-Cell Manufacturing in Southeast Asia: A Hub-and-Spoke Model for Therapeutic Equity.
    Prasad Iyer.
      
    DOI:  https://doi.org/10.1002/1545-5017.70749
  41. Nat Protoc. 2026 Oct 06.
    T cell immunomonitoring: a comparative analysis of traditional and novel methods to quantify and characterize human antigen-specific T cells.
    Sandra Lazzaro, Geert Leroux-Roels, Sylvia Janetzki, Bruno Salaun, Laura Cook, Katka Franke, Isabel Poschke, Lukas Bunse, Marij J P Welters, Michael Fehlings, Sofie Pattyn, Gwenn Waerlop, Liselotte Brix, Noah J Tubo, Jeffrey J Molldrem, Viola Denninger, Wim J E van Esch, Nikolaj Pagh Kristensen, Yolanda D Mahnke, Florian Mair, Kilian Schober, Sven D Koch.
      T cells are a key component of the adaptive immune system, playing a central role in the body's defense against pathogens and diseases. Antigen discovery and longitudinal immunomonitoring of antigen-specific T cell responses offer valuable insights into the activity and efficacy of immunotherapies and can guide development of new prophylactic or therapeutic treatments, such as vaccines and cellular therapies. Traditional immunomonitoring methods for T cell analysis, while foundational, offer limited insights because of the complexity and vast heterogeneity of antigen-specific T cells. Here, traditional and cutting-edge technologies for profiling antigen-specific T cells are reviewed, highlighting the evolution from low- to high-dimensional analyses. The principles, applications, benefits and limitations of each technique are outlined, and the need for assay harmonization and standardization is discussed. The importance of careful sample processing is also considered. This review highlights how immunomonitoring techniques can complement each other to maximize understanding of T cell-mediated immunity, a key aspect shaping immunotherapeutic development, now and in the future.
    DOI:  https://doi.org/10.1038/s41596-026-01453-8
  42. Pharm Stat. 2026 Nov-Dec;25(6):25(6): e70133
    BOIN12-PFS: A Bayesian Optimal Interval Phase I/II Design Incorporating Progression-Free Survival Endpoint.
    Yusuke Tanaka, Kentaro Takeda, Ryo Kitabayashi, Hiroyuki Sato, Akihiro Hirakawa.
      Modern oncology drug development is increasingly focused on identifying the optimal biological dose (OBD) rather than just the maximum tolerated dose (MTD). Early-phase oncology trials have conventionally relied on short-term endpoints, such as overall response rate (ORR), to evaluate efficacy. However, there is a growing perception that incorporating longer-term endpoints, such as progression-free survival (PFS), into early-phase dose-finding trials can provide more informative guidance for dose optimization. This study proposes a new design, BOIN12-PFS, to identify the optimal dose based on PFS, short-term efficacy, and toxicity. As an extension of the BOIN12 design, BOIN12-PFS is expected to be comparatively straightforward to implement in clinical oncology dose-finding trials. Simulation studies demonstrate that the BOIN12-PFS design offers advantages over existing designs in terms of the probability of selecting the OBD, the average number of patients allocated to the OBD, reducing overdosing, and requiring a smaller total sample size across various realistic settings.
    Keywords:  dose optimization; model‐assisted design; progression‐free survival
    DOI:  https://doi.org/10.1002/pst.70133
  43. Clin J Oncol Nurs. 2026 Sep 30. 30(5): 352-356
    Nurse Practitioner-Led Antibiotic Stewardship for Febrile Chimeric Antigen Receptor T-Cell Recipients.
    Natalie McRae, Heather Tayloe, Anna Messer, Kathryn W Anzueto, Miranda Cozzone, Rebecca D Suttle.
      In patients with cytokine release syndrome receiving chimeric antigen receptor (CAR) T-cell therapy, fever often leads to unnecessary use of IV antibiotics. Early antibiotic de-escalation may reduce antibiotic exposure withou.
    Keywords:  antibiotics; chimeric antigen receptor T-cell therapy; cytokine release syndrome
    DOI:  https://doi.org/10.1188/26.CJON.352-356
  44. Int J Nanomedicine. 2026 ;21 625844
    Organelle-Targeted Nanocarriers for Cancer Therapy: Design Principles, Intracellular Trafficking, and Translational Barriers in Precision Drug Delivery.
    Hang Zhang, Jia Guo, Xinmiao Wang, Yuchen Shen, Yijie Yao, Sushilkumar Shivaji Ghadage, Sainath Kamble, Sami A Al-Hussain, Magdi E A Zaki, Shravan Jadhav, Vijay H Masand, Rohit Bavi.
      The clinical translation of cancer nanomedicine remains constrained by inefficient intracellular delivery, poor subcellular specificity, and limited tumor accumulation, highlighting the need for more precise drug delivery strategies. Organelle-targeted nanocarriers have emerged as a promising platform for enhancing therapeutic efficacy by directing drugs to specific intracellular compartments, including the nucleus, mitochondria, lysosomes, and endoplasmic reticulum. However, the design principles governing efficient organelle-specific delivery and the barriers limiting clinical translation remain incompletely understood. This review provides a mechanistic framework linking nanoparticle physicochemical properties-including size, surface charge, ligand functionalization, and stimuli responsiveness to intracellular trafficking, organelle targeting, and therapeutic performance. We critically discuss the biological barriers encountered during delivery, including cellular uptake, endosomal escape, cytosolic transport, and organelle membrane penetration, together with current engineering strategies to overcome these challenges. Organelle-specific targeting approaches are comparatively evaluated to highlight their therapeutic advantages, limitations, and suitable clinical applications. Beyond summarizing recent advances, this review examines the major translational hurdles that impede clinical implementation, including non-specific biodistribution, manufacturing scalability, regulatory challenges, and the lack of standardized preclinical evaluation models. Emerging solutions such as hierarchical targeting, charge-reversal systems, size-transformable nanocarriers, and multifunctional theranostic platforms are discussed as strategies to improve clinical feasibility. Finally, we propose practical design guidelines and future research priorities that integrate nanomaterial engineering, predictive biological models, and scalable manufacturing to facilitate the development of clinically translatable organelle-targeted nanomedicines.
    Keywords:  cancer treatment; endoplasmic reticulum; golgi apparatus; lysosome; nano-drugs; organelle-targeted mitochondrion therapy; organelle-targeted nucleus therapy
    DOI:  https://doi.org/10.2147/IJN.S625844
  45. Hum Gene Ther. 2026 Oct 08. 10430342261492461
    Automated Production of Gene-Edited CAR-T Cells for People Living with HIV.
    Lea Isabell Schwarze, Niklas Nuppenau, Jan Hendrik Müller, Almut Uhde, Nahla Al Ashkar, Tanja Schröder, Kristoffer Riecken, Boris Fehse.
      Adoptive transfer of gene-modified autologous T cells, for example, expressing chimeric antigen receptors (CARs), is a promising therapy option for a variety of malignant and nonmalignant diseases. Given their increased risk to develop certain cancer types, namely lymphoma, and the current progress with HIVenv-directed CARs, people living with HIV (PLWH) might particularly profit from CAR-T therapies. At the same time, clinical translation of novel advanced therapy medicinal products remains challenging, partly due to the elaborate ex vivo production under good manufacturing practice (GMP) conditions. This holds especially true for T-cell products from PLWH, which require special manufacturing conditions to suppress HIV replication. We aimed to exemplarily address this limitation in the context of CD19-CAR-T cells for HIV-positive cancer patients. To this end, we developed an integrated, GMP-compliant process for lentiviral CAR transfer and simultaneous knockout of the HIV coreceptor C-C chemokine receptor 5 (CCR5) by mRNA electroporation of our transcription activator-like effector nuclease (CCR5-Uco-hetTALEN) based on the CliniMACS Prodigy. We successfully performed three manufacturing runs to produce CCR5-edited CD19-CAR-T cells on a clinical scale, generating up to 3.9 × 109 viable T cells. Thirty-seven percent to 55% of the T cells in the final product expressed functional CD19-CARs, the overall CCR5 editing rates ranged from 42% to 54%. The third large-scale process was performed in the presence of the antiretroviral drug saquinavir to suppress potential viral replication during manufacturing of cells from HIV-positive patients. In summary, we have developed a GMP-compliant manufacturing process for gene-edited CAR-T cells under antiretroviral suppression, which might help to accelerate the translation of cellular immunotherapies, namely CAR-T cells for patients living with HIV in the future.
    Keywords:  CCR5-TALEN; CD19-CAR; GMP; HIV; antiretroviral drug; gene editing
    DOI:  https://doi.org/10.1177/10430342261492461
  46. Lancet Rheumatol. 2026 Oct 05. pii: S2665-9913(26)00249-3. [Epub ahead of print]
    CAR T cells for autoimmune diseases: 2026 update of the EBMT-ISCT-JACIE practice harmonisation and consensus recommendations.
    participants to the Cell Therapies for Autoimmune Diseases: CAR-T from Biology to Clinical Application course
      Autoimmune diseases are a heterogeneous group of chronic diseases characterised by loss of immune tolerance with substantial morbidity and mortality. Since 2021, chimeric antigen receptor (CAR) T cells have recently emerged as a promising treatment option for patients with severe, refractory autoimmune diseases. In 2024, an international expert panel from the European Society for Blood and Marrow Transplantation (EBMT), the International Society for Cell and Gene Therapy (ISCT), and the Joint Accreditation Committee of ISCT and EBMT (JACIE) released the first best-practice recommendations on CAR T cells for autoimmune diseases. Using the same consensus methodology, these living recommendations were updated thereafter. The 2026 consensus reviews current evidence and expert practices on CAR T cells for rheumatic, neurological, haematological, other autoimmune diseases, and paediatric indications, providing updated, expert-based recommendations on patient selection, diagnostic investigation, clinical management, follow up, and immune monitoring for each disease group. Unmet needs and future research priorities are also highlighted.
    DOI:  https://doi.org/10.1016/S2665-9913(26)00249-3
  47. Front Immunol. 2026 ;17 1941235
    Targeting innate immunity in cancer: mechanistic foundations, therapeutic vaccination, and clinical translation.
    Xinghan Li, Yitong Meng, Jijun Dong, Yue Ma, Dequan Liu, Xiaodong Zhang, Lingjie Zhao.
      Cancer evolves within tissue ecosystems in which innate immune surveillance and tumor-promoting inflammation jointly shape disease progression and therapeutic response. Innate receptors detect cellular stress, altered-self ligands, damaged-cell products and tumor-derived nucleic acids, thereby initiating cytotoxicity, phagocytosis, antigen presentation and adaptive immune priming. However, tumors can redirect these mechanisms through suppressive cytokines, metabolic competition, hypoxia and dysregulated chemokine networks, promoting immune exclusion, metastasis and treatment resistance. This Review examines innate recognition, immunoediting and innate-adaptive crosstalk. We discuss the heterogeneity, dysfunction and therapeutic targeting of dendritic cells, macrophages, natural killer cells, neutrophils, myeloid-derived suppressor cells, innate lymphoid cells and other tissue-resident populations. We also evaluate Toll-like receptor, cGAS-STING, RIG-I-MAVS, inflammasome and complement pathways as therapeutically actionable but potentially tumor-promoting signaling systems. Finally, we consider how innate adjuvants, antigen selection, delivery technologies and rational combinations can improve therapeutic cancer vaccines. Emerging clinical studies demonstrate feasibility, but inconsistent efficacy and treatment-associated toxicity emphasize the need for biomarker-guided patient selection, spatially restricted delivery and mechanism-based sequencing. Clinical translation will depend on biomarker-guided patient selection, localized delivery and treatment sequencing that preserves antimicrobial defense and tissue homeostasis.
    Keywords:  cancer immunotherapy; cancer vaccines; innate immune sensing; innate immunity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1941235
  48. J Med Internet Res. 2026 Oct 09. 28 e91531
    Priorities and Implementation Barriers in End-to-End Digital Transformation in the Pharmaceutical Industry: Sequential Mixed Methods Analysis.
    Isaac Rogelio Rodriguez-Chavez, Adama Ibrahim, Baris Ersezer, Angela Radcliffe, Victoria Gamerman, Bert Hartog, Lars Fogh Iversen, Marcus Schindler.
       Background: The pharmaceutical industry faces unprecedented challenges, including declining drug approval rates, plummeting research and development returns, and escalating protocol complexity. Digital transformation represents the most promising end-to-end approach for addressing these challenges, yet there is limited understanding of industry-wide priorities and implementation barriers.
    Objective: This study aimed to identify digital transformation priorities across diverse pharmaceutical industry stakeholders and to explore the specific barriers preventing successful implementation through a collaborative, mixed methods approach.
    Methods: The study used a sequential mixed methods design with three phases: (1) workshop 1 in Copenhagen, Denmark, with 47 participants randomly divided into 3 working groups, all discussing three main theme areas and generating 110 digital transformation topics; (2) a follow-up online survey of workshop 1 participants (administered 4 wk after workshop 1); and (3) workshop 2 in Boston, United States, with expert keynote and panel discussions exploring implementation challenges. Participants were recruited via convenience sampling through industry networks and professional associations. The study was conducted between March 2023 and June 2025 across international workshop sites in Copenhagen and Boston. Data sources included workshop outputs, survey responses, and transcribed panel discussions. Analysis involved thematic coding, convergence analysis, and tension identification.
    Results: Workshop 1 identified 19 common categories across all working groups, despite the 3 diverse starting themes. Workshop 1 produced 7 consolidated categories for theme 1 (desired outcomes), 5 for theme 2 (pathways), and 7 for theme 3 (measuring success), totaling 19 consolidated categories. The survey achieved a 55.3% (26/47 participants) response rate and identified patient-centered outcomes, FAIR (Findable, Accessible, Interoperable, and Reusable)-aligned data practices, collaboration, access and equity, and the reduction of patient burden as leading priorities. Workshop 2 identified 5 key implementation tensions: innovation speed vs safety standards, collaboration vs competition, technology vs change management, patient preferences vs operational efficiency, and data democratization vs privacy protection. Panel discussions provided deep insights into implementation challenges and solutions. The results obtained support exploratory generalization across comparable settings and do not establish causal effects.
    Conclusions: The pharmaceutical industry demonstrates strong consensus on patient-centric digital transformation priorities across the value chain, with universal recognition of the need for precompetitive collaboration. However, significant implementation barriers exist beyond technology, requiring integrated approaches to organizational change, regulatory innovation, and industry-wide standards development. Panel discussions and expert insights provide a pathway for continued collaboration and knowledge sharing. An incremental approach to sharing industry-wide knowledge is further recommended.
    Keywords:  FAIR data principles; Findable, Accessible, Interoperable, and Reusable; change management; clinical trials; data governance; digital transformation; health equity; implementation barriers; mixed methods research; organizational innovation; patient-centered care; pharmaceutical industry; technology adoption
    DOI:  https://doi.org/10.2196/91531
  49. J Med Internet Res. 2026 Oct 07. 28 e96098
    Blockchain for Digital Health Governance: Evidence Gap Map and Scoping Review.
    Sarina Yaghobian, Nina Sulkowski, Gary Galambos, Linda Scarazzini, Nicolas Maloumian, Stephane Verhaeghe.
       Background: Digital health increasingly depends on data exchange across institutions, technologies, and jurisdictions, creating persistent challenges for the governance of access, consent, interoperability, provenance, and accountability. Blockchain and distributed ledger technology (DLT) systems have been proposed as mechanisms for coordinating and verifying governance processes across distributed actors. However, existing research has examined individual applications or technical domains, leaving unclear how blockchain/DLT systems function as governance infrastructure across health care, and whether these systems have progressed toward real-world implementation.
    Objective: This evidence gap map and scoping review aim to characterize how blockchain/DLT systems are applied to health data governance, identify the health care application domains, and governance functions addressed by these systems, and assess their evidence maturity.
    Methods: We searched PubMed/MEDLINE, Embase, Scopus, and Dimensions (Digital Science), and conducted backward and forward citation searching to identify peer-reviewed studies reporting blockchain/DLT systems in health care with an implemented artifact, technical evaluation, simulation, benchmark, pilot/usability assessment, or operational deployment, published between January 1, 2010, and February 28, 2026. Conceptual or architecture-only papers were excluded. Studies were charted by application domain, governance function, and evidence maturity (proof-of-concept/prototype, simulated/benchmarked evaluation, pilot/usability-tested implementation, or operational/real-world deployment). A focused narrative synthesis was conducted for studies reporting pilot/usability-tested implementation or operational/real-world deployment.
    Results: Of 892 included studies, the evidence base was dominated by proof-of-concept/prototype (n=418) and simulated/benchmarked evaluation (n=455) work; only 18 reported pilot/usability-tested implementation, and 1 reported operational/real-world deployment. Studies were concentrated in electronic health record management/health information exchange (n=372) and telemedicine/distributed care/Internet of Things (IoT)-enabled remote monitoring (n=250), followed by clinical decision support/smart health care (n=82), public health surveillance/certification (n=72), clinical trials/research governance (n=67), and health data marketplace/monetization (n=49). Across 3273 nonmutually exclusive governance-function codes, the most frequent functions were privacy/security, interoperability/data sharing, access control, data/model integrity, and identity/authentication. Publication activity increased over time, with the highest annual volumes in 2022 and 2025. This growth was not accompanied by a shift toward higher-maturity evidence. Privacy/security and interoperability/data sharing remained prominent across publication years, while other governance functions varied over time. Higher-maturity evidence was unevenly distributed across application domains, particularly clinical trials/research governance and electronic health record management/health information exchange. Within the 19 higher-maturity studies, evidence remained limited by small-scale evaluations, short follow-up, and a lack of sustained routine use beyond the evaluation period.
    Conclusions: Across digital health, blockchain/DLT systems were positioned as governance infrastructure for verifiable access, consent, provenance, identity, and audit trails, rather than as repositories for health data. Despite a growing literature, real-world implementation evidence remained limited. Whether blockchain/DLT systems improve governance outcomes over conventional architectures remains largely untested. Future research should prioritize comparative, implementation-focused evaluation of whether these systems can be integrated, sustained, and shown to provide governance benefits in real-world settings.
    Keywords:  blockchain; data governance; digital health; distributed ledger technology; evidence gap map; health information exchange; interoperability; scoping review
    DOI:  https://doi.org/10.2196/96098
  50. Brief Bioinform. 2026 Sep 01. pii: bbag511. [Epub ahead of print]27(5):
    Unsupervised identification of low-frequency antigen-specific TCRs using distance-based anomaly scoring.
    Kyohei Kinoshita, Tetsuya J Kobayashi.
      Identifying antigen-specific T cell receptors (TCRs) within the diverse human repertoire remains challenging, particularly for low-frequency clonotypes. Here, we present TCR-RADAR (TCR Rare Antigen-specific Detection by Anomaly Ranking), an unsupervised approach that detects low-frequency antigen-specific TCRs through distance-based anomaly detection in TCR sequence space. Using TCRdist3 to quantify sequence distances, we identify query TCRs that are anomalous relative to reference repertoires within their V-J gene combinations. We validated this approach across three immunological contexts: COVID-19 infection, influenza vaccination, and yellow fever vaccination. For SARS-CoV-2-specific TCR detection in a COVID-19 patient, our method achieved 34.3% precision, substantially higher than similarity-based (ALICE: 8.0%) and frequency-based methods (edgeR: 5.8%, the Pogorelyy method: 6.3%), and uniquely detected low-frequency antigen-specific TCRs present at a clone count of 1. The minimal overlap with conventional approaches (0%-6.7% across the three datasets) indicates our method captures distinct TCR clones overlooked by existing analyses. This distance-based approach provides a complementary strategy for TCR specificity detection, particularly valuable for identifying rare antigen-specific clones essential for understanding immune responses.
    Keywords:  T cell receptor; TCR repertoire; antigen specificity; immunoinformatics; unsupervised learning
    DOI:  https://doi.org/10.1093/bib/bbag511
  51. Biochem Pharmacol. 2026 Oct 08. pii: S0006-2952(26)00872-5. [Epub ahead of print] 118530
    Recent advances in Tumor microenvironment-responsive pro-antibody to overcome on-target, off-Tumor toxicity.
    Zhihao Wang, Mengjia Zhang, Yanchen Li, Ali Sahraianali Jahromi, Kangdong Liu, Jimin Zhao, Guoming Li.
      In recent years, monoclonal antibodies(mAbs) have become a new type of drug for disease treatment. Especially, the bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, all derived from targeting properties of mAbs, have achieved great success in the field of tumor treatment. However, due to the low expression of tumor-associated antigens in normal tissues, the "on-target, off-tumor" toxicity produced by these therapies has limited their development. To solve this problem, researchers have designed protease-activated, low pH-sensing, and high extracellular ATP-responsive pro-antibodies leveraging the special biochemical conditions of the tumor microenvironment (TME). This review summarizes the mechanism of action, recent advances, and the limitations of different TME-responsive pro-antibodies. Given the relative maturity of the protease-activated platform, its applications have been extended to bispecific antibodies, ADCs, and CAR-T cell therapies, which are also summarized in this review. Finally, we discuss the problems faced in the clinical translation of TME-responsive pro-antibodies low production yield and the lack of suitable preclinical animal models for safety assessment. In summary, this review provides a new perspective on the development of safe and efficient next-generation antibody therapies.
    Keywords:  ATP responsive; On-target, off-tumor toxicity; Pro-antibody; Protease-activated; Tumor microenvironment; pH sensing
    DOI:  https://doi.org/10.1016/j.bcp.2026.118530
  52. Pharmacoeconomics. 2026 Oct 06.
    Methods in Systematic Reviews of Health Economic Evaluations in Submissions to Health Technology Assessment Agencies: How Systematic Are They, and Does This Matter?
    Chris Bartlett, Rachael McCool, Matthew Taylor.
      Systematic reviews of health economic evaluations (SR-HEEs) are perceived as mandatory components of the health technology assessment (HTA) process in many jurisdictions. However, HTA agencies vary in how they prescribe reviews of HEEs should be conducted and the explicit purpose they serve. This article identifies the requirements of prominent HTA agencies, reports on the real-world conduct of SR-HEEs by health technology developers (HTDs), and explores their utility in the HTA process. International HTA guidelines were consulted, alongside a targeted review of SR-HEEs submitted to the National Institute for Health and Care Excellence (NICE) in 2024. While a systematic approach is a constant requirement to reviews of HEEs, it is defined inconsistently across agencies, with clinical and safety systematic reviews (SRs) receiving more rigid prescription. Consequently, SR-HEEs submitted to NICE demonstrated mixed methods. Despite these pragmatic deviations of SR-HEEs, External Assessment Groups (EAGs) raised no major concerns, and reimbursement decisions do not appear to be influenced. Our findings suggest a rigor gap between SR theory and practice, driven by the inherent heterogeneity of economic models, which renders quantitative pooling inappropriate. We submit that a more pragmatic approach to reviews of HEEs would be appropriate for HTA. To maximize utility and reduce resource waste, we propose a two-stage framework: early pragmatic "landscape mapping" to inform early model conceptualization, followed by a formal SR-HEE only when a specific useful research question is identified. This strategic realignment, possibly supported by emerging technologies, would enable HTA resources to be reallocated toward higher-value activities.
    DOI:  https://doi.org/10.1007/s40273-026-01672-7
  53. IEEE J Biomed Health Inform. 2026 Oct 06. PP
    Efficient Privacy-Preserving Medical Cross-Silo Federated Learning.
    Benjamin Hamm, Yannick Kirchhoff, Maximilian Rokuss, Philipp Schader, Peter Neher, Santhosh Parampottupadam, Ralf Floca, Klaus Maier-Hein.
      Federated Learning (FL) is becoming increasingly important for advancing machine learning in the medical domain, as it enables collaborative model training across multiple institutions without requiring them to share raw patient data. Unlike traditional centralized machine learning, which gathers data and trains the model in a single location, FL shares model updates among multiple independent participants, thereby keeping their data private. However, this decentralized structure-while privacy-preserving in principle-significantly expands the attack surface. Model updates exchanged between sites introduce new vulnerabilities, increasing the risk of unauthorized access, model poisoning, server-side eavesdropping, and potential leakage of sensitive patient information. Although established homomorphic encryption (HE) schemes such as CKKS, BFV, and BGV offer strong theoretical guarantees for secure computation, their high computational overhead often renders them impractical for real-world medical applications. To address this, we introduce a novel Secure Multi-Party Computation (SMPC)-based protocol tailored specifically for FL in the healthcare context. Our approach holistically rethinks the entire FL-SMPC pipeline, incorporating concurrency at critical stages to improve runtime efficiency while preserving strong security guarantees for the aggregated global model on the server side-an often overlooked aspect in existing SMPC approaches.
    DOI:  https://doi.org/10.1109/JBHI.2026.3740976
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