bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–10–04
fifty-two papers selected by
Luca Bolliger, lxBio
  1. Anti-CD19 CAR T-cell therapy for autoimmune diseases: from exploratory clinical trials to quantitative pharmacodynamic modeling development.
  2. Next-generation CAR-T cell therapy against cancer: precision engineering, programmable immunity, and emerging clinical frontiers.
  3. Recent advancements and persisting challenges in the evolution of next generation car t cell therapy for solid malignancies: a comprehensive review.
  4. CAR T cell cancer immunotherapy: who does the job?
  5. Chimeric antigen receptor T-cell therapy in neuroimmune diseases: mechanistic rationale, clinical experience, and translational challenges.
  6. Adoptive T Cell therapy for cancer and autoimmune disease: current advances, challenges, and future directions.
  7. Chimeric Antigen Receptor T Cell Therapy for Glioblastoma: Clinical Advances and Emerging Strategies.
  8. Managing Novel CAR T-Cell Toxicities in Multiple Myeloma.
  9. AI-powered biotherapies: Artificial intelligence and informatics at the intersection of transfusion medicine and biotherapies.
  10. The future directions of CAR-T Cell therapy: unlocking the potential of immunotherapy in cancer treatment.
  11. CAR-T Cell Therapy: Engineering Remission in Refractory Myeloma.
  12. Epigenetic programming via lysine-specific demethylase 1 regulates responses to immune checkpoint blockade.
  13. Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
  14. Advancing In Vivo Chimeric Antigen Receptor T-Cell Engineering to Accelerate Clinical Translation.
  15. mRNA processing in cancer immunotherapy: emerging targets, resistance mechanisms, and therapeutic opportunities.
  16. Discovery of candidate antibodies and antigens for acute myeloid leukemia therapy by combining whole-cell phage display selection and CRISPR-Cas9 library screening.
  17. Chimeric antigen receptor T cell therapy in autoimmune neurological disease: current status of efficacy and safety.
  18. BEACON: An Adaptive Bayesian Early-Phase Oncology Trial Design Integrating Dose Optimization and Proof-of-Concept Across Survival and Binary Endpoints.
  19. Safety Challenges and Emerging Solutions in Regenerative Medicine: Tissue Engineering, Cell Therapy, and Gene Therapy.
  20. Developing and validating a regulatory science competency framework for immune cell therapy: a mixed-methods study.
  21. Discovery of Post-Translationally Modified Epitopes in Autoimmunity: Someone Has to Fish so Everyone Can Eat.
  22. Orphan drug regulation: a global comparison of the United States Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency approaches.
  23. Systematic evaluation of MAIT and iNKT abundance as checkpoint blockade biomarkers.
  24. Clinical management strategies for cytokine release syndrome and their impact on CAR T-cell efficacy in lymphoma.
  25. Extracellular vesicle signaling in regulatory T cell biology: From immune suppression to microenvironmental crosstalk.
  26. Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis.
  27. A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
  28. The SPIZ study: rationale and protocol of a randomized controlled trial to optimize interdisciplinary care of patients following cellular therapy through a digitally supported, cross-regional and cross-sectoral care model.
  29. Next-generation CAR-T therapy for malignant brain tumors: latest updates from the 2026 AACR Annual Meeting.
  30. Chimeric Antigen Receptor T-cell therapy in systemic lupus erythematosus and other autoimmune diseases: a literature review.
  31. Defining value criteria for outcomes-based managed entry agreements in CAR-T therapy for relapsed/refractory multiple myeloma: a multi-criteria decision analysis study.
  32. The role of CHIP and pre-treatment neutropenia in patients treated with chimeric antigen receptor T cells for hematological malignancies.
  33. Lineage-specific immune checkpoint dynamics define a context-dependent regulatory framework with translational relevance in human γδ T cells.
  34. [Research on the Immunotherapy of T Cell Exhaustion in Multiple Myeloma --Review].
  35. Cost-effectiveness of Orca-T vs allo-HCT with conventional GVHD prophylaxis for the treatment of advanced hematologic malignancies in the United States.
  36. China now leads the world in trials for next-gen CAR-T therapies.
  37. Personalised neoantigen vaccines for precision oncology in Southeast Asia: clinical opportunities, infrastructure challenges, and policy perspectives.
  38. Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.
  39. Preventing infections after CD19-directed chimeric antigen receptor T-cell therapies for lymphoma: a consensus practice statement.
  40. Artificial intelligence in oncology: linking biological discovery to clinical utility.
  41. PTPN22 as a novel therapeutic target: a key intracellular checkpoint for NK cell therapy.
  42. mRNA lipid nanoparticle vaccines: current status, challenges and future prospects.
  43. Genetically inducible coordinators of cytokine signaling pathways for interrogating T cell motility.
  44. Comparative Cost and Utilization Analysis of CAR-T Therapy and Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma in Germany: Insights from Statutory Health Insurance Billing and Nationwide Inpatient Data.
  45. Immunophenotyping of Cellular Therapy Products Against Oncogenic and Viral Targets.
  46. CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.
  47. CAR-T Versus Non-CAR-T Bridging Strategies Before Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia: A Systematic Review.
  48. Beyond T cells: B cells in immune checkpoint blockade.
  49. Immunotherapy refractoriness and early post-alloHCT relapse define ultra-high-risk B-ALL after CD19 CAR T-cell therapy.
  50. The future of cancer therapy? Integrating oncolytic adenoviruses with epigetic modulation.
  51. Nanobodies as Versatile Next-Generation Biologics.
  52. Computational identification of B- and T-cell epitopes: a unified task taxonomy and review of databases, datasets, predictive pipelines, and gaps.
  1. Front Immunol. 2026 ;17 1823722
    Anti-CD19 CAR T-cell therapy for autoimmune diseases: from exploratory clinical trials to quantitative pharmacodynamic modeling development.
    Yuqin Sun, Xiao Heng, Guang Hu, Xiumei Bo.
      Anti-CD19 CAR T-cell therapy has produced major advances in treating hematologic malignancies. Recently, researchers have explored its use in autoimmune diseases. However, the complex pathogenesis and high heterogeneity of these disorders create substantial uncertainty about treatment efficacy and safety in clinical settings. Quantitative systems pharmacology (QSP) models integrate multiple pathophysiological mechanisms and map real patients onto virtual "digital twins" to simulate the in vivo behavior of a given CAR T-cell dose after infusion and to predict benefits and risks. Such models can also inform optimization of infusion dosing, advancing personalized therapy. This review summarizes current applications of anti-CD19 CAR T cells in autoimmune diseases and surveys the state of quantitative mathematical modeling in the field. Building on existing models, we propose an idealized QSP framework intended to guide the development of more refined, actionable models.
    Keywords:  Anti-CD19 CAR T; autoimmune diseases; immunotherapy; individualized treatment; quantitative systems pharmacology models
    DOI:  https://doi.org/10.3389/fimmu.2026.1823722
  2. J Egypt Natl Canc Inst. 2026 Sep 29. pii: 76. [Epub ahead of print]38(1):
    Next-generation CAR-T cell therapy against cancer: precision engineering, programmable immunity, and emerging clinical frontiers.
    Faizan-E- Mustaffa, Muhammad Shahbaz Aslam, Muhammad Junaid.
      While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematological malignancies, there are significant hurdles to overcome, such as antigen escape, T-cell exhaustion, limited persistence in the body, severe toxicities, manufacturing complexity, high costs, and low effectiveness in the treatment of solid tumors. There are many reviews describing novel CAR-T technologies, the evidence strength, clinical maturity and unmet translational risks of each are largely included in those reviews. This review highlights the ways in which next-generation engineering increases the safety, efficacy and programmability of CAR-T. The primary and authoritative clinical, regulatory and preclinical evidence on recent advances from 2022 to 2026 was carefully evaluated, including the quality and quality control of the evidence for each strategy. New innovations are Armored CARs, dual-target and logic-gated/synNotch systems, universal and switchable platforms, CRISPR/Cas9 and base/prime editing, allogeneic CAR-Ts, non-viral manufacturing, and lipid-nanoparticles in vivo CAR-T generation. Additionally, the engineering and combination approaches for the treatment of solid tumors with checkpoint inhibitors, radiotherapy, oncolytic viruses, nanotechnology, and artificial intelligence are discussed. An evidence-to-maturity framework separates the clinically proven methods from the emerging technologies and highlights some of the critical translation hurdles related to safety, immunogenicity, durability, manufacturing and scale. Precision Immunotherapy is becoming more and more possible with the next generation CAR-T engineering, however the validation and translational optimization of these cells is dominant to their eventual clinical use.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor T cells (CAR-T); Genome editing; Precision immunotherapy; Synthetic biology
    DOI:  https://doi.org/10.1186/s43046-026-00415-1
  3. Immunol Res. 2026 Sep 30. pii: 117. [Epub ahead of print]74(1):
    Recent advancements and persisting challenges in the evolution of next generation car t cell therapy for solid malignancies: a comprehensive review.
    Muhammad Ahsan Waqar, Aqsa Malik, Naeem Mubarak.
      Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising types of immunotherapies for the treatment of cancer. Unlike conventional T cells, which recognize antigens only when presented by the major histocompatibility complex (MHC), CARs use an antibody-derived binding domain to recognize native tumor-associated surface antigens directly, enabling MHC-independent target recognition. The two main cytotoxic mechanisms used by CAR T cells are the quick release of lytic granules containing granzymes and perforin to cause target cell apoptosis and the activation of death-receptor pathways (FasL/Fas or TRAIL) to cause caspase-dependent cell death. Four generations of CAR designs have been created to improve therapeutic efficacy and an advanced fifth generation is under development. Although CAR-T therapies have been very successful in treating hematological malignancies, their efficacy in solid tumors is limited because of immunosuppressive tumor microenvironments, tissue architecture, and antigen expression patterns that prevent CAR-T cell infiltration, activation, and persistence. With encouraging but early results, CAR T-cell therapy is moving forward into many clinical studies aimed at different solid tumors. Antigens including epidermal growth factor receptor (EGFR), mesothelin (MSLN), Disialoganglioside 2 (GD2), and B7-H3 were the subject of important clinical research conducted between 2021 and 2025. Emerging cellular treatments such as Chimeric Antigen Receptor Natural Killer cells (CAR-NK), CAR-macrophages and T-cell receptor (TCR)-engineered T cells offer alternate options to circumvent the limitations of CAR T-cells in solid tumors. This review aims to examine the evolution of next-generation CAR-T cell therapy for solid tumors by highlighting recent innovations, key clinical advancements, and persisting therapeutic challenges. It further seeks to analyze the biological and translational barriers limiting efficacy in solid malignancies and to explore emerging strategies and future directions that may enhance clinical outcomes.
    Keywords:  CAR T-cell therapy; CAR-NK cells; CAR-macrophages; Next-generation cellular therapies; Solid tumors; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12026-026-09850-7
  4. Front Immunol. 2026 ;17 1955025
    CAR T cell cancer immunotherapy: who does the job?
    Dennis Christoph Harrer, Markus Barden, Hinrich Abken.
      Chimeric antigen receptor (CAR) T cells are capable to eliminate cancer cells in the treatment of hematologic malignancies, yet the efficacy is frequently inconsistent and limited by cancer cell resistance and antigen-loss resulting in early tumor relapses. While CAR T cells are deemed to be the primary effectors in controlling the tumor, maturing evidence indicates that therapeutic outcomes are shaped by a broader immune cell network involving both the endogenous adaptive and innate immunity. In this review, we reframe CAR T cell therapy as the induction of a multi-system immune response rather than a uni-directional cytotoxic cell-autonomous intervention. We discuss the respective contributions of CAR T cells, innate immune cells, and host adaptive immunity in controlling tumor progression and outline strategies to recruit innate immunity using TRUCKs, armored CAR T cells, as well as immunological adjuvants to surmount current limitations. Finally, we address the risks associated with excessive innate immune activation and propose that a calibrated, broad immune cell activation should be viewed as design principle for next-generation CAR T cell therapies.
    Keywords:  CAR - T therapy; T cell; anti-tumor response; chimeric antigen receptor (CAR); innate cell
    DOI:  https://doi.org/10.3389/fimmu.2026.1955025
  5. Front Immunol. 2026 ;17 1913956
    Chimeric antigen receptor T-cell therapy in neuroimmune diseases: mechanistic rationale, clinical experience, and translational challenges.
    Yaqiao Yi, Hui Xiao, Yitong Yin, Rong Zeng, Qingqing Yan, Yonghe Wu, Kailin Yang, Guilong Fu, Hui Xu, Xiongmei Zhang.
      Neuroimmune diseases comprise a heterogeneous group of disorders in which B cells, plasmablasts, plasma cells, autoantibodies, and T cells contribute differently to tissue injury. Although B-cell-directed biologics have improved disease control, some patients continue to experience treatment-refractory activity, relapse after treatment withdrawal, or cumulative neurological disability. Chimeric antigen receptor T-cell (CAR-T cell) therapy offers a means of achieving deeper and potentially sustained depletion of defined pathogenic immune-cell compartments. This narrative review integrates the mechanistic rationale, target selection, platform design, published human experience, and translational challenges of CAR-T cell therapy in neuroimmune diseases. Current strategies predominantly target CD19-expressing B-lineage cells or BCMA-expressing antibody-secreting cells; these therapeutic targets are distinct from disease autoantigens, and their relevance depends on the immunopathology of each disorder. CAR design, persistence, lymphodepletion, and the use of integrating or transient expression platforms further influence treatment activity and risk. Clinical development remains uneven across indications. Myasthenia gravis has the most diverse clinical experience, encompassing integrating CD19-, BCMA-, and dual CD19/BCMA-targeted products, together with a transient BCMA-targeted mRNA platform evaluated in a randomized, placebo-controlled phase 2b study. In neuromyelitis optica spectrum disorder, an open-label phase 1 study has demonstrated early clinical and immunological activity of BCMA-targeted CAR-T cells. Evidence in multiple sclerosis and stiff-person syndrome is derived from individual reports, small early-phase studies, and conference data, whereas experience in other neuroimmune diseases remains limited to isolated reports or small case series. Across indications, interpretation is constrained by small and heterogeneous cohorts, limited follow-up, and the predominance of uncontrolled observations. Major translational considerations include target breadth and selectivity, the contribution of lymphodepletion, the disease-dependent relevance of central nervous system trafficking, acute and delayed toxicity, patient selection, manufacturing feasibility, biomarker development, and standardized long-term outcome assessment. CAR-T cell therapy has shown preliminary clinical activity in selected patients with refractory neuroimmune diseases, but its comparative efficacy, durability, and long-term safety remain undefined. It therefore remains investigational for most neuroimmune indications.
    Keywords:  Stiff-Person syndrome; autoimmune encephalitis; chimeric antigen receptor T-cell therapy; multiple sclerosis; myasthenia gravis; myelin oligodendrocyte glycoprotein antibody-associated disease; neuroimmune diseases; neuromyelitis optica spectrum disorder
    DOI:  https://doi.org/10.3389/fimmu.2026.1913956
  6. Oncol Rev. 2026 ;20 1905358
    Adoptive T Cell therapy for cancer and autoimmune disease: current advances, challenges, and future directions.
    Qiu-Hong Bao, Angel Wu, Jianming Pang, Junwei Wang, Qingqing Chen, SuWen Wu.
      Adoptive T Cell Therapy (ACT) is a kind of immunotherapy that eliminates target cells by autologous T cells. Since the mechanism of adoptive immune was elucidated, ACT has been developed for more than half a century. As one of ACTs, chimeric antigen receptor (CAR)-T cell therapy produced remarkable clinical responses in some hematological malignancies that is considered revolutionary strategy of immunotherapy. However, the effects of CAR-T cell therapy in solid tumors are hindered by immunosuppressive environment and limit of CAR to only recognize antigens on the cell surface. T cell receptor-engineered T cell (TCR-T) therapy is another type of ACT that the TCR is programmed to match crucial tumor antigens according to next-generation sequencing and bioinformatics analysis. The therapy overcomes the obstacles in solid tumor treatment by CAR-T, while there are also some problems dampening the response such as tumor immune escape, T cell exhaustion and toxicity. Beyond oncology, ACT is also applied in autoimmune diseases for it can specifically target and kill related immunocytes. In this review, we summarize the characteristics and clinical trials of CAR-T and TCR-T for cancer and autoimmune diseases. Differences, challenges and prospect of these ACTs are also described for reference to novel strategy of ACT.
    Keywords:  T cell receptor-engineered T cell (TCR-T) therapy; autoimmune diseases; cancer; cancer treatment; chimeric antigen receptor T cell (CAR-T) therapy,
    DOI:  https://doi.org/10.3389/or.2026.1905358
  7. Hematol Oncol Clin North Am. 2026 Sep 30. pii: S0889-8588(26)00102-4. [Epub ahead of print]
    Chimeric Antigen Receptor T Cell Therapy for Glioblastoma: Clinical Advances and Emerging Strategies.
    Eric P Grewal, Rishab Ramapriyan, William T Curry, Bryan D Choi.
      Chimeric antigen receptor (CAR) T cell therapy is a promising investigational modality for glioblastoma (GBM), but durable disease control has been limited by antigen heterogeneity, adaptive resistance, and an immunosuppressive tumor microenvironment. Early phase I studies targeting IL-13Rα2, HER2, EGFRvIII, EphA2, B7-H3, and GD2 established proof-of-concept for CAR T cell therapy in recurrent GBM and provided important clinical insights regarding feasibility, safety, and resistance mechanisms. More recent approaches, including multi-antigen targeting and locoregional delivery, aim to address these limitations, and ongoing trials evaluating new antigens and engineered platforms may further expand the clinical potential of CAR T cells in GBM.
    Keywords:  Cellular engineering; Chimeric antigen receptor therapy; Glioblastoma; Intraventricular injections; Investigational therapies; Neoplasm antigens; Single-chain antibodies; Tumor escape
    DOI:  https://doi.org/10.1016/j.hoc.2026.08.001
  8. Cancer J. 2026 Sep-Oct 01;32(5):pii: e00849. [Epub ahead of print]32(5):
    Managing Novel CAR T-Cell Toxicities in Multiple Myeloma.
    Kwan-Keat Ang, Jodi Lipof, Anupama Kumar, Lekha Mikkilineni, Alfred Chung, Shagun Arora, Peter Sayre, Jeffrey Wolf, Ajai Chari, Thomas Martin, Darren Pan.
      B-cell maturation antigen (BCMA) targeted chimeric antigen receptor T-cell (CAR-T) cell therapy has proven highly efficacious for relapsed multiple myeloma, inducing deep and durable remissions. Recent reporting has bolstered significant enthusiasm, describing upwards of one-third of patients in continued remission, 5 years following BCMA CAR-T without receiving any subsequent therapy, suggesting the possibility that this treatment may offer the hope of a cure. There are many well-characterized side effects from CAR-T, and mitigation strategies have been established to make this therapy safe. However, as the use of CAR-T cells has become more widespread, several novel and unanticipated side effects have emerged. These novel toxicities of CAR-T can be delayed, occurring within the first 3 to 6 months, and can be life-threatening or life-altering. Thus, early detection and timely management are essential. This comprehensive review will cover the diagnosis and management of common and emerging toxicities associated with CAR T-cell therapy for multiple myeloma.
    Keywords:  B-cell maturation antigen; CAR-T; G-protein coupled receptor 5D; Multiple myeloma ; cytokine release syndrome; immune effector cell associated enterocolitis; immune effector cell associated hemophagocytic lymphohistiocytosis-like syndrome; immune effector cell associated neurotoxicity; motor neurocognitive toxicity; neurotoxicity
    DOI:  https://doi.org/10.1097/PPO.0000000000000849
  9. Transfusion. 2026 Sep;66 Suppl 2 S94-S107
    AI-powered biotherapies: Artificial intelligence and informatics at the intersection of transfusion medicine and biotherapies.
    Ruchika Goel, Kevin Land, Brianna Schoen, Ralph Vassallo, Becky Cap.
       BACKGROUND: The rapid evolution of biotherapies-encompassing hematopoietic stem cell transplantation (HSCT), chimeric antigen receptor T-cell (CAR-T) therapies, gene-modified cellular therapies, and CRISPR-based platforms-has fundamentally transformed hematology, oncology, and regenerative medicine. Artificial intelligence (AI) and machine learning (ML) are increasingly recognized as potential central enablers of precision biotherapies, yet their systematic applications across the biotherapy pipeline remain incompletely characterized.
    METHODS: This narrative review synthesizes published literature, registry data, and emerging regulatory frameworks to examine 12 transformative applications of AI/ML and informatics in the biotherapy ecosystem, organized within three thematic domains: (1) precision donor-recipient matching, cell and gene therapy engineering, and outcomes monitoring; (2) AI/ML-enabled simulation, adaptive clinical trials, and quality control; and (3) informatics infrastructure, multi-omics integration, and regulatory science.
    RESULTS: AI/ML demonstrates significant potential across the biotherapy pipeline: from advanced HLA donor-recipient matching and CAR construct optimization to manufacturing process analytics, digital twin simulation, automated quality control, and long-term survivorship prediction. Applications span a maturity spectrum from early clinical adoption (HLA matching, manufacturing QC) to largely conceptual stages (digital twins, personalized conditioning). Critical challenges include algorithmic bias, explainability deficits, reproducibility gaps, and evolving data privacy and regulatory frameworks.
    CONCLUSION: AI and informatics are positioned to usher in a new era of precision, data-driven biotherapies. Realizing this potential requires interdisciplinary collaboration, rigorous external validation, equitable dataset representation, and alignment with emerging regulatory standards to ensure safe, transparent, and patient-centered integration into clinical and manufacturing workflows.
    Keywords:  Biotherapies; Cell Therapy; Gene Therapy; Machine Learning; Transfusion Medicine;  Artificial Intelligence
    DOI:  https://doi.org/10.1111/trf.70324
  10. Front Mol Med. 2026 ;6 1931159
    The future directions of CAR-T Cell therapy: unlocking the potential of immunotherapy in cancer treatment.
    Angel Alberto Justiz-Vaillant, Sachin Soodeen, Rodolfo Arozarena-Fundora, Patrick Eberechi Akpaka, Chandrashekhar Unakal.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment landscape for relapsed and refractory haematological malignancies, producing durable clinical responses in patients with otherwise limited therapeutic options. Despite these advances, significant biological, clinical, and economic barriers continue to limit its broader application, particularly in solid tumours. This literature review critically evaluates recent developments in CAR-T cell therapy, with emphasis on areas that have received limited discussion in previous reviews. Multi-target CAR strategies, including bispecific, tandem, and pooled CAR-T cell approaches, are comparatively assessed with respect to antigen escape, manufacturing complexity, therapeutic efficacy, and safety. Current challenges in solid tumour treatment are examined through evidence from clinical trials, highlighting key obstacles such as antigen heterogeneity, the immunosuppressive tumour microenvironment, poor cellular trafficking, and treatment-related failures that have informed the development of next-generation CAR constructs. Emerging approaches to overcoming antigen loss, including γδ CAR-T cells, are reviewed alongside their current limitations, including restricted ex vivo expansion, donor variability, isolation challenges, and uncertain long-term persistence. The review also addresses the growing importance of improving affordability and accessibility through allogeneic "off-the-shelf" CAR-T products, genome editing technologies, automated manufacturing platforms, and rational combination therapies designed to enhance efficacy while reducing treatment costs. In addition, advances in toxicity prediction are evaluated, focusing on biomarkers beyond interleukin-6, including ferritin, C-reactive protein, soluble interleukin-2 receptor alpha, and multiparametric cytokine signatures for the early identification of severe cytokine release syndrome. Collectively, these developments demonstrate that future progress in CAR-T cell therapy will depend not only on enhancing antitumour efficacy but also on improving safety, accessibility, manufacturing efficiency, and equitable global implementation through evidence-based innovation.
    Keywords:  CAR cost; CAR-T cell therapy; allogeneic CAR-T cells; cytokine release syndrome; multi-target CAR-T cells; precision medicine; predictive biomarkers; solid tumours
    DOI:  https://doi.org/10.3389/fmmed.2026.1931159
  11. Cancer J. 2026 Sep-Oct 01;32(5):pii: e00854. [Epub ahead of print]32(5):
    CAR-T Cell Therapy: Engineering Remission in Refractory Myeloma.
    Adam S Sperling.
      Chimeric antigen receptor (CAR) T cells have rapidly reshaped the treatment of relapsed and refractory multiple myeloma (MM), progressing from an experimental salvage option to a therapy with a demonstrated overall survival advantage and durable, potentially curative remissions in a subset of patients. This review surveys the current evidence supporting their use, the biology underlying their successes and failures, established and emerging toxicities, and novel approaches that will define the field in the coming years. Approved products directed against B cell maturation antigen (BCMA) induce rapid and deep responses even in heavily pretreated patients, and long-term follow-up now suggests a meaningful fraction of patients achieve prolonged remission after a single infusion without maintenance therapy. These benefits are accompanied by distinctive toxicities that shape the risk-benefit calculus as therapy moves to earlier lines and even to treatment naïve patients. We discuss the determinants of response and relapse, as well as the mechanisms of antigen-positive and antigen-negative escape that next-generation approaches aim to overcome. These include novel antigen targets, multi-antigen and armored constructs, rapid manufacturing, and in vivo CAR generation, all with the goal of extending durable remissions to every patient.
    Keywords:  CAR-T; cell therapy; multiple myeloma
    DOI:  https://doi.org/10.1097/PPO.0000000000000854
  12. Trends Pharmacol Sci. 2026 Oct 01. pii: S0165-6147(26)00235-X. [Epub ahead of print]
    Epigenetic programming via lysine-specific demethylase 1 regulates responses to immune checkpoint blockade.
    Xiaoshuang Niu, Bin Yu.
      Immune checkpoint blockade has revolutionized cancer therapy, but durable benefit remains limited by immune-cold tumor states, poor antigen presentation, T cell exhaustion, and adaptive resistance. Recent studies position lysine-specific demethylase 1 (LSD1) as a druggable epigenetic regulator that links these barriers across tumor and immune cells. Emerging evidence shows that targeting LSD1 can restore major histocompatibility complex class I antigen presentation, activate viral mimicry and interferon programs, modulate programmed death-ligand 1 in a context-dependent manner, influence CD8+ T cell state transitions, and restrain tumor plasticity. In this review, we feature these mechanistic advances, compare evolving drug classes, and outline biomarker-guided strategies that may support the rational development of next-generation combination immunotherapy.
    Keywords:  LSD1; cancer immunotherapy; epigenetic therapy; immune checkpoint blockade; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tips.2026.09.006
  13. Signal Transduct Target Ther. 2026 Oct 01. pii: 419. [Epub ahead of print]11(1):
    Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.
    Zhuolin Fan, Xu Zheng, Chuan Jin, Jingting Zhang, Ningqiang Gong, Xuexin Li.
      The application of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies has driven significant advancements in this form of immunotherapy. The therapeutic strategy of CAR-T cells targeting specific cell populations has opened new avenues for treating non-oncological diseases, such as autoimmune diseases, aging-related conditions, and infections. For instance, in non-oncological diseases like systemic lupus erythematosus (SLE), abnormal B cell development or dysfunction leads to the production of autoantibodies, triggering localized deposition of immune complexes and resulting in tissue or organ damage and dysfunction. Relevant studies have identified disease-specific surface antigens or pathogenic cell subsets, making CAR-T cell therapy a feasible treatment approach. Moreover, in non-oncological diseases, CAR-T cells can mediate immune remodeling for certain conditions, thereby achieving long-term therapeutic remission. Although no CAR-T therapies have yet been approved for non-oncological diseases, multiple clinical trials have been initiated, with some achieving interim successes (e.g., allogeneic CAR-T cells have demonstrated efficacy in treating rheumatic diseases). Meanwhile, ongoing research into the pathogenesis of non-neoplastic diseases further supports the potential application of CAR-T cells. With this background, this article aims to introduce the latest research, mechanisms, and applications of CAR-T cell therapy in non-oncological diseases, summarize the pathogenesis of related disorders, and discuss the advantages, challenges, and future prospects of CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s41392-026-02783-5
  14. MedComm (2020). 2026 Oct;7(10): e71030
    Advancing In Vivo Chimeric Antigen Receptor T-Cell Engineering to Accelerate Clinical Translation.
    Zhenxin Bai, Ming Yi, Shengtao Hu, Dixuan Xue, Luxin Wei, Lifeng Zhang, Zhijun Dai.
      Chimeric antigen receptor T-cell (CAR-T) therapy is a transformative tumor immunotherapy that redirects autologous T cells to eliminate malignant cells. However, its broader clinical translation is constrained by complex and costly ex vivo manufacturing, variable product quality, and limited control over in vivo activity. In vivo CAR-T engineering enables direct T-cell programming in the body, reducing reliance on ex vivo manufacturing while improving T-cell fitness and antitumor efficacy. This approach also enables flexible dosing and may obviate lymphodepletion. This review first summarizes recent advances in in vivo CAR-T engineering and the evolution of CAR architectures. We then examine viral and non-viral delivery systems, including lentiviral vectors (LVs), adeno-associated virus (AAV) vectors, lipid nanoparticles (LNPs), polymeric nanoparticles (PNPs), and emerging platforms, highlighting their distinct advantages and limitations. We further evaluate strategies to facilitate clinical translation, focusing on safety and efficacy. Finally, we discuss emerging opportunities enabled by biomaterials and artificial intelligence to improve scalability and accessibility while broadening therapeutic applications. This review provides a framework for understanding in vivo CAR-T engineering and highlights key strategies for overcoming translational barriers and advancing next-generation CAR-T therapies.
    Keywords:  delivery systems; in vivo chimeric antigen receptor T‐cell; translational strategies; tumor immunology
    DOI:  https://doi.org/10.1002/mco2.71030
  15. Front Immunol. 2026 ;17 1889279
    mRNA processing in cancer immunotherapy: emerging targets, resistance mechanisms, and therapeutic opportunities.
    Yunus Yukselten, Haseeb Ahmad, Mohammed Shoultout, Uzair Iqbal, Faizan Masood, Richard E Sutton.
      Cancer immunotherapy has improved outcomes across many tumor types, but primary and acquired resistance, tumor heterogeneity and a shortage of safe targets remain unresolved. Part of this gap arises because tumor cells evade immune recognition not only through genomic mutation but also through post-transcriptional mRNA processing, a network comprising 5' capping, splicing, alternative polyadenylation (APA), RNA editing, epitranscriptomic modification, nonsense-mediated decay (NMD), RNA stability and translational control. These processes govern antigen presentation, transcript degradation, checkpoint expression and the suppression of innate immune sensing. Here we examine how mRNA processing can extend the target space of cancer immunotherapy. We consider alternative splicing as a source of tumor-specific isoforms, public neoantigens and chimeric antigen receptor (CAR) or T-cell receptor (TCR)-based targets; the effect of APA and 3'UTR remodeling on checkpoints such as PD-L1; the role of m6A, ac4C and other epitranscriptomic marks in antigen presentation, interferon signaling and the tumor microenvironment; the contribution of ADAR1-mediated editing to immunotherapy resistance through suppressed dsRNA and Z-RNA sensing; and the function of NMD as an antigen filter. We also review the discovery technologies that make these targets accessible, and assess the current state of clinical translation, including agent development, target specificity, patient selection, biomarkers and safety. mRNA processing-derived targets offer new sources of antigens, biomarkers and combination strategies in tumors with low mutational burden or refractory to checkpoint blockade. Realizing this will require validation of RNA-level candidates at the protein and HLA-peptide level, together with attention to tumor-normal specificity, HLA restriction, tumor heterogeneity and toxicity.
    Keywords:  3′UTR remodeling; RNA editing; cancer immunotherapy; chemokines; epitranscriptomics; immunopeptidomics; mRNA processing; splicing-derived neoantigens
    DOI:  https://doi.org/10.3389/fimmu.2026.1889279
  16. Antib Ther. 2026 Oct;9(4): 576-594
    Discovery of candidate antibodies and antigens for acute myeloid leukemia therapy by combining whole-cell phage display selection and CRISPR-Cas9 library screening.
    Koji Hashimoto, Verena Konetzki, Andoni Garitano-Trojaola, Sabrina Kraus, Sabrina R Friedel, Michael Hudecek, Haiyong Peng, Christoph Rader.
       Background: Acute myeloid leukemia (AML) remains challenging to treat and often requires intensive chemotherapy. In contrast to other hematologic malignancies, the development of effective antibody-based and cellular immunotherapies for AML has been limited by the scarcity of suitable target antigens.
    Methods: We applied a phage display-based whole-cell panning method in which Fab-phage were biotinylated and captured, followed by next-generation sequencing (NGS), bioinformatic, and statistical analyses. Target deconvolution was performed using a CRISPR-Cas9 knockout library, fluorescence-activated cell sorting of antigen-negative cells, and NGS-based gRNA analysis. Selected candidates were further evaluated using primary AML patient cells and chimeric antigen receptor (CAR)-T cell assays.
    Results: We identified 28 unique monoclonal antibodies that preferentially bound AML cell lines. CRISPR-Cas9-based target deconvolution enabled efficient identification of three cognate antigens. Selected lead candidates were validated by staining primary cells from AML patients and were engineered into CAR constructs. CAR-T cells targeting the identified antigens mediated efficient eradication of AML cell lines and primary AML cells.
    Conclusions: This integrated antibody-based antigen discovery and validation approach may accelerate the development of monoclonal antibody- and CAR-based immunotherapies for AML and other indications.
    Keywords:  CAR-T; CRISPR-Cas9 library screening; acute myeloid leukemia; antibody discovery; cancer immunotherapy; phage display
    DOI:  https://doi.org/10.1093/abt/tbag043
  17. BMJ Neurol Open. 2026 ;8(2): e001611
    Chimeric antigen receptor T cell therapy in autoimmune neurological disease: current status of efficacy and safety.
    Peter Bradhurst, Todd A Hardy, Sean Riminton.
      Autoimmune neurological diseases affecting the central nervous system, peripheral nervous system and neuromuscular junction are frequently refractory to conventional B-cell-depleting therapies such as CD20-directed monoclonal antibodies, highlighting a need for more effective treatment approaches. Chimeric antigen receptor T (CAR-T) cell therapy, initially developed for haematological malignancy, has been repurposed to more comprehensively deplete pathogenic B-cell and plasma cell populations in autoimmune disease, raising the possibility of durable, treatment-free remission. This scoping review, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-ScR guidelines, examined published clinical studies from January 2023 to January 2026 in which CAR-T cells targeting CD19, CD20 or B-cell maturation antigen were used to treat autoimmune neurological disease, identifying 19 eligible studies. Efficacy signals were most consistent in refractory acetylcholine receptor antibody-positive generalised myasthenia gravis and Aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, with encouraging but more preliminary results reported in multiple sclerosis, Lambert-Eaton myasthenic syndrome, myelin oligodendrocyte glycoprotein antibody-associated disease, chronic inflammatory demyelinating polyneuropathy, stiff-person syndrome and autoimmune encephalitis. Relapse was reported across several conditions, with follow-up generally limited to under two years. The safety profile compared favourably with that seen in oncological CAR-T use, with lower rates of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, although cytopenias, infection and prolonged hypogammaglobulinaemia remain clinically significant, and local immune effector cell-associated toxicity syndrome is an emerging concern not yet formally reported in this population. Current evidence remains limited to small, largely uncontrolled studies with heterogeneous outcome reporting. Adequately powered, longer-term controlled trials are needed before CAR-T therapy can be recommended more broadly in the management of refractory autoimmune neurological disease.
    Keywords:  MULTIPLE SCLEROSIS; MYASTHENIA; NEUROIMMUNOLOGY; NEUROPATHY; STIFF MAN SYNDROME
    DOI:  https://doi.org/10.1136/bmjno-2026-001611
  18. Pharm Stat. 2026 Nov-Dec;25(6):25(6): e70127
    BEACON: An Adaptive Bayesian Early-Phase Oncology Trial Design Integrating Dose Optimization and Proof-of-Concept Across Survival and Binary Endpoints.
    Yike Tang, Feng Tian, Xiaochen Zhu, Guotao Chu, Liangang Liu, Hsin-Ju Hsieh, Shu-Pang Huang.
      Conventional dose selection in oncology, which focuses on the maximum tolerated dose (MTD), has certain limitations for targeted agents and immunotherapies, where the efficacy-toxicity relationship may not be monotonic. Regulatory initiatives such as FDA's Project Optimus highlight the need for improved dose optimization methods early in drug development. Although recent Bayesian dose-finding designs enhance flexibility by integrating efficacy data and adopting adaptive monitoring, most depend on binary response outcomes and lack sufficient proof-of-concept (PoC) assessment before advancing doses to confirmatory trials. To address these gaps, we propose BEACON, an extended Bayesian optimization framework for randomized phase II oncology trials. BEACON incorporates time-to-event endpoints into both dose selection and PoC assessment. Extending from the DODII method (Bayesian dose optimization for randomized phase II trials), BEACON combines Bayesian safety and futility monitoring with a pick-the-winner strategy for both survival and binary outcomes. The design dynamically borrows information across dose levels during PoC to enhance decision-making. By allowing both survival and binary outcomes within a unified dose optimization with PoC strategy, BEACON enhances design flexibility and delivers robust confirmation of clinical benefit, aligned with regulatory expectations for dose justification in early-phase oncology studies. Simulation studies demonstrate that the BEACON design exhibits favorable operating characteristics, effectively controlling false go and selection error rates for the recommended doses and reducing the total sample sizes of the trial. With adaptive borrowing across dose levels, the design robustly maintains the desired proof-of-concept power.
    Keywords:  bayesian design; dose optimization; information borrowing; proof‐of‐concept; survival endpoints
    DOI:  https://doi.org/10.1002/pst.70127
  19. Clin Ther. 2026 Sep 26. pii: S0149-2918(26)00345-0. [Epub ahead of print]
    Safety Challenges and Emerging Solutions in Regenerative Medicine: Tissue Engineering, Cell Therapy, and Gene Therapy.
    Seema Kumbhat.
       PURPOSE: Regenerative medicines such as tissue, cell therapy, and gene therapy have revolutionized the treatment paradigm for difficult-to-treat diseases. Despite their therapeutic promise, these therapies pose safety challenges due to risks in manufacturing, contamination, inadvertent biologic behavior, and immune reactivity. This commentary highlights key safety concerns across major regenerative medicine categories and emerging solutions to address these risks.
    METHODS: This commentary reviews current literature, manufacturer prescribing information, and regulatory perspectives involving tissue-engineered products, cell, and gene therapies. Key safety challenges common to and unique among these categories are examined, along with technological and regulatory approaches in development to improve product safety and consistency.
    FINDINGS: Major safety concerns include microbial and manufacturing process-related contamination, variability in product quality, off-target biological effects, unintended cell differentiation or persistence, insertional mutagenesis, and immune responses to transplanted cells or gene delivery vectors. Recent advances in manufacturing controls, close system processing, and vector engineering are improving safety profiles across these products. Additionally, new regulatory frameworks are promoting greater standardization and risk management throughout product development and commercialization.
    IMPLICATIONS: As regenerative medicine continues to expand, addressing safety challenges remains essential. Continued innovation in manufacturing, gene editing, and cell activation is critical for maximizing benefits while minimizing safety events. Understanding the safety challenges and emerging solutions will support broader integration of these therapies in clinical practice.
    Keywords:  CAR-T; Cell Therapy; Gene Therapy; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.clinthera.2026.09.005
  20. Front Med (Lausanne). 2026 ;13 1917978
    Developing and validating a regulatory science competency framework for immune cell therapy: a mixed-methods study.
    Jung-A Lee.
       Background: Advanced therapy medicinal products (ATMPs), particularly immune cell therapies, present distinctive regulatory challenges due to biological variability, evolving manufacturing processes, and uncertainty throughout the product lifecycle. Existing competency frameworks for regulatory science are predominantly generalist and may not adequately capture the domain-specific competencies required for immune cell therapy.
    Objective: To develop and validate a consensus-based competency framework for regulatory science professionals in immune cell therapy.
    Methods: An exploratory sequential mixed-methods design was employed, comprising a multi-source literature review, preliminary expert consultation, semi-structured expert interviews, and a two-round Delphi consensus process. Experts representing academia, industry, regulatory authorities, and government/public-sector organizations participated in the preliminary consultation and interviews (n = 11) and the Delphi consensus process (n = 20). Qualitative data were analyzed using reflexive thematic analysis. Delphi responses were analyzed using descriptive statistics, the content validity ratio, and the item-level content validity index to assess content validity in Round 1, and retention agreement, importance, educational applicability, and measurability in Round 2.
    Results: The final framework comprised nine core competencies and 32 sub-competencies organized into three areas: Scientific and Regulatory Foundations, Strategic Application of Regulatory Science, and Regulatory Leadership and Responsibility. High retention agreement (95%-100%) indicated the stability of the framework. Sub-competencies related to leadership, ethics, and higher-order judgment received relatively lower ratings for educational applicability and measurability but were retained because of their conceptual importance.
    Conclusion: This study presents a domain-specific competency framework that conceptualizes regulatory competence in immune cell therapy as an integrative and adaptive capability. The framework provides a practical foundation for competency-based training, assessment, and regulatory science workforce development in immune cell therapy and related ATMPs.
    Keywords:  Delphi method; adaptive expertise; advanced therapy medicinal products; competency framework; competency-based education; immune cell therapy; mixed-methods research; regulatory science
    DOI:  https://doi.org/10.3389/fmed.2026.1917978
  21. Immunol Rev. 2026 Oct;343(1): e70179
    Discovery of Post-Translationally Modified Epitopes in Autoimmunity: Someone Has to Fish so Everyone Can Eat.
    Sanya Arshad, Benjamin M Cameron, Alok V Joglekar.
      Post-translational modifications (PTMs) chemically diversify the ~20,000 genomically encoded proteins into millions of functional variants, and this diversity has profound consequences for T cell-mediated immune responses. PTM-reactive T cells have been identified across numerous autoimmune diseases and, in several cases, implicated directly as pathogenic drivers. Mechanistically, PTMs promote autoimmunity through two intertwined routes: by altering peptide-MHC and TCR binding to favor recognition of self-epitopes, and by generating neoepitopes in peripheral and/or inflamed tissues that are absent from the thymus, allowing PTM-reactive T cells to escape central tolerance. This cascade is amplified by inflammatory cytokines, upregulated antigen-processing machinery, disease-associated HLA alleles, and, in some cases, exogenous triggers such as diet. We use three well-characterized examples-citrullination in multiple autoimmune disorders, hybrid insulin peptide (HIP) formation in type 1 diabetes, and gluten deamidation in celiac disease-to illustrate how distinct PTM biology, tissue specificity, and genetic encodability shape the antigenic landscape and dictate feasible discovery strategies. We then review four complementary approaches for identifying PTM-specific T cell responses: mass spectrometry-based proteomics and immunopeptidomics, computational MHC-binding prediction, antigen-directed methods, and high-throughput T cell receptor (TCR)-directed library screening methods. For each, we discuss underlying principles, strengths, and limitations, with particular attention to the challenge posed by non-canonical, PTM-bearing residues. By comparing citrullination, HIPs, and gluten deamidation across these methodologies, we highlight how biochemical alterations, tissue accessibility, and mouse-to-human conservation determine which discovery approach is most tractable. We conclude that while synthetic peptide-based methods remain the standard for validating known epitopes, emerging high-throughput, cell-based platforms are rapidly expanding the accessibility of the PTM antigenic landscape for both known and undiscovered autoimmune epitopes.
    DOI:  https://doi.org/10.1111/imr.70179
  22. Farm Hosp. 2026 Sep 29. pii: S1130-6343(26)00209-6. [Epub ahead of print]
    Orphan drug regulation: a global comparison of the United States Food and Drug Administration, European Medicines Agency, and Japanese Pharmaceuticals and Medical Devices Agency approaches.
    Robinraja Elango, Russell Martin, Shivanand K Mutta.
       OBJECTIVE: To perform a comparative review of orphan drug policies and designation criteria implemented by the US Food and Drug Administration, the European Medicines Agency, and Japan's Pharmaceuticals and Medical Devices Agency, assessing their influence on development, approval, and access.
    METHOD: A targeted review of legislation, guidance documents, and peer-reviewed analyses from each regulatory body was conducted.
    RESULTS: The Food and Drug Administration accelerates development via robust tax credits and seven-year market exclusivity, though high pricing remains challenging. The European Medicines Agency emphasizes unmet medical needs and ten-year exclusivity, ensuring more homogeneous pricing despite slower approvals. Japan's Pharmaceuticals and Medical Devices Agency utilizes specific subsidies and the "Sakigake" designation to counter "drug loss" and encourage innovation. Despite expedited pathways globally, significant disparities in affordability and patient access persist.
    CONCLUSIONS: While national incentives successfully boost orphan drug approvals, global access inequities remain unresolved. Harmonizing regulatory criteria and promoting international collaboration on evidence requirements are essential for equitable and sustainable access to rare disease therapies worldwide.
    Keywords:  Administración de Alimentos y Medicamentos de Estados Unidos; Agencia Europea de Medicamentos; Agencia Japonesa de Productos Farmacéuticos y Dispositivos Médicos; Aprobación de medicamentos; Drug approval; Enfermedades raras; European Medicines Agency; Japanese Pharmaceuticals and Medical Devices Agency; Orphan drug regulation; Rare diseases; Regulación de medicamentos huérfanos; United States Food and Drug Administration
    DOI:  https://doi.org/10.1016/j.farma.2026.08.009
  23. Front Immunol. 2026 ;17 1917317
    Systematic evaluation of MAIT and iNKT abundance as checkpoint blockade biomarkers.
    Yueyi Li, LinLin Chen, Shiwen Shan, Haiyang Wang, Xiaofang Xing, Jian Zhang.
       Introduction: MAIT and iNKT cells are unconventional T cell lineages that bridge innate and adaptive immunity and have been implicated in antitumor immune responses and immunotherapy outcomes. However, evidence to date has largely derived from individual studies of selected cancer types or specialized immune profiling cohorts. Whether MAIT and iNKT abundance provides reproducible clinical information across large, multi-cancer immune checkpoint blockade (ICB) cohorts remains insufficiently evaluated.
    Methods: We applied an AI-based TCRβ inference framework to estimate MAIT and iNKT relative abundance from bulk TCRβ repertoires in healthy controls, patients with cancer, and ICB-treated cohorts. The main dataset included 1,619 samples from 420 healthy controls and 595 patients across 13 cancer types; response analyses used a discovery cohort of 964 samples from 436 patients across 9 cancer types and an independent validation cohort of 361 samples from 81 patients across 5 cancer types.
    Results: TCRβ-inferred estimates showed that both MAIT and iNKT abundance were reduced in pretreatment cancer PBMCs compared with healthy controls, supporting systemic perturbation of unconventional T cells in cancer. Abundance estimates were also tissue dependent, with MAIT showing lower inferred abundance in tumor biopsies than in PBMCs. In ICB cohorts, baseline MAIT and iNKT estimates in PBMCs or tumors were insufficient to distinguish responders from non-responders. Although on-treatment tumor iNKT estimates showed a modest enrichment in responders in the discovery cohort, this pattern had limited standalone predictive value and was not reproduced as a robust biomarker in validation.
    Discusson: These findings indicate that MAIT/iNKT abundance captures cancer-associated and tissue dependent immune variation but has limited value alone for predicting ICB response, highlighting the need to incorporate functional state, spatial localization, and broader immune context.
    Keywords:  T cell receptor (TCR); immune checkpoint blockade (ICB); invariant natural killer T (iNKT) cells; mucosal-associated invariant T (MAIT) cells; unconventional T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1917317
  24. Int Immunopharmacol. 2026 Sep 28. pii: S1567-5769(26)01312-3. [Epub ahead of print]190 117465
    Clinical management strategies for cytokine release syndrome and their impact on CAR T-cell efficacy in lymphoma.
    Kaihang Shi, Xueyan Sun, Gaoxiang Wang.
      Chimeric antigen receptor T-cell (CAR-T) therapy has significantly advanced the treatment of relapsed/refractory (R/R) lymphoma. However, its broader clinical application is often limited by cytokine release syndrome (CRS), a major immune-mediated complication. Because the in vivo expansion of CAR-T cells drives both tumor clearance and CRS, addressing this toxicity without impairing anti-tumor efficacy remains a critical clinical necessity. This review comprehensively evaluates current and emerging CRS management strategies across the entire treatment process. First, we explore proactive pre-infusion measures, such as bridging therapies and lymphodepletion regimens, which help mitigate baseline inflammatory risks. Next, we outline standard-of-care treatments for established CRS, focusing on the optimized dosing of corticosteroids and cytokine-blocking agents. We then discuss novel investigational approaches, including targeted kinase inhibitors and emerging cytokine-directed antibodies, that show potential to decouple inflammatory signaling from CAR-T cytotoxicity. Overall, our findings highlight that effective CRS management relies on a comprehensive strategy that optimizes established treatments and integrates novel targeted therapies. When adapted to individual clinical profiles, these customized approaches can effectively control systemic inflammation while potentially preserving anti-tumor efficacy, though more prospective trials are needed to confirm these findings.
    Keywords:  CAR-T; Cytokine release syndrome; Immunotherapy; Lymphoma; Pharmacotherapy
    DOI:  https://doi.org/10.1016/j.intimp.2026.117465
  25. Int Rev Immunol. 2026 Sep 28. 1-22
    Extracellular vesicle signaling in regulatory T cell biology: From immune suppression to microenvironmental crosstalk.
    Shruti Talekar, Vibha Lade, Sayantani Ghosh.
      Regulatory T cells (Tregs) are essential for maintaining immune homeostasis, yet classical suppressive mechanisms alone do not fully explain how tolerance is propagated across tissues and sustained over time. Extracellular vesicles (EVs), particularly exosome-enriched small EVs, have emerged as an important additional layer of Treg-associated communication by enabling the selective transfer of proteins, lipids and regulatory RNAs between cells. In this review, we examine the reciprocal EV-Treg axis, highlighting how Treg-derived EVs extend suppressive function beyond direct cell contact by modulating dendritic cells, restraining effector T-cell responses, promoting regulatory macrophage polarization and supporting tissue repair. We further discuss how EVs released by immune, epithelial, stromal, microbial and tumor-associated cells shape Treg differentiation, stability and functional specialization in diverse physiological and pathological settings. Across autoimmunity, transplantation, barrier inflammation, infection and cancer, this bidirectional crosstalk emerges as a context-dependent regulator of immune tolerance that may either preserve tissue homeostasis or promote pathological immune suppression. We finally consider the therapeutic potential of targeting or engineering EV-Treg interactions as a cell-free strategy for precision immunomodulation.
    Keywords:  EV cargo; exosomes; extracellular vesicles (EV); immune modulation; immunosuppression; regulatory T cells
    DOI:  https://doi.org/10.1080/08830185.2026.2736246
  26. medRxiv. 2026 Sep 11. pii: 2026.09.11.26361992. [Epub ahead of print]
    Immune Profiling after treatment with an Anti-CD19 Chimeric Antigen Receptor T Cell Therapy in Treatment-Refractory Progressive Multiple Sclerosis.
    Sasha Gupta, Madhav R Seshadri, Ravi Dandekar, Leonie Müller-Jensen, Krista McCutcheon, Leslie A Scarffe, ShiLu Vanasupa, Megumi Sunahara, Fumie Hayashi, Colette Caspar, Robin Lincoln, Naomi Okinishi, Nancy Thomas, Samantha Shenoy, Samantha Zylberman, Camille Fouassier, Ebtesam Hassan, Sam Klauer, Jenai Wilmoth, Joseph J Sabatino, Aaron Bodansky, Ahmed Abdelhak, Stephen L Hauser, Michael R Wilson, Bruce A C Cree.
      Treatment targeting progressive multiple sclerosis (MS) have limited efficacy, as central nervous system (CNS) resident B cells are resistant to peripheral B cell depletion by anti-CD20 monoclonal antibodies. CD19-targeted chimeric antigen receptor (CAR)-T cells offer the promise to deplete B cells more extensively in both the peripheral and CNS compartments. Two adult participants with treatment-refractory progressive MS were treated with 0.33×10^8 autologous anti-CD19 CAR-T cells (mivocabtagene autoleucel, miv-cel) intravenously after a preconditioning regimen. Participant 1 (50's year old female, EDSS 6) had no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Participant 2 (60's year old female, EDSS 4.5) had grade 1 CRS and no ICANS. Expansion of CAR-T cells in the cerebrospinal fluid (CSF) at Day 14 was noted in both participants, remarkably with sustained disappearance of disease-associated oligoclonal band (OCB) or normalization of IgG index despite peripheral naive B cell reconstitution. MRI and clinical outcomes showed sustained stability at Week 48. Serologic studies showed a decline in anti-Epstein Barr Virus seropositivity. Single cell myeloid and proteomic signatures showed a decline in proinflammatory profiles. In the 2 subjects with progressive MS reported here, low dose anti-CD19 CAR-T cell therapy (miv-cel) was safe, penetrated the CSF effectively, reduced intrathecal humoral activity, modulated peripheral immune tone, and appeared to stabilize EDSS scores. Overall, these results support the continued investigation of CAR-T cell therapy in MS.
    One Sentence Summary: Anti-CD19 CAR-T cell was safe in two progressive MS patients with CSF penetration, OCB/IgG index resolution, and improved inflammatory background.
    DOI:  https://doi.org/10.64898/2026.09.11.26361992
  27. Adv Sci (Weinh). 2026 Sep 27. e77992
    A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
    Lina Wang, Yanlei Zhang, Shuixiu Peng, Chenchen Hou, Huaqi Guo, Tianyu Zhou, Alex H Chang, Lifeng Yan, Weining Xiong.
      Chimeric antigen receptor (CAR)-T cell therapy for solid tumors is limited by antigen heterogeneity and T cell exhaustion. To address these limitations, we develop a novel multi-targeting "Bicephali" CAR-T platform featuring a dual-transmembrane protein with two distinct extracellular antigen-binding domains and a shared intracellular 4-1BB co-stimulatory/CD3ζ signaling domain. CD276 and NKG2D ligands (NKG2DLs) show high and heterogeneous expression in non-small cell lung cancer (NSCLC) and are undetectable in normal tissues. Bicephali CAR-T cells targeting CD276 and NKG2DLs demonstrate superior tumoricidal activity against NSCLC than conventional BB002 CAR-T cells in vitro and in vivo, together with improved immunological synapse formation and mitochondrial metabolic fitness. In homogeneous NSCLC models co-expressing CD276 and NKG2DLs, Bicephali CAR-T cells achieve prolonged survival outcomes compared to monospecific CAR-T cells. In antigenically heterogeneous NSCLC, Bicephali CAR-T cells more consistently control tumors and prolong survival, whereas monospecific CAR-T cells fail to eliminate tumors following antigen loss. Mechanistically, improved mitochondrial fitness and antioxidant capacity in Bicephali CAR-T cells are associated with sustained T cell function, preserved stem-like differentiation, and durable effector responses. These findings support a multi-targeting CAR-T approach to address antigen heterogeneity in NSCLC and potentially other solid tumors.
    Keywords:  CAR‐T cells; CD276; NKG2D ligands; NSCLC; antigen heterogeneity; bicephali
    DOI:  https://doi.org/10.1002/advs.77992
  28. Ann Hematol. 2026 Sep 26. pii: 429. [Epub ahead of print]105(10):
    The SPIZ study: rationale and protocol of a randomized controlled trial to optimize interdisciplinary care of patients following cellular therapy through a digitally supported, cross-regional and cross-sectoral care model.
    Martin M K Schneider, Gabriele Müller, Sabrina Herbst, Julia Slesaczeck, Roman Schmädig, Franziska Schmidt, Thomas Illmer, Lynn Leppla, Sabine Valenta, Sabina De Geest, Alexandra Teynor, Markus Wolfien, Alice Ernst, Lara Bischof, Jochen Schmitt, Mathias Hänel, Klaus H Metzeler, Uwe Platzbecker, Vladan Vučinić, Johannes Schetelig, Martin Bornhäuser, Jan Moritz Middeke, Katharina Egger-Heidrich.
      Allogeneic hematopoietic cell transplantation (alloHCT) and chimeric antigen receptor T (CAR T)-cell therapy represent established therapeutic modalities for selected hematologic malignancies but are associated with substantial morbidity, high healthcare costs, and a considerable risk of severe complications, including death. This necessitates specialized and continuous post-treatment care, which is currently insufficiently standardized and still largely delivered predominantly through in-person and nonintegrated processes. We aimed to develop a comprehensive and innovative post-treatment care program for patients after alloHCT and CAR T-cell therapy based on an interdisciplinary, digitally supported, cross-regional and, cross-sectoral approach, and to evaluate its effectiveness in a randomized controlled trial (RCT). Developed by a multidisciplinary team, the intervention involves case managers and home visits by onco nurses, supported by digital components. These include patient-reported monitoring of vital signs and symptoms via a mobile application, video consultations, and virtual case conferences with community-based hematologists. The evaluation of effectiveness includes both quantitative outcomes, such as mortality and rehospitalization rates, and qualitative data derived from semi-structured interviews. The required ethics approvals were obtained in due time, and the three study centers were successfully initiated in 2024. As of January 2026, recruitment has been completed, and a total of 306 patients were successfully enrolled and randomized in a 1:1 ratio to receive either the SPIZ intervention or routine care. Funded and supported by the Federal Joint Committee (G-BA), a positive evaluation could facilitate the integration of the proposed care model into routine clinical practice, thereby strengthening post-treatment care for patients undergoing cellular therapy across Germany.
    Keywords:  Allogeneic hematopoietic cell transplantation; CAR T-cell therapy; digital health; post-treatment care
    DOI:  https://doi.org/10.1007/s00277-026-07290-9
  29. Exp Hematol Oncol. 2026 Sep 28. pii: 101. [Epub ahead of print]15(1):
    Next-generation CAR-T therapy for malignant brain tumors: latest updates from the 2026 AACR Annual Meeting.
    Valbert Oliveira Costa Filho, Silvia Helena Barem Rabenhorst, Felipe Pantoja Mesquita.
      The 2026 AACR Annual Meeting showcased rapid progress in chimeric antigen receptor (CAR) T-cell therapy for malignant brain tumors. This correspondence synthesizes 12 clinical and translational abstracts addressing early efficacy, resistance mechanisms, target discovery, and next-generation engineering. Phase I studies in glioblastoma demonstrated feasibility, manageable toxicity, cellular persistence, and preliminary radiographic activity, while revealing antigen loss and treatment-associated myeloid suppression. Longitudinal and spatial analyses further identified limited CAR T-cell persistence, anti-CAR immune responses, and remodeling of suppressive tumor niches. Preclinical strategies sought to overcome these barriers through programmable antigen recognition, alternative KIR/DAP12 signaling, stress-granule modulation, inducible metabolic support, membrane-tethered cytokine agonists, resistance to transforming growth factor beta, and dual targeting of tumor cells and immunosuppressive macrophages. Surfaceome profiling and affinity-guided receptor optimization also identified promising targets in glioblastoma and medulloblastoma. Collectively, these findings support mechanism-informed CAR T-cell platforms, while emphasizing that durability, neurotoxicity, trafficking, immunogenicity, and patient selection require validation in larger clinical studies.
    Keywords:  AACR 2026; CAR T-cell therapy; Glioblastoma; Immunotherapy; Malignant brain tumors
    DOI:  https://doi.org/10.1186/s40164-026-00834-9
  30. J Rheum Dis. 2026 Oct 01. 33(4): 238-254
    Chimeric Antigen Receptor T-cell therapy in systemic lupus erythematosus and other autoimmune diseases: a literature review.
    Faryal Razzaq, Rana Uzair Ahmad, Ahmad Iftikhar, Farva Gondal, Mohammad Ebad Ur Rehman, Muhammad Suhaib, Muhammad Seerat Ali, Ernest Vina, Muhammad Husnain.
      Autoimmune diseases such as systemic lupus erythematosus (SLE), arise when the immune system inappropriately attacks the body's own tissues, leading to chronic inflammation and significant morbidity. Traditional treatments, including corticosteroids, immunosuppressive drugs, and biologic agents, often provide incomplete disease control and are associated with substantial side effects. Chimeric Antigen Receptor (CAR) T-cell therapy, which targets and eliminates autoreactive B cells, has emerged as a promising novel approach for these conditions. This review evaluates the efficacy, safety, and therapeutic potential of CAR T-cell therapy in SLE and other autoimmune diseases, focusing on recent the most recent clinical studies. The review shows significant clinical improvements and sustained remissions in patients with severe, refractory autoimmune conditions, particularly with CD19 and B Cell Maturation Antigen (BCMA)-targeted CAR T-cell preparations. The review also examines adverse effects and safety profiles, emphasizing the differences in toxicity between cancer patients and those with autoimmune diseases. Overall, the findings highlight the transformative potential of CAR T-cell therapy in autoimmune diseases management, offering new possibilities for more effective and longer-lasting disease control while underscoring the need for further research to optimize therapy protocols and better understand long-term outcomes and safety.
    Keywords:  Autoimmune disease; Chimeric Antigen Receptor T-cell therapy; Systemic lupus erythematosus
    DOI:  https://doi.org/10.4078/jrd.2025.0075
  31. Expert Rev Pharmacoecon Outcomes Res. 2026 Sep 30.
    Defining value criteria for outcomes-based managed entry agreements in CAR-T therapy for relapsed/refractory multiple myeloma: a multi-criteria decision analysis study.
    María Victoria Mateos Manteca, José Luis Poveda Andrés, Albert Oriol Rocafiguera, Vicente Escudero-Vilaplana, José Luis Trillo Mata, Pedro Gómez Pajuelo, Alberto Arribas Ruiz, Teresa Domínguez Lubillo, Neus Vidal-Vilar, Asís Ariznavarreta Martín.
       BACKGROUND: This study aimed to identify and prioritize criteria for designing and monitoring outcomes-based managed entry agreements (MEAs) for chimeric antigen receptor T-cell (CAR-T) therapy in relapsed/refractory multiple myeloma (RRMM), from the perspective of healthcare professionals and decision-makers.
    RESEARCH DESIGN AND METHODS: A structured MCDA-informed expert weighting exercise was conducted using an adapted EVIDEM framework. The study comprised two phases: a) selection and structuring of criteria through a targeted literature review and scientific committee (SC) consensus; and b) nonhierarchical weighting of criteria and sub-criteria by a multidisciplinary expert group (n = 19) of hospital pharmacists, physicians, and evaluators/decision-makers.
    RESULTS: Twelve criteria were identified. Following SC discussion, five criteria were selected for weighting: efficacy, safety, patient-reported outcomes, treatment cost, and other direct medical costs. Among the weighted sub-criteria, overall survival (OS) and progression-free survival (PFS) achieved the highest scores, with mean values of 4.21 (95% CI: 3.68-4.74) and 4.05 (95% CI: 3.52-4.58), respectively.
    CONCLUSIONS: In this structured MCDA-informed expert weighting exercise, OS and PFS were identified as the highest-priority value criteria for designing and monitoring outcomes-based MEAs for CAR-T therapies in RRMM. These findings may support feasible, evidence-based reimbursement models but require validation in larger and more diverse stakeholder groups.
    Keywords:  CAR-T therapy; EVIDEM framework; health technology assessment; managed entry agreements; multi-criteria decision analysis; outcomes-based agreements; relapsed/refractory multiple myeloma
    DOI:  https://doi.org/10.1080/14737167.2026.2739076
  32. Haematologica. 2026 Oct 01.
    The role of CHIP and pre-treatment neutropenia in patients treated with chimeric antigen receptor T cells for hematological malignancies.
    Andreas Riedel, Alisha Weiß-Haug, Britta Merz, Saskia Rudat, Lea Kramer, Hildegard Keppeler, Jan Christian Schroeder, Lennart Harland, Christoph Faul, Elena Mirovic, Laurent Phely, Kristina Reuss, Luca Hensen, Wolfgang Bethge, Friederike Schwartz, Claudia Lengerke.
      Chimeric antigen receptor T-cell (CAR-T) therapies are effective in relapsed and refractory Bcell neoplasia but can cause immune-effector cell (IEC)-related toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity (ICAHT), and hemophagocytic lymphohistiocytosis-like syndrome (IECHS). We hypothesized that clonal hematopoiesis of indeterminate potential (CHIP) may influence outcomes by modulating inflammatory responses. We retrospectively analyzed 113 patients treated with CAR-T-cells for B-cell neoplasia, evaluating the impact of CHIP and pretreatment neutropenia on patient outcomes. CHIP was detected in 30.8% of patients with multiple myeloma (MM); 13.7% of patients with large B-cell lymphoma (LBCL) and 28.6% in follicular and mantle cell lymphoma, with DNMT3A being the most frequently detected CHIPassociated mutation among 62 sequenced patients. CHIP remained stable after CAR T-cell therapy, with comparable variant allele frequencies (VAFs) and mutational burden in paired pre- and post-treatment samples (n=33). Pre-treatment neutropenia was present in approximately 30%. Neither CHIP nor pre-treatment neutropenia influenced overall survival (OS), progression-free survival (PFS), or the incidence of CRS and ICANS. However, CHIP was associated with increased IEC-HS and higher ferritin levels in MM, while pre-treatment neutropenia was associated with severe ICAHT in the overall cohort and CD19-directed cohort. These findings suggest that CHIP and pre-treatment neutropenia are not major determinants of outcome after CAR-T cell therapy but may identify patients at increased risk for specific toxicities. This study is limited by its small sample size, heterogeneous cohort, and retrospective design. Prospective studies in larger cohorts are warranted to further investigate these effects.
    DOI:  https://doi.org/10.3324/haematol.2026.301037
  33. J Transl Med. 2026 Sep 30. pii: 1229. [Epub ahead of print]24(1):
    Lineage-specific immune checkpoint dynamics define a context-dependent regulatory framework with translational relevance in human γδ T cells.
    Anna Maria Corsale, Marta Di Simone, Juan Pablo Cerapio, Elena Lo Presti, Gabriele Pizzolato, Claudia Avellone, Costanza Dieli, Salvatore Marchiafava, Laura Di Paola, Francesco Dieli, Serena Meraviglia.
       BACKGROUND: Immune checkpoint receptors (ICRs) are widely used as markers of T-cell exhaustion, yet their interpretation remains context-dependent and is poorly described in γδ T cells. Here, we investigated the dynamics, functional impact, and differentiation-associated distribution of ICRs across human γδ and αβ T-cell subsets.
    METHODS: Peripheral blood mononuclear cells from healthy donors were stimulated in vitro to assess ICR dynamics in γδ and αβ T-cell subsets by flow cytometry. Functional effects of PD-1 and TIM-3 blockade were evaluated through proliferation, cytokine production, and degranulation assays. In parallel, previously published single-cell RNA-sequencing datasets of tumor-infiltrating γδ and CD8 T cells were subjected to secondary bioinformatic analysis to characterize differentiation-associated ICR expression patterns and their modulation following immune checkpoint blockade (ICB) therapy.
    RESULTS: ICR expression was regulated in a receptor-, lineage- and context-dependent manner. Polyclonal stimulation induced broad ICR upregulation, whereas phosphoantigen-driven Vδ2 T cell expansion resulted in a selective profile with sustained TIM-3 expression and transient modulation of PD-1 and TIGIT. Checkpoint distribution was structured across differentiation states, with TIGIT enriched in antigen-experienced subsets, LAG-3 and TIM-3 in naive compartments, and PD-1 broadly expressed. PD-1 blockade was associated with donor-dependent trends toward increased proliferation and cytokine production, particularly under IL-15 stimulation, whereas TIM-3 inhibition showed variable effects and combined blockade did not produce a consistent additive response. Single-cell transcriptomic analyses revealed that tumor-infiltrating γδ T cells displayed heterogeneous ICR expression across differentiation states, whereas CD8 T cells showed a more progressive pattern of checkpoint expression. Because classical exhaustion-associated transcriptional and epigenetic programs were not evaluated, these patterns neither establish nor exclude the presence of exhausted γδ T-cell subsets. ICB therapy was associated with persistence or upregulation of alternative checkpoints.
    CONCLUSIONS: These findings indicate that ICR expression in γδ T cells is dynamically shaped by activation, differentiation, and environmental context. However, ICR expression alone is insufficient to define or exclude a state of T-cell exhaustion.
    Keywords:  Gamma delta T cells; Immune checkpoint blockade; Immune checkpoint receptors
    DOI:  https://doi.org/10.1186/s12967-026-09004-1
  34. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2026 Aug;34(4): 1226-1229
    [Research on the Immunotherapy of T Cell Exhaustion in Multiple Myeloma --Review].
    Ya Nan Cai, Xu Zhang Lu, Min Zhou.
      Multiple myeloma (MM) has strong heterogeneity and is still an incurable tumor. The new immunotherapy represented by bispecific antibody (BsAb) and chimeric antigen receptor T-cell immunotherapy (CAR-T) has shown significant efficacy in MM treatment. However, these therapies directly utilize T cell activity, and the efficacy is affected by the functional state of T cells. T cell exhaustion (Tex), one of the important characteristics of MM, is closely related to the progression, drug resistance, recurrence, and poor prognosis of MM. Therefore, Tex is the key factor limiting the efficacy of BsAb and CAR-T technologies. This article reviews the latest research progress on the mutual influence between Tex and these therapies.
    Keywords:  T cell exhaustion; multiple myeloma; immunotherapy; bispecific antibody; chimeric antigen receptor T-cell immunotherapy
    DOI:  https://doi.org/10.19746/j.cnki.issn1009-2137.2026.04.044
  35. J Med Econ. 2026 Dec;29(1): 2386-2405
    Cost-effectiveness of Orca-T vs allo-HCT with conventional GVHD prophylaxis for the treatment of advanced hematologic malignancies in the United States.
    Rawan Faramand, James Scott McClellan, Anna Pavlova, Rocio Manghani, Andrea Blank, Matia Saeedian, Shivani Yadav, Miguel-Angel Perales.
       AIMS: Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies, but its success is limited by graft‑versus‑host disease (GVHD), which carries considerable clinical and economic burden. A cost-effectiveness model was developed to evaluate whether the higher upfront costs of allogeneic regulatory T cell-based immunotherapy with HSPC and T cells-vldq (Tregzi [Orca-T; Orca Bio, Menlo Park, CA, USA]) are offset by reductions in GVHD and associated healthcare costs compared with conventional allo-HCT using TAC/MTX or PTCy.
    METHODS: A three-state partitioned survival model (relapse-free, relapsed, and dead) with a lifetime horizon and monthly cycles was developed. Overall survival and relapse-free survival data from the Phase 3 Precision-T study (ClinicalTrials.gov Identifier NCT05316701) were incorporated using a cure-mixture modeling approach to estimate long-term survival, relapse status, and cure fraction for patients. Costs included transplant procedure, GVHD management, infection management, and terminal care. Outcomes included life-years, quality-adjusted life-years (QALYs), and direct healthcare costs. Both costs and outcomes were discounted at 3% annually. A scenario analysis was conducted to determine the cost-effectiveness of Orca-T vs allo-HCT with PTCy for GVHD prophylaxis, and sensitivity analyses were conducted to test the uncertainty of the model inputs.
    RESULTS: Orca‑T was associated with lower lifetime costs ($1,026,856 vs $2,170,875) and higher QALYs (15.28 vs 13.00) than conventional allo‑HCT with TAC/MTX, yielding cost savings of $1,144,019 and a gain of 2.28 QALYs per patient. GVHD-related costs were substantially lower with Orca‑T ($495,447 vs $1,998,621). Compared with PTCy, Orca‑T remained dominant, with cost savings of $158,144, a gain of 2.85 QALYs, and lower GVHD-related costs ($476,448 vs $999,945).
    CONCLUSIONS: Orca‑T reduced costs and increased QALYs versus conventional allo‑HCT with TAC/MTX or PTCy, driven by lower GVHD and infection burden. These findings support Orca‑T as a high‑value treatment option.
    Keywords:  Cost-effectiveness; D61; I11; I18; United States; allogeneic hematopoietic cell transplantation; graft-versus-host disease; hematological malignancies; mixture cure model; post-transplant cyclophosphamide
    DOI:  https://doi.org/10.1080/13696998.2026.2732644
  36. Nature. 2026 Sep 28.
    China now leads the world in trials for next-gen CAR-T therapies.
    Rachel Fieldhouse.
      
    Keywords:  Cancer; Diseases; Medical research; Policy
    DOI:  https://doi.org/10.1038/d41586-026-03004-3
  37. Front Immunol. 2026 ;17 1934309
    Personalised neoantigen vaccines for precision oncology in Southeast Asia: clinical opportunities, infrastructure challenges, and policy perspectives.
    Yingying Gao, Yuan Wang, Junwei Li.
      Personalised neoantigen vaccines are patient-specific immunotherapies designed to target tumour-restricted antigens arising from genomic and transcriptomic alterations, including single-nucleotide variants, insertions and deletions, frameshifts, gene fusions and aberrant splicing. Early clinical studies have established manufacturing feasibility and immunogenicity, while randomised phase 2b evidence in resected melanoma has provided a signal of clinical activity that requires confirmation in larger trials. Clinical development nevertheless remains concentrated in high-income academic centres, raising questions about equitable implementation in Southeast Asia. This narrative review evaluates the published clinical evidence and the documented health-system capacity of the 11 ASEAN member states. Regional capacity is heterogeneous: national or institutional genomic programmes and tertiary molecular services are documented in several countries, whereas routine nationwide availability, public reimbursement and equitable geographic access remain incompletely characterised. Potential implementation barriers include access to clinical-grade tumour-normal sequencing, bioinformatics and molecular pathology expertise, patient-specific GMP manufacturing, chain-of-identity control, product release testing, temperature-controlled distribution, financing and country-specific regulatory requirements. Current immunopeptidomic training datasets provide uneven HLA coverage, and published neoantigen-prediction tools have not undergone prespecified, prospective, allele-stratified validation across representative Southeast Asian HLA class I and class II repertoires. Their regional transportability should therefore be considered uncertain rather than assumed to be either equivalent or inferior. A staged hub-and-spoke model linking clinical centres, national genomic nodes and a limited number of regional GMP facilities could support prospective implementation studies. Whether personalised neoantigen vaccines reduce or widen existing cancer inequities will depend on evidence-based patient selection, health-system investment, sustainable financing and nationally appropriate regulatory oversight.
    Keywords:  Southeast Asia (ASEAN); cancer health equity; genomic infrastructure; personalised neoantigen vaccines; precision oncology; translational policy
    DOI:  https://doi.org/10.3389/fimmu.2026.1934309
  38. bioRxiv. 2026 Sep 27. pii: 2026.09.25.754490. [Epub ahead of print]
    Engineering CAR-T cells to remodel the mucin-rich cancer cell glycocalyx.
    Sangwoo Park, Cassidy Ho, Alexandra N Wolff, Yueyang Fan, Amanda A Bouffard, Justin Paek, Adele Mucci, Trisha R Berger, Matthew J Paszek, Marcela V Maus.
      The dense glycocalyx of cancer cells can restrict immune-cell access to surface antigens and limit CAR-T cell activity. Here, we show that mucin density and epitope position determine how glycocalyx remodeling affects CAR-T cell recognition and killing. We identify KLK5 as a human protease that cleaves tumor-associated mucins, increases access to membrane-proximal antigens, and enhances CAR-T cell function. We then engineer CAR-T cells to display or secrete KLK5, enabling remodeling of the tumor glycocalyx during antigen recognition. KLK5-engineered CAR-T cells improved tumor control across multiple xenograft models, and KLK5-secreting MUC17 CAR-T cells produced the strongest in vivo benefit, prolonging survival compared with conventional MUC17 CAR-T cells. These findings show that CAR-T cells can be engineered to breach the mucin-rich glycocalyx while preserving accessible target epitopes.
    DOI:  https://doi.org/10.64898/2026.09.25.754490
  39. Intern Med J. 2026 Sep 30.
    Preventing infections after CD19-directed chimeric antigen receptor T-cell therapies for lymphoma: a consensus practice statement.
    Aine Hurley, Philip George, Gemma Reynolds, Adam Stewart, Hang Quach, Nicole O'Leary, Zoe McQuilten, Andrea S Henden, Lynette Chee, Chan Y Cheah, Olivia Bupha-Intr, Emily Blyth, Ben Teh, Monica Slavin, Michael Dickinson, Robert Weinkove.
      Chimeric antigen receptor (CAR) T-cell therapies directed against cluster of differentiation 19 (CD19) are a standard of care for relapsed or refractory B-cell lymphomas. Infection is the leading cause of non-relapse mortality, and this risk may persist for years after CAR T-cell receipt. Recipients of CAR T-cells can present in various clinical settings, and few trials have prospectively assessed prevention and management of infection in this group. This position statement provides Australian and New Zealand clinicians with a rational approach to preventing, investigating and managing infections after CD19-directed CAR T-cell therapy for lymphoma.
    Keywords:  adoptive immunotherapy; chimeric antigen receptor T‐cell therapy; infection; non‐Hodgkin lymphoma; practice guideline
    DOI:  https://doi.org/10.1111/imj.70644
  40. Mol Cancer. 2026 Aug 22. pii: 229. [Epub ahead of print]25(1):
    Artificial intelligence in oncology: linking biological discovery to clinical utility.
    Sai Kiran Kuchana, Nikhilesh V Alahari, Rohith Kode, Karishma R Jalapu, Suresh K Alahari.
       BACKGROUND: Artificial intelligence (AI) has expanded rapidly across the oncology continuum-spanning early detection, histopathology, molecular profiling, treatment selection, drug discovery, toxicity surveillance, and survivorship care. However, these varied applications occupy fundamentally different stages of clinical and biological translation.
    METHODS: We conducted a critical narrative review searching PubMed/MEDLINE, Europe PMC, IEEE Xplore, arXiv, and ClinicalTrials.gov (updated to July 21, 2026). From these sources, an evidence map of 202 publications (including 182 original studies) was assembled based on study design, prospective or external validation, mechanistic rigor, clinical utility, and representation across the cancer continuum.
    RESULTS: The primary synthesis demonstrates evidence gradient rather than uniform translation across oncology: Detection & Imaging: Select mammography and colonoscopy tools are supported by randomized controlled trials demonstrating workflow efficiency and detection gains. Conversely, negative pragmatic trials highlight that robust technical accuracy does not automatically translate into improved diagnostic pathways.
    PATHOLOGY: Large self-supervised and vision-language foundational models exhibit strong cross-task and cross-institutional transferability. However, prospective real-world deployment remains rare, and reporting on calibration, subgroup performance, and data provenance is inconsistent. Molecular & Systems Biology: Multi-omics, single-cell, spatial transcriptomics, graph-based, and perturbation models increasingly yield falsifiable hypotheses regarding tumor microenvironments, regulatory networks, and drug vulnerabilities; most, however, lack upstream functional validation. Therapeutic Decision Support: Applications in treatment response, surgical assistance, toxicity monitoring, and clinical large language models (LLMs) remain limited by cohort heterogeneity, temporal drift, unstandardized endpoints, and a lack of evidence that model-guided care alters patient outcomes.
    CONCLUSION: AI applications must be evaluated using evidence matched directly to their specific clinical or biological claims: external validation for transportability, calibration/decision analysis for utility, prospective workflow studies for operational value, randomized trials for patient outcome benefits, and perturbation experiments for biological mechanism. This claim-matched framework clarifies the boundary between promising computational models and clinically or mechanistically credible oncology, establishing a roadmap for reliable integration into precision cancer care.
    Keywords:  Artificial intelligence; Clinical translation; Digital pathology; Foundation models; Multi-omics; Oncology; Precision oncology; Radiology; Single-cell transcriptomics; Spatial transcriptomics
    DOI:  https://doi.org/10.1186/s12943-026-02771-x
  41. J Immunother Cancer. 2026 Oct 01. pii: e016896. [Epub ahead of print]14(10):
    PTPN22 as a novel therapeutic target: a key intracellular checkpoint for NK cell therapy.
    Tung Nguyen Thanh Uong, Meesun Yoon, Nhat Phuoc Nguong Minh Nguyen, Mijeong Lee, Seung Kwon Koh, Jae-Uk Jeong, Yong-Hyub Kim, Duck Cho.
       BACKGROUND: PTPN22, a protein tyrosine phosphatase (PTP) family member, has recently emerged as an intracellular regulator in adaptive immune cells. However, its function in natural killer (NK) cells remains unclear despite its high expression in innate immune cells.
    METHODS: We analyzed single-cell RNA-sequencing (scRNA-seq) datasets and The Cancer Genome Atlas (TCGA) to evaluate PTPN22 expression in NK cells and its association with clinical outcomes. We established a CRISPR-mediated PTPN22 knockout platform for NK cell gene editing and evaluated PTPN22 function using both genetic deletion and pharmacological inhibition across multiple NK cell platforms. Cytotoxicity and cytokine production were assessed against hematologic and solid tumor targets, including CD19+ and mesothelin-positive (MSLN+) cancer cells. PTPN22 knockout (PTPN22KO) anti-CD19/CAR-NK92 cells were tested in Nalm6 xenograft models.
    RESULTS: Published scRNA-seq datasets showed that PTPN22 was highly expressed in tumor-infiltrating NK cells. PTPN22high NK cells exhibited stress and dysfunction signatures within inflammatory and immunosuppressive tumor microenvironments (TME), with elevated PTPN22 expression in TCGA associated with poorer patient survival. Genetic deletion of PTPN22 or pharmacological inhibition enhanced NK-cell cytotoxicity and pro-inflammatory cytokine release and improved the antitumor activity of chimeric antigen receptor (CAR)-NK cells against CD19+ and MSLN+ targets. PTPN22KO preserved CAR-NK cell function under cytokine-based TME-like conditions and improved the functional persistence of primary anti-CD19 CAR-NK cells during prolonged tumor exposure. PTPN22KO NK and CAR-NK cells showed increased or preserved signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced FAS expression under inflammatory conditions. Notably, PTPN22KO anti-CD19/CAR-NK92 cells demonstrated superior anti-leukemic activity and significantly prolonged survival compared with non-knockout controls in vivo.
    CONCLUSIONS: These findings identify PTPN22 as a novel intracellular checkpoint that limits NK and CAR-NK cell function. Targeted deletion of PTPN22 represents a promising strategy to enhance the therapeutic efficacy and persistence of both unmodified and CAR-engineered NK cells for cancer immunotherapy.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; Immunosuppression; Natural killer - NK
    DOI:  https://doi.org/10.1136/jitc-2026-016896
  42. Mol Biomed. 2026 Sep 28. pii: 186. [Epub ahead of print]7(1):
    mRNA lipid nanoparticle vaccines: current status, challenges and future prospects.
    Zhineng Wu, Jinghu Lou, Yi Cheng, Meng Li, Zengming Wang, Nan Liu, Xiang Gao, Aiping Zheng, Hui Zhang.
      mRNA vaccines have become a clinically validated vaccine platform, as demonstrated by the success of COVID-19 vaccines such as Comirnaty and Spikevax, owing to their rapid design, manufacturing scalability, and capacity to induce in situ antigen expression. A key factor underlying this success is the lipid nanoparticle (LNP) delivery system, which protects mRNA from degradation and promotes efficient cellular uptake and cytoplasmic delivery, thereby enabling the full potential of mRNA technology. The continued advancement of mRNA-LNP vaccines requires integrated optimization of mRNA design, LNP composition, and delivery strategies to achieve improved stability, efficient intracellular delivery, and balanced immune responses. Despite remarkable progress, challenges related to formulation stability, long-term storage stability, safety and reactogenicity concerns, and durability of immune protection continue to hinder the broader application of mRNA-LNP vaccine platforms. This review provides an integrated overview of recent advances in mRNA-LNP vaccines, covering mRNA molecular engineering, LNP composition and delivery mechanisms, immune responses, clinical progress, and current developmental challenges. Furthermore, emerging strategies, including thermostable formulations, next-generation LNPs with improved targeting capability, emerging RNA platforms, and artificial intelligence-assisted optimization of RNA sequences and lipid materials, are discussed. By summarizing current achievements and future opportunities, this review highlights key principles guiding the rational design of safer, more stable, and more precise mRNA-LNP vaccine platforms and provides insights into accelerating their clinical translation.
    Keywords:  AI-assisted design; Cancer immunotherapy; Infectious diseases; Lipid nanoparticles; MRNA vaccines; Stability; Thermostable formulations
    DOI:  https://doi.org/10.1186/s43556-026-00600-7
  43. bioRxiv. 2026 Sep 22. pii: 2026.09.21.753259. [Epub ahead of print]
    Genetically inducible coordinators of cytokine signaling pathways for interrogating T cell motility.
    Yannick R Schreiber, Madeleine R Keller, Xavier S Bower, Ethan C Fuller, Jieun Woo, Nikolaos Memmos, David J Odde, Joshua N Leonard.
      Chimeric antigen receptor (CAR) T cell therapy is promising for treating hematologic malignancies, but extending this success to treat solid tumors is challenging. Improving T cell phenotype to address this need is desirable, and one such property is increasing T cell infiltration into tumors. A promising potential approach comprises rewiring cytokine signaling using engineered receptors to change how the T cell responds to environmental cues. However, we currently lack the tools and mechanistic understanding to iterate and improve upon such strategies. Notably, receptors that rewire signaling make it challenging to decouple paracrine effects from those conferred by the signaling inducer. To address this gap, we developed a genetically inducible toolkit of proteins termed Constitutive Activators of Motility-associated Pathways (CAMPs). Building on prior knowledge, CAMPs incorporate domains from IL5R (interleukin-5 receptor) and TNFR (tumor necrosis factor receptor) to place cytokine-associated signaling under direct genetic control, such that expression of a CAMP using a small molecule cue or a condition-responsive promoter induces CAMP signaling. We first identified receptor configurations driving constitutive signaling through targeted pathways. TNFR-based signaling modules drove NF-κB activation across diverse receptor designs, while IL5R-based signaling modules exhibited stringent requirements for membrane-proximity and organization of subunits. We engineered primary human T cells with inducible CAMP circuits, enabling us to probe pathway-specific effects on motility and transcriptomic responses. Pharmacological induction of motility-associated programs downstream of PKC (protein kinase C) was shown to be feasible and dependent on T cell activation state. CAMP induction drove an inflammatory program, particularly when signaling through both NF-κB and STAT5, but none of the conditions tested enhanced 3D motility in our assay. Altogether, our findings are consistent with a model in which migratory behavior may be coupled and regulated by multiple stimuli. These findings and new CAMP tools provide a foundation for interrogating and ultimately harnessing motility for improved T cell therapy performance.
    DOI:  https://doi.org/10.64898/2026.09.21.753259
  44. J Cancer Res Clin Oncol. 2026 Sep 30. pii: 190. [Epub ahead of print]152(10):
    Comparative Cost and Utilization Analysis of CAR-T Therapy and Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma in Germany: Insights from Statutory Health Insurance Billing and Nationwide Inpatient Data.
    Ann-Cathrine Froitzheim, Melina Sophie Kurte, Katja Gehrke, Sebastian Lempfert, Katja Hesse, Florian Kron.
       PURPOSE: Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment of diffuse large B-cell lymphoma (DLBCL) but carries higher drug acquisition costs than autologous stem cell transplantation (autoSCT), while administration and follow-up costs remain underrepresented in economic evaluations and reimbursement decision-making. This study compares administration-related and subsequent treatment costs of CAR-T and autoSCT for DLBCL from the German statutory health insurance (SHI) perspective.
    METHODS: A two-step analysis based on two German databases was performed. In step 1, SHI billing data (representing 5 million insured individuals, ≙ 8% of SHI) from 2020-2022 were analyzed longitudinally. Costs were divided into initial regime (IR) (all services except CAR-T drug acquisition) and a following regime (FR). In step 2, a cross-sectional analysis of all German inpatient cases from 2020-2023 (17 million cases/year) assessed inpatient costs.
    RESULTS: Step 1 included 12 CAR-T and 59 autoSCT patients. Median IR costs per patient were €61,703 (CAR-T) versus €55,802 (autoSCT), while FR costs were lower for CAR-T (€44,832 versus €69,453). Most frequently reported adverse events (any grade) for CAR-T versus autoSCT were: B-cell aplasia/neutropenia (77% versus 64%), thrombocytopenia (38% versus 64%). Step 2 included 1,229 CAR-T and 2,239 autoSCT inpatient cases (2020-2023). Average LOS was comparable (27.3 versus 27.8 days), and average inpatient costs were lower for CAR-T (€13,991 versus €29,432).
    CONCLUSION: Although associated with higher IR costs, CAR-T therapy in DLBCL demonstrated lower inpatient and FR costs compared to autoSCT. This analysis focused on administration and follow-up costs, excluding drug acquisition costs, characterizing the economic burden beyond drug pricing.
    Keywords:  CAR-T; Cost; Health economics; Hematology; Real world data; Stem cell transplant
    DOI:  https://doi.org/10.1007/s00432-026-06628-0
  45. Methods Mol Biol. 2027 ;3087 211-228
    Immunophenotyping of Cellular Therapy Products Against Oncogenic and Viral Targets.
    Christopher A Lazarski, Anushree A Datar, Patrick J Hanley, Sandeep K Srivastava.
      Flow cytometric analysis can provide valuable information on the viability, phenotype, and therapeutic potential of cell therapy products using a minimal amount of cell numbers. In this chapter, we describe methods for the analysis of clinical products that incorporate extra considerations within the protocols to help maintain consistency and confidence of staining. This can include methods for evaluating the transduction efficiency for T cells expressing chimeric antigen receptors (CAR-T), characterizing the frequency of diverse lymphocyte populations within polyclonal cell cultures and postinfusion research samples, and measuring the activity or exhaustion in response to antigen-specific stimulation. This chapter also includes recommendations for storage and management of staining materials, frequency of compensation analysis, and reference standards.
    Keywords:  Chimeric antigen receptors T cell (CAR-T cell); Multicolor flow cytometry; Sequential gating; T cell subsets; Virus-specific antigens (VST cells)
    DOI:  https://doi.org/10.1007/978-1-0716-5607-5_13
  46. Cell Mol Immunol. 2026 Sep 30.
    CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.
    Xiomar E Bustos, Leticia Tordesillas, Elena Martinez Planes, Miguel G Fontela, Sebastian Snedal, Renata Ariza Marques Rossetti, Victoria Izumi, Bin Fang, John M Koomen, Eric A Welsh, Patrick Hwu, Daniel Abate-Daga.
      γδ T-cell-based immunotherapies have become relevant as alternatives to conventional αβ T-cell products, with preclinical data demonstrating tumor burden reduction and the mitigation of tumor-induced tissue damage. Given that most CAR constructs have been optimized for αβ T cells, we hypothesized that distinct T-cell types may require tailored CAR architectures to achieve optimal function. To test this hypothesis, we conducted a systematic comparative analysis of γδ and αβ T cells transduced with a second-generation PSCA-targeting CAR (PSCA-8t28z). We found that although γδ and αβ CAR-T cells exhibit comparable levels of cytotoxicity, they differ phenotypically. Through a system-level phosphoproteomic analysis, we identified 307 phosphosites whose abundance differed between γδ and αβ CAR-T cells. Pathway enrichment analysis placed glycolysis/gluconeogenesis and TCR signaling within the top significantly overrepresented signaling networks. The results of functional validation studies confirmed that γδ CAR-T cells have lower glycolytic and oxidative phosphorylation capacity than αβ-CAR-T cells do and weaker activation of activator protein 1 (AP-1). Notably, we identified thioredoxin-interacting protein (TXNIP) as a potential actionable target to enhance γδ CAR-T-cell metabolism. Finally, we designed a new synthetic costimulatory receptor that potentiates AP-1 activation, resulting in improved in vivo persistence. These results highlight the fundamental biological differences between γδ and αβ T cells and support the development of cell type-specific receptor engineering strategies to maximize γδ CAR-T-cell function and therapeutic benefit.
    Keywords:  AP-1 transcription factor; PSCA CAR-T cell; RANKL; TXNIP; c-Jun
    DOI:  https://doi.org/10.1038/s41423-026-01475-y
  47. Cureus. 2026 Aug;18(8): e115393
    CAR-T Versus Non-CAR-T Bridging Strategies Before Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia: A Systematic Review.
    Omar Halloumi, Sanae Sabbar, Laila Lahlou, Salma Fares.
      Relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) remains a major therapeutic challenge despite recent advances in immunotherapy. Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a promising bridging strategy to allogeneic hematopoietic stem cell transplantation (allo-HSCT), although its impact on post-transplant outcomes compared with non-CAR-T bridging strategies remains uncertain. This systematic review compared CAR-T-based with non-CAR-T bridging strategies before allo-HSCT in patients with R/R B-ALL or persistent/recurrent measurable residual disease (MRD) during first complete remission (CR1). PubMed/MEDLINE and Scopus were searched from database inception to August 18, 2026. Eligible comparative studies reported post-transplant outcomes according to the pre-transplant bridging strategy. Two reviewers independently screened the studies, extracted data, and assessed methodological quality using the appropriate Joanna Briggs Institute (JBI) critical appraisal tools. Given the substantial clinical and methodological heterogeneity, a narrative synthesis was performed rather than a meta-analysis. Of 1,957 records identified, 10 comparative reports met the eligibility criteria. Potential patient-level overlap could not be excluded between two reports from the same institution, and all included studies were conducted at single-center institutions in China. CAR-T-based bridging produced deep pre-transplant remissions, but no consistent advantage over non-CAR-T strategies in achieving MRD negativity was observed. One study reported a significantly lower cumulative incidence of relapse (CIR) and higher disease-free survival (DFS) after CAR-T bridging (18.9% vs. 42.2%, p = 0.02; 82.5% vs. 53.7%, p = 0.01), with CAR-T remaining independently associated with a reduced risk of relapse in multivariable analysis. A significant unadjusted overall survival (OS) advantage favoring CAR-T was observed in one small pediatric cohort (84.6% vs. 40.0%, p = 0.008), although potential overlap with another included cohort limits the independent interpretation of this finding. In the largest cohort, CAR-T bridging was independently associated with improved OS in multivariable analysis (hazard ratio = 0.365, 95% CI 0.154-0.857, p = 0.025), despite a nonsignificant unadjusted OS comparison and significantly lower leukemia-free survival (LFS). Across the remaining studies, OS did not differ significantly between bridging strategies, including in two studies comparing CAR-T with blinatumomab. Non-relapse mortality (NRM), hematopoietic engraftment, graft-versus-host disease (GVHD), infectious complications, and endothelial toxicity showed no consistent direction of effect across studies, although delayed platelet recovery and increased viral reactivation emerged as potential safety signals in specific cohorts, particularly following dual-target CD19/CD22 CAR-T therapy. Overall, CAR-T-based bridging before allo-HSCT may improve disease control in selected patients with R/R B-ALL, but the expanded evidence base does not demonstrate a consistent survival or safety advantage over non-CAR-T bridging strategies. The choice of bridging strategy should therefore be individualized according to MRD status, disease biology, CAR-T construct, and transplant eligibility. Prospective multicenter comparative studies are needed to define the optimal sequencing of CAR-T therapy, alternative immunotherapies, and allo-HSCT.
    Keywords:  allogeneic hematopoietic stem cell transplantation; bridging therapy; car-t cells; measurable residual disease; relapsed/refractory b-cell acute lymphoblastic leukemia; systematic review
    DOI:  https://doi.org/10.7759/cureus.115393
  48. Trends Immunol. 2026 Sep 30. pii: S1471-4906(26)00258-9. [Epub ahead of print]
    Beyond T cells: B cells in immune checkpoint blockade.
    Yumin Kim, In Kang, Heung Kyu Lee.
      Immune checkpoint blockade is usually framed as a T cell-directed therapy. Recent studies challenge this view by showing that B cells, plasma cells, and tumor-reactive antibodies are reshaped by programmed cell death protein-1 and cytotoxic T-lymphocyte-associated protein-4 blockade and can contribute to efficacy. Humoral immunity should therefore be integrated into models of checkpoint efficacy.
    Keywords:  B cells; antibodies; humoral immunity; immune checkpoint blockade; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.it.2026.09.003
  49. Blood Adv. 2026 Sep 30. pii: bloodadvances.2026019855. [Epub ahead of print]
    Immunotherapy refractoriness and early post-alloHCT relapse define ultra-high-risk B-ALL after CD19 CAR T-cell therapy.
    Valentín Ortiz-Maldonado, Jacques-Emmanuel Galimard, Giorgio Ottaviano, Anna Alonso-Saladrigues, Shatha Farhan, Sowjanya Vuyyala, Eva Michel, Fizza Imran, Nazaret Sánchez-Sierra, Nuria Martínez-Cibrian, Samppa Johannes Ryhänen, Richard Mitchell, Stephan Mielke, Soeren Lykke Petersen, Anne-Charlotte Teyssier, Thomas Pabst, Jürgen Kuball, Pere Barba, Antonio Pérez-Martínez, Andishe Attarbaschi, Arnon Nagler, José Antonio Pérez-Simón, Malte von Bonin, Emma K Nicholson, David Beauvais, Federica Sorà, Muriel Paganessi, Olaf Penack, Cristina Castilla-Llorente, Yves Beguin, Julio Delgado, Susana Rives, Krzysztof Kalwak, Fabio Ciceri, Annalisa Ruggeri, Adriana Cristina Balduzzi, Sebastian Giebel.
      CD19-directed CAR T-cell therapy (CART19) has transformed relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) management, but the prognostic impact of immunotherapy sensitivity and post-allogeneic hematopoietic cell transplantation (alloHCT) relapse timing in real-world practice remains unclear. We retrospectively analyzed EBMT registry patients with R/R B-ALL treated with CART19 (2016-2023), stratifying by prior alloHCT and classifying prior blinatumomab and inotuzumab ozogamicin (InO) as naïve, responder (CR/CRi), or refractory. Among 345 patients (173/172 adults/children), median age was 18 years (range 1.1-78.2); 58% were alloHCT-exposed, 27% blinatumomab-exposed, 29% InO-exposed, and 52% had pre-lymphodepletion morphological disease. With a median follow-up of 2.3 years, the 3-month MRD-negative complete remission cumulative incidence was 78%; 2-year overall survival (OS) and event-free survival (EFS) were 65% and 49%. In alloHCT-naïve patients, 2-year OS/EFS were 83%/60% (blinatumomab responders), 65%/55% (blinatumomab-naïve), and 31%/17% (blinatumomab-refractory); for InO, OS/EFS were 68%/54% (naïve), 62%/55% (responders), and 22%/18% (refractory). In alloHCT-exposed patients, blinatumomab category did not discriminate outcomes, whereas InO refractoriness was associated with inferior OS/EFS (49%/29%) versus InO-naïve (71%/54%) and responders (60%/38%). Early relapse after alloHCT (<6 vs ≥6 months) was associated with worse 2-year OS (43% vs 74%) and EFS (31% vs 54%). In multivariable models, immunotherapy refractoriness independently predicted inferior EFS (HR 2.56 in alloHCT-naïve; HR 2.20 in alloHCT-exposed); overt morphological disease at lymphodepletion in alloHCT-naïve (HR 3.34) and early post-alloHCT relapse (HR 1.85) further worsened EFS. These findings support pragmatic pre-CAR T risk stratification and prioritization of trials or intensified strategies for refractory disease and early post-alloHCT relapse.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019855
  50. Epigenomics. 2026 Sep 29. 1-14
    The future of cancer therapy? Integrating oncolytic adenoviruses with epigetic modulation.
    Saira Zulfiqar, Xiaoyan Wang, Baofu Chen, Yigang Wang.
      Therapeutic resistance remains a defining limitation in the management of advanced solid tumors, where conventional modalities including chemotherapy, radiotherapy, and immune checkpoint blockade often fail to achieve durable responses. Oncolytic adenoviruses (OAds) have emerged as tumor-selective and immunogenic platforms capable of inducing direct oncolytic and systemic antitumor immunity. However, their clinical efficacy is frequently constrained by intrinsic tumor resistance mechanisms, including impaired viral entry, antiviral immune responses, and immunologically "cold" tumor microenvironments. Epigenetic modulation represents a promising strategy to overcome these barriers by reprogramming chromatin accessibility, restoring antigen presentation, and enhancing viral permissiveness. This review explores the mechanistic and translational rationale for integrating OAds with epigenetic therapies, highlighting preclinical and clinical evidence supporting synergistic interactions. We further discuss the implications of this combinatorial approach for precision oncology and its potential to redefine therapeutic paradigms in resistant malignancies.
    Keywords:  Oncolytic adenoviruses; cancer therapy; epigenetic modulation; immunogenic cell death; tumor microenvironment
    DOI:  https://doi.org/10.1080/17501911.2026.2739787
  51. Annu Rev Pharmacol Toxicol. 2026 Oct 02.
    Nanobodies as Versatile Next-Generation Biologics.
    Serge Muyldermans, Jan Steyaert.
      Nanobodies, also known as single-domain antibodies or variable domains of heavy-chain-only antibodies (VHHs), are the antigen-binding domains derived from heavy-chain-only antibodies that naturally occur in camelids. Since their discovery in the early 1990s, Nanobodies have attracted significant attention in the fields of biotechnology, structural biology, diagnostics, and therapeutics. Their unique structural and biochemical properties distinguish them from conventional antibodies and offer several practical advantages as versatile modular units in next-generation biologics. We discuss the most important and useful properties of Nanobodies, including their generation, physicochemical characteristics, manufacturability, stability, immunogenicity, antigen recognition capabilities, functional modulation, and engineering flexibility. We review the development and production of multivalent and multispecific Nanobody constructs; strategies to extend their in vivo half-life; and various functional fusions, including immunotoxins, imaging agents, and cellular therapies such as CAR T cell constructs.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-060425-094846
  52. Front Immunol. 2026 ;17 1873135
    Computational identification of B- and T-cell epitopes: a unified task taxonomy and review of databases, datasets, predictive pipelines, and gaps.
    Muhammad Ali Ibrahim, Arooj Zaib, Tayyaba Asif, Andreas Dengel, Jens Posma, Wolfram Ruf, Muhammad Nabeel Asim.
      The immune system leverages B and T cells to recognize specific molecular patterns, known as epitopes, on pathogens and cancer cells to effectively combat infections and diseases. The critical success of immunotherapies in cancer treatment and COVID-19 vaccine development has established precise epitope identification as a central and rapidly growing priority in therapeutic design. Because traditional wet-lab based identification of B- and T-cell epitopes is expensive and timeconsuming, our systematic literature search (2015-2026) identified 148 Artificial Intelligence (AI) based linear B-cell, conformational B-cell, and T-cell epitope prediction models within the stated search scope. However, the true potential of these models remains unclear due to fragmented evaluation practices, with models rarely tested across a comprehensive range of datasets, insufficient comparison with existing predictors, systematic under-utilization of available public databases, and other methodological inconsistencies across five different stages of the predictive pipeline. Moreover, the 7 existing review papers fail to adequately highlight these research gaps or to support the development of robust AI models. This review paper consolidates the computational landscape of B-cell and T-cell epitope recognition and introduces a unified taxonomy that organises the field into twelve prediction tasks: linear and conformational B-cell prediction together with ten T-cell subtasks (T1-T10) that span the antigen-recognition cascade from human leukocyte antigen (HLA) typing to vaccine design. It analyses these twelve tasks across five major stages of a shared predictive pipeline. Within this taxonomy, the recognition sub-tasks (T1-T7) apply to the epitopes of any antigen, whereas neoantigen identification (T8) and tumor T-cell antigen (TTCA) classification (T9) are oncology-specific translational applications and multi-epitope vaccine design (T10) spans infectious-disease and cancer targets. It systematically examines 155 studies published from 2015 to 2026 to perform comprehensive categorization of 43 dedicated epitope/immunology databases, 144 benchmark datasets, 272 representation learning approaches, 148 classifiers, 54 evaluation and optimization approaches, and 148 predictive models accessibility status across all twelve prediction tasks. Additionally, it highlights persistent challenges across each stage of the predictive pipeline and offers key directions for improvement. This comprehensive analysis provides actionable recommendations for developing more robust, generalizable epitope predictors, and it ultimately accelerates the translation of computational predictions into effective immunotherapies against diverse diseases.
    Keywords:  B-cell epitopes; T-cell immunoinformatics; antigen epitope recognition; artificial intelligence; computational immunology; dataset benchmarking; deep learning and protein language models; epitope databases
    DOI:  https://doi.org/10.3389/fimmu.2026.1873135
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