bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–02–22
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Time to access matters: patient gains from faster CAR T-cell reimbursement in Europe.
  2. T cell immunotherapy for solid tumors: limitations, progress, and future prospects.
  3. Tailored strategies for improved control of CAR-T cells in multiple myeloma.
  4. Advancements and challenges in CAR-NK cell therapy for cancer treatment.
  5. Cell therapy for brain tumors: The first 60 years.
  6. CAR-T and BiTE: new horizons in the treatment of rheumatic autoimmune diseases.
  7. Strategies of AI-Driven CAR-T Cell Therapy Towards Solid Tumours.
  8. Current state of CAR-T cell therapies for solid tumors.
  9. Natural killer and CAR-NK cell therapies in urological cancers: Progress, mechanistic lessons from CAR-T, and future directions.
  10. Severe Cytokine Release Syndrome After CAR T Cell Therapy in a Pediatric Patient With Relapsed ALL.
  11. Efficacy, safety and cost-effectiveness of CAR-T therapy.
  12. Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.
  13. Clinical progress of engineered cellular immunotherapies for autoimmunity.
  14. Reprogramming CD22 CAR-T cells in vivo Using CD8-Targeted mRNA-LNPs to Treat Hematological Malignancies.
  15. Strengthening Health Technology Assessment (HTA) in the European Union: Insights from Slovenia's Implementation Journey.
  16. Engineered Bacterial Biomaterials for Augmenting Adoptive Immune Cell Therapy Against Solid Tumors.
  17. Immunotherapy-related cardiovascular toxicity: from mechanisms to management.
  18. Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.
  19. Second-line chimeric antigen receptor T-cell therapy versus standard of care in relapsed or refractory large B-cell lymphoma: A systematic review and meta-analysis.
  20. The gut microbiome in graft-versus-host disease: mechanisms of immune modulation and therapeutic approaches.
  21. From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy.
  22. CAR-T cell immunotherapy in rhabdomyosarcoma.
  23. Efficacy of chimeric antigen receptor natural killer cells in treatment of ovarian cancer. A meta-analysis of pre-clinical studies.
  24. The adenylyl cyclase activator forskolin pretreatment reprograms CAR-T cells toward a stem-like state to enhance solid tumor therapy.
  25. Tumour-infiltrating lymphocyte therapy in melanoma: ready for prime time?
  26. Interleukin-15 and innate effector cells as predictors of outcome in allogeneic hematopoietic cell transplantation.
  27. Lymphocyte Suppression and Exhaustion, Conventional, and Accelerated.
  28. Cost-effectiveness thresholds in policy and practice: do HTA guidelines align with estimates of health opportunity cost?
  29. The Role of Human Microbiota in Autoimmune Diseases: Exploring Dysbiosis and Mechanisms.
  30. [CAR-T: an effective option in primary refractory patients].
  31. Efficacy and Safety Comparisons of Four Approved Chimeric Antigen Receptor T-Cell Therapies in Multiple Myeloma.
  32. Repurposing Tumor Cells: A Paradigm Shift in Cell-Based Therapies for Cancer.
  33. Adoptive γδ T cell therapy controls cytomegalovirus infection in preclinical transplantation models.
  34. Charting Bird Tregs.
  35. Do drugs approved via expedited approval pathways have therapeutic advantages? A systematic review and meta-analysis.
  36. Human Leukocyte Antigen (HLA) and Tumor Immunity: A Critical Link in Cancer Immunotherapy.
  37. Nanobody-Engineered CLL-1 CAR-T Cells: Optimizing Tumor-Specific Cytotoxicity and Minimizing Off-Tumor Toxicity.
  38. CAR-T therapy provides relief for children with autoimmune diseases.
  39. Disrupting the information order in health care: Institutions, policy regimes, and the value of data.
  40. Engineered nanovesicles as a DC vaccine to enhance the antitumor efficacy of CAR-T cells against solid tumors.
  41. The Thymus Regeneration Paradox: The Search for Stemness in an Involuting Organ.
  42. Artificial intelligence-driven nano-enhanced stem cell therapy for neurodegenerative diseases: from rational design to clinical translation.
  43. Rewriting the RNA code: an m6a-centric framework to classify tumors and guide combination therapies.
  44. Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.
  45. Value of information analyses for advanced cell therapies: a systematic review.
  46. Cell death pathways in graft-versus-host disease.
  47. CAR-T manufacturing reduces heterogeneity between CIDP and multiple myeloma patient-derived T cells.
  48. Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
  49. Securing Federated Learning With Blockchain in the Medical Field: Systematic Literature Review.
  50. Landscape analysis towards data quality and utility labelling in the European Health Data Space.
  51. VNAR: shark single-domain antibodies for the new era of medical biotechnology.
  1. J Med Econ. 2026 Dec;29(1): 481-497
    Time to access matters: patient gains from faster CAR T-cell reimbursement in Europe.
    Yan Zhi Tan, Emily Breislin, Matthew Woods, Matthew Madin-Warburton, Daniel Gladwell, Alexandra Zang, Sachin Vadgama, Brett Doble, Adriana Wiesinger, Oriol Sola-Morales.
       BACKGROUND: Despite clinical efficacy and cost-effectiveness, time to reimbursement for chimeric antigen receptor (CAR) T-cell therapies varies greatly across Europe. We examined these differences, and quantified potential patient benefits with faster access.
    METHODS: A targeted literature search collated reimbursement statuses for all approved CAR T-cell therapy indications by 1 October 2024. Time to reimbursement decision (TTRD), defined as time between marketing authorization and published reimbursement decision, was assessed. By benchmarking against the TTRD of the three fastest countries, patient impact, in the form of potential gains in lives, life-years (LYs) and long-term survivors, for the first three approved indications for CAR T-cell therapies were estimated. Each outcome was multiplied by population size, incidence, CAR T-cell eligibility, and market share to obtain population-level impact. Scenario analyses were conducted by examining different TTRD assumptions.
    RESULTS: Across 12 identified indications for CAR T-cell therapy, France, Germany, and Switzerland had the fastest TTRD, compared to Denmark, the Netherlands, and Ireland which had the slowest. Among an estimated annual incident population of 6,594 across 3 L + diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and pediatric acute lymphoblastic leukemia (ALL), 1,199 lives, 1,222 long-term survivorships, and 37,229 LYs, could potentially be gained by ensuring time to access across these countries was equivalent to the fastest three assessors in these 3L + DLBCL, MCL, and pediatric ALL.
    CONCLUSION: Access to CAR T-cell therapies varied widely across European countries. Faster access to these therapies can result in significant health gains. Ensuring prompt and equitable access to innovative therapies requires proactive alignments between manufacturers and HTA bodies, possibly through mechanisms such alternative pricing models and risk-sharing agreements.
    Keywords:  CAR T-cell therapy; I15; I18; innovative therapy; oncology; reimbursement; time to access
    DOI:  https://doi.org/10.1080/13696998.2026.2626239
  2. Front Immunol. 2026 ;17 1755751
    T cell immunotherapy for solid tumors: limitations, progress, and future prospects.
    Yinuo Wang, Boyu Zhang, Yajie Wang, Yuan Tan, Xiaoqian Hu, Xuan Che, Mei Feng.
      T cell-based immunotherapies have achieved notable success in the treatment of hematological malignancies, particularly through the application of chimeric antigen receptor (CAR) T cells. However, the clinical efficacy of such approaches in solid tumors remains limited due to a range of intrinsic and extrinsic barriers, including tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), and insufficient T cell infiltration and persistence. Despite these challenges, significant advances have been made in recent years in the development of CAR-T cells, T cell receptor-engineered T cells (TCR-T), and tumor-infiltrating lymphocytes (TILs) for solid tumors. This review provides a comprehensive overview of the current landscape of T cell immunotherapies targeting solid tumors. We examine the underlying mechanisms and design principles of each therapeutic modality and summarize the clinical progress in a tumor-specific context. Particular attention is given to the biological and technical challenges that impede treatment efficacy, including antigen escape, on-target off-tumor toxicity, and the suppressive features of the TME. Furthermore, we discuss emerging strategies aimed at overcoming these obstacles, such as combinatorial antigen targeting, immune checkpoint blockade, synthetic biology tools, and gene editing technologies. Finally, we outline future perspectives in the field, emphasizing the importance of precision immunotherapy and the integration of multi-omics data to enhance T cell functionality and specificity. This review aims to inform ongoing research and guide the clinical translation of T cell-based therapies for solid tumors.
    Keywords:  T cell receptor-engineered T cells; T cell therapy; chimeric antigen receptor T cells; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1755751
  3. Front Immunol. 2026 ;17 1740345
    Tailored strategies for improved control of CAR-T cells in multiple myeloma.
    Anna Bielowski, Teresa Kilian, Sarah Vera-Cruz, Quentin Deveuve, Sabrina Kraus, Hermann Einsele, Michael Hudecek, Sophia Danhof.
      Recent advances in chimeric antigen receptor (CAR) T cell therapy have transformed the treatment landscape of multiple myeloma, yet almost all patients ultimately relapse. Chromosomal 1q gains are associated with a higher risk of disease progression and poor prognosis, suggesting that CAR-T targeting of chromosome 1-encoded antigens, such as SLAMF7, may be particularly relevant in advanced disease. However, novel CAR targets raise the risk of on-target, off-tumor toxicities, underscoring the need for controllable CAR-T systems. We systematically assessed pharmacologic and antibody-based strategies to modulate CD19- and SLAMF7-directed CAR-T cells. Tyrosine-kinase inhibitor dasatinib rapidly and reversibly inhibited CAR-T activation, serving as an efficient "on/off" switch with the limitation of also inhibiting unmodified T cells. To surpass this issue, we used antibody-dependent cell cytotoxicity to inhibit CAR-T cells. However, conditioning with fludarabine/cyclophosphamide profoundly depletes NK cells, limiting antibody-dependent CAR-T clearance in patients. Moreover, as NK cells express SLAMF7, they are susceptible to fratricidal cytotoxicity by SLAMF7 CAR-T cells, further reducing this potential off-switch mechanism. To bypass this immune effector cell dependence, we developed a novel strategy using antibody-drug conjugates (ADCs). In this work, we demonstrate that the BCMA-targeting ADC belantamab-mafodotin selectively eliminates BCMA co-expressing CAR-T cells without affecting unmodified T cells. These findings suggest ADCs as a potent, effector cell-independent safety mechanism for CAR-T therapies, potentially enhancing controllability and safety in future clinical applications.
    Keywords:  BCMA-targeting ADC belantamab-mafodotin; antibody-dependent cell cytotoxicity; antibody–drug conjugates (ADCs); chimeric antigen receptor (CAR) T cell therapy; controllable CAR-T systems; multiple myeloma
    DOI:  https://doi.org/10.3389/fimmu.2026.1740345
  4. Trends Biotechnol. 2026 Feb 16. pii: S0167-7799(25)00541-4. [Epub ahead of print]
    Advancements and challenges in CAR-NK cell therapy for cancer treatment.
    Zhengshui Xu, Yu Li, Yundong Zhou, Changchun Ye, Junjie Kuang, Chengliang Yin, Danwen Zhao, Hui Guo, Narmatha Chellamani, Manimurugan Shanmuganathan, João Conde, Shiyuan Liu.
      Chimeric antigen receptor natural killer (CAR-NK) cell therapy is an emerging cancer treatment offering advantages over CAR-T therapy, including reduced risks of cytokine release syndrome and graft-versus-host disease. This review highlights how genetic engineering enhances natural killer cells' innate tumor-killing abilities through CAR expression. Preclinical and clinical studies show promising antitumor responses, yet challenges remain, such as ensuring in vivo persistence, overcoming the immunosuppressive tumor microenvironment, and addressing manufacturing hurdles. Strategies such as cytokine support, combination therapies, and novel CAR designs are explored to improve efficacy. Future directions include personalized approaches, novel antigen targets, and artificial intelligence integration. CAR-NK therapy holds strong potential as a safe, scalable, and effective modality in cancer immunotherapy.
    Keywords:  CAR-NK; CAR-T cell therapy; cancer treatment; cell therapy
    DOI:  https://doi.org/10.1016/j.tibtech.2025.12.020
  5. Cell Rep Med. 2026 Feb 17. pii: S2666-3791(26)00043-1. [Epub ahead of print]7(2): 102626
    Cell therapy for brain tumors: The first 60 years.
    Sanya Mehta, Giedre Krenciute, Stephen Gottschalk.
      Primary brain tumors remain among the most lethal cancers, but immunotherapy holds immense potential to overcome limitations of current standard treatment modalities. Since the late 1960s, early-phase clinical trials have iteratively tested cellular immunotherapies for the treatment of brain tumors. Six decades ago, in the earliest studies, brain tumor patients were treated with infusions of nonspecific leukocytes, peripheral blood mononuclear cells (PBMCs), and bone marrow cells. These earliest studies demonstrated safety and occasional durable antitumor responses, particularly when cell therapies were combined with conventional modalities or administered in the upfront setting. These early cell therapy approaches were chronologically followed by lymphokine-activated killer (LAK) cells, tumor-infiltrating lymphocytes (TILs), ex vivo nonspecifically expanded and antigen-specific T cells, natural killer (NK) cells, and chimeric antigen receptor (CAR) T cells. In this historical review, we summarize the clinical experience with adoptive cell therapies for brain tumors and review key findings from published clinical studies.
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102626
  6. Front Immunol. 2026 ;17 1747777
    CAR-T and BiTE: new horizons in the treatment of rheumatic autoimmune diseases.
    Jie Li, Qianyu Guo, Linxin Li, Juanjuan Wang, Liyun Zhang.
      Autoimmune diseases arise from immune system dysfunction, in which immune cells erroneously attack the body's own tissues, leading to systemic disorders or localized pathological changes. The number of patients with autoimmune diseases is gradually increasing, and patients with relapsing-refractory conditions face the dilemma of inadequate efficacy when treated with conventional medications and biologic agents. However, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor T-cell (CAR-T) therapy, as emerging immunotherapeutic strategies, have opened up new possibilities for the treatment of these diseases. BiTEs activate T-cell-mediated immune responses by simultaneously targeting T cells and tumor-associated antigens, while CAR-T therapy involves genetic engineering of T cells to enable them to specifically recognize and eliminate target cells. Both therapeutic approaches have demonstrated unique advantages and potential in the treatment of rheumatic immune diseases, providing novel insights and methods to address this challenging clinical issue. This article will conduct a comparative analysis of the applications of CAR-T cell therapy and BiTEs in rheumatic immune diseases, exploring their mechanisms of action, therapeutic efficacy, safety profiles, and future development prospects, with the aim of providing references for clinical practice.
    Keywords:  CAR-T; bispecific T cell engager; clinical efficacy; immunotherapy; rheumatic immune diseases
    DOI:  https://doi.org/10.3389/fimmu.2026.1747777
  7. Immunology. 2026 Feb 19.
    Strategies of AI-Driven CAR-T Cell Therapy Towards Solid Tumours.
    Ahmed M E Abdalla, Yu Miao, Yasir A Taha, Ning Meng, Chenxi Ouyang.
      Chimeric antigen receptor (CAR)-T cell immunotherapy shows significant success in hematologic malignancies. However, it faces critical challenges in solid tumours, such as suppressive tumour microenvironment (TME) and antigenic heterogeneity, highlighting the urgent need for effective and safe CAR products. The integration of artificial intelligence (AI) into CAR-T cell immunotherapy offers exceptional opportunities to improve its therapeutic efficacy. More specifically, this paper highlights the transformative role of AI in addressing key challenges that impede the success of CAR-T cell therapy in solid tumours, including assisting in CAR design and manufacturing process, identifying novel CAR-targeted genes, and detecting cell heterogeneity in solid tumours. We remain optimistic about AI-driven strategies for enhancing CAR T-cell persistence, trafficking, and visualisation in the TME. In addition, we highlight the current challenges and prospects for advancing AI-driven CAR-T cell therapies.
    Keywords:  CAR‐T cell therapy; TME; artificial intelligence (AI); heterogeneity; solid tumours
    DOI:  https://doi.org/10.1111/imm.70124
  8. Med. 2026 Feb 16. pii: S2666-6340(26)00031-0. [Epub ahead of print] 101028
    Current state of CAR-T cell therapies for solid tumors.
    Reginaldo Rosa, Jiangyue Liu, Cathy Lu, Mohamed Abou-El-Enein, John P Murad, Saul J Priceman.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies. However, its application in treating solid tumors has encountered significant obstacles. This review explores the current state of CAR-T cell therapy for solid tumors, highlighting challenges including the pronounced heterogeneity of tumor antigens and the immunosuppressive tumor microenvironment. We explore a range of preclinical and clinical strategies to enhance the efficacy of solid tumor CAR-T cells. These strategies encompass engineering chimeric receptors that can simultaneously target multiple antigens expressed by tumor cells, as well as implementing combination therapies and armored CAR-T cells to overcome existing limitations. While encouraging advancements using solid tumor CAR-T cell therapies have been seen, addressing intrinsic challenges remains a significant endeavor. Ongoing investigation of these innovative strategies is essential for the successful application of CAR-T cells in the context of solid tumors.
    Keywords:  CAR-T cells; antigen heterogeneity; clinical trials; combination therapy; synthetic engineering; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.medj.2026.101028
  9. Crit Rev Oncol Hematol. 2026 Feb 13. pii: S1040-8428(26)00095-8. [Epub ahead of print]221 105208
    Natural killer and CAR-NK cell therapies in urological cancers: Progress, mechanistic lessons from CAR-T, and future directions.
    Zhongze Zhou, Kun Zhao, Xi Xiao, Weiguang Yang, Yunchen Miao, Tongxin Wu, Xiangbin Kong, Yan Tao, Wenyun Wang, Zhilong Dong.
      This review aims to synthesize the current progress, challenges, and future directions of Natural Killer (NK) and Chimeric Antigen Receptor-NK (CAR-NK) cell therapies for urological cancers, including renal cell carcinoma, bladder cancer, and prostate cancer. We detail the unique biology of NK cells, such as 'missing-self' recognition and intrinsic antibody-dependent cellular cytotoxicity (ADCC), which offer potential safety and efficacy advantages over CAR-T cells, including a lower risk of severe cytokine release syndrome and graft-versus-host disease. The analysis covers conventional NK-based strategies, the engineering and 'armouring' of CAR-NK platforms to overcome the immunosuppressive tumour microenvironment, and preclinical and early clinical advances with target antigens like CAIX, CD70, PSMA, and nectin-4 across different urological malignancies. We conclude that while CAR-NK therapy represents a promising 'off-the-shelf' modality for these cancers, its success in solid tumours hinges on next-generation designs that solve critical challenges of in vivo persistence, efficient tumour homing, and resistance to local metabolic and immunosuppressive pressures.
    Keywords:  CAR-NK; CAR-T; Cell therapy; Immunotherapy; Natural killer cells; Tumor microenvironment; Urologic cancers
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105208
  10. Case Rep Oncol Med. 2026 ;2026 6680945
    Severe Cytokine Release Syndrome After CAR T Cell Therapy in a Pediatric Patient With Relapsed ALL.
    Abdulrahman Alotaibi, Noura Alajmi, Mohammed Alnuhait.
       Background: Cytokine release syndrome (CRS) is a potentially life-threatening complication of chimeric antigen receptor (CAR) T cell therapy, particularly in pediatric relapsed acute lymphoblastic leukemia (ALL).
    Case Presentation: A 7-year-old boy with early bone-marrow relapse of hypodiploid ALL received anti-CD19 CAR T cells and developed severe CRS with persistent fever, hypotension, hypoxemia, encephalopathy, and multiorgan dysfunction requiring pediatric intensive care.
    Management: He received tocilizumab, high-dose dexamethasone, continuous intravenous (IV) anakinra, and emapalumab, plus advanced supportive care (mechanical ventilation, vasopressors, and continuous renal replacement therapy). Sequential, multiagent immunomodulation was associated with transient hemodynamic stabilization.
    Conclusion: This case highlights practical bedside sequencing and escalation for refractory pediatric CRS and suggests a potential role for continuous IV anakinra and emapalumab when first-line therapy is inadequate.
    Keywords:  ALL; CAR-T; anakinra; cytokine release syndrome; emapalumab; intensive care; pediatrics
    DOI:  https://doi.org/10.1155/crom/6680945
  11. Br J Clin Pharmacol. 2026 Feb 18.
    Efficacy, safety and cost-effectiveness of CAR-T therapy.
    Emina Karahmet Sher, Amina Džidić-Krivić, Emma Pinjic, Nejra Selak, Kanita Omerbasic, Alexandar Chupin, Andrej Belancic, Almir Fajkic.
      Chimeric Antigen Receptors (CAR) T-cell therapy is a ground-breaking discovery in immunotherapy, mainly known for its exceptional results in treating haematological malignancies. The latest research has revealed that the potential of CAR T-cell therapy extends far beyond its current capabilities and could represent a novel therapeutic approach for treating various cancers. This review aims to summarize the latest innovations in CAR T-cell therapy applied in cancer treatment, including multiple myeloma, osteosarcoma, glioblastoma, melanoma and various childhood malignancies. However, several challenges limit success of CAR T-cell therapy, including the antigen escape phenomenon, 'on-target off-tumour' toxicity, penetration into solid tumour tissue, alongside the cost-effectiveness concerns. The improvement of cancer immunotherapies currently available requires an increase in the effectiveness of CAR T-cells in managing refractory and solid cancers. This could be achieved by using CAR T-cells to target various antigens, enhancing their local delivery and tumour infiltration capabilities and utilizing CAR T-cells in combination with checkpoint blockade and immunotherapy, such as PD-1 blockade and CD19 CAR T-cell combined therapy. Although CAR T-cell treatment offers a lot of promise, its cost needs to be taken into account, especially in healthcare systems with limited funding. More importantly, frameworks for Health Technology Assessment (HTA) must adapt to incorporate ethical, sociological and psychological aspects. Reducing CAR T-cell toxicity is also essential, as it remains among biggest obstacles to their widespread application in clinical practice. Future research should therefore focus on enhancing our understanding of CAR T-cell therapy and expanding the application of immunotherapy in treatment.
    Keywords:  CAR T‐cells; Cancer treatment; Cost‐effectiveness; Equity; Haematology; Immunotherapy; Quality of life; Relapsed disease
    DOI:  https://doi.org/10.1002/bcp.70478
  12. Front Oncol. 2026 ;16 1659869
    Advancing CAR-T therapy in prostate cancer: overcoming the tumor microenvironment and enhancing efficacy.
    Zhongze Zhou, Yongfeng Lao, Kun Zhao, Long Cheng, Xi Xiao, Wenxuan Li, Shuai Liu, Xiangbin Kong, Zhilong Dong.
       Background: Prostate cancer (PCa) is one of the most common malignancies in men, and metastatic castration-resistant PCa (mCRPC) has limited treatment options. While chimeric antigen receptor T (CAR-T) therapy has revolutionized treatment of hematologic cancers, its efficacy in PCa is constrained by factors such as scarce tumor-specific antigens, an immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and safety issues (e.g., cytokine release syndrome).
    Methods: We performed a comprehensive literature review of CAR-T therapy in PCa. We summarized known PCa-specific CAR targets, identified major TME-related and technical barriers, and highlighted recent advances in CAR engineering (including armored CAR-T cells, gene editing, and metabolic reprogramming) as well as combination approaches with other therapies.
    Results: Emerging strategies show promise for overcoming these obstacles. Next-generation CAR designs, such as cytokine-armed CAR-T cells, may enhance T cell infiltration and persistence despite the suppressive TME. Modulating tumor metabolism and immune checkpoints can reverse T cell exhaustion. Multi-antigen CARs and targeted gene edits (for example, PD-1 disruption) may limit antigen escape. Early clinical trials in PCa have demonstrated CAR-T cells specifically recognizing prostate-associated antigens and eliciting antitumor immune responses, although durable remissions remain rare.
    Conclusion: CAR-T therapy for prostate cancer is a rapidly advancing field. This review provides an updated perspective on CAR-T targets, engineering strategies, and combination approaches in PCa. Ongoing innovations in CAR design and therapeutic combinations offer the potential to develop more effective and durable CAR-T treatments for advanced prostate cancer.
    Keywords:  CAR design; chimeric antigen receptor T-cell; immunotherapy; prostate cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1659869
  13. Nat Biotechnol. 2026 Feb 16.
    Clinical progress of engineered cellular immunotherapies for autoimmunity.
    Farzan Solimani, Masayuki Amagai, Catherine M Bollard, Aimee S Payne.
      Cellular immunotherapies encompass a broad and rapidly developing group of treatments comprising expanded and/or genetically engineered immune cells, which use the specific properties of human immune cells to counteract human immune-mediated disease. Initially approved for cancers of the B cell lineage, a growing arsenal of cellular immunotherapies are being applied to autoimmune diseases, including chimeric antigen receptor (CAR) T cells, chimeric autoantibody receptor T cells, regulatory T cells and CAR-engineered innate immune cells. These approaches represent a major shift in the way scientists and physicians pursue the treatment of human disease compared to standard immunosuppressive therapies. Here, we review the clinical progress of engineered cellular immunotherapies for autoimmunity. We focus on how antigenic target, engineered cell type, CAR design and treatment regimens affect the therapeutic efficacy and safety of these treatments and how these emerging clinical data can inform future directions in the field.
    DOI:  https://doi.org/10.1038/s41587-026-03001-x
  14. Mol Ther. 2026 Feb 13. pii: S1525-0016(26)00106-1. [Epub ahead of print]
    Reprogramming CD22 CAR-T cells in vivo Using CD8-Targeted mRNA-LNPs to Treat Hematological Malignancies.
    Viktor T Lemgart, Andrew J Sawyer, William Kuhlman, Aaron P Griset, Mir M Ali, Allison Caron, Dharini Shah, Tiffany Le, Laura Strauss, Jing Jiao, Francis Descamps, Sampa Maiti, Michael T Monte, Ralston Augspurg, Eyoung Shin, Ernesto Luna, Pankaj Agrawal, Jan Pype, Olga Lihoradova, James Cao, Brandon Quido, Laura Powers, Fazila Nasimi, Jacob Scantland, Kavana Girish, Rasika D Kunden, Jennifer Richards, Samantha Stewart, Seunghee Lee, Garry Cuneo, Janina Schwarte, Christian Mueller, Christopher M Borges, Austin W Boesch, Valeria R Fantin, Ulrik B Nielsen, Donald Shaffer, Daryl C Drummond.
      Ex vivo chimeric antigen receptor (CAR) T cell therapy has proven successful in patients with B cell hematologic malignancies. However, current approaches are limited by the requirement for personal manufacturing processes and by barriers such as limited efficacy against solid tumors, treatment-associated toxicities, insufficient CAR-T cell trafficking to the tumor microenvironment, on-target off-tumor effects, and tumor antigen escape. Here, we describe a novel delivery platform that overcomes many of these barriers by employing targeted lipid nanoparticles (LNPs) to reprogram circulating human T cells in vivo. Using a NANOBODY®-based targeting moiety, we deliver mRNA encoding a novel CD22 CAR specifically to CD8+ cells, enabling transient functional CAR expression in vitro and in vivo. Our targeted LNP formulation allows for repeated dosing and minimizes mRNA expression in off-target cells. Furthermore, in a humanized Nalm6 tumor mouse model, non-stimulated T cells reprogrammed in vivo inhibit tumor cell growth. Our platform is a flexible and broadly applicable CAR-T treatment for hematologic malignancies which promises to be adaptable to other diseases.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.02.020
  15. Int J Technol Assess Health Care. 2026 Feb 16. 1-10
    Strengthening Health Technology Assessment (HTA) in the European Union: Insights from Slovenia's Implementation Journey.
    Katarina Beravs-Bervar, Wim Goettsch, Iñaki Gutierrez-Ibarluzea, Adam Skali, Alric Rűther, Iga Lipska, Eva Turk.
      
    DOI:  https://doi.org/10.1017/S0266462325103383
  16. Adv Mater. 2026 Feb 15. e22140
    Engineered Bacterial Biomaterials for Augmenting Adoptive Immune Cell Therapy Against Solid Tumors.
    Chaojie Zhu, Zhongquan Sun, Qing Wu, Feifan Wang, Lingxiao Zhang, Weilin Wang, Yuan Ding, Hongjun Li.
      Adoptive immune cell therapy (ACT) represents one of the most promising strategies in cancer immunotherapy, leveraging genetically engineered immune cells to recognize and eradicate tumor cells with high specificity. Durable remissions have been achieved in hematological malignancies, particularly with CD19-targeted chimeric antigen receptor T (CAR-T) cell therapies. However, the efficacy of ACT in solid tumors remains limited due to the immunosuppressive tumor microenvironment, tumor heterogeneity, and poor infiltration and persistence of the effector cells within tumor sites. Bacterial biomaterials, encompassing live bacteria and their acellular platforms, for example, outer membrane vesicles, represent emerging classes of programmable systems capable of reshaping the tumor immune microenvironment. In this review, we briefly illustrate the underlying molecular mechanisms by which bacterial biomaterials remodel the tumor environment and underscore the advances in the use of engineered bacterial biomaterials to enhance the efficacy of ACT in solid tumors, highlighting the underlying basic principles and engineering strategies to augment current adoptive cellular therapies for overcoming their faced dilemmas in solid tumor settings.
    Keywords:  adjuvant; adoptive cell therapy; bacteria; biomaterials; cancer immunotherapy; drug delivery; tumor microenvironment
    DOI:  https://doi.org/10.1002/adma.202522140
  17. Front Pharmacol. 2026 ;17 1762011
    Immunotherapy-related cardiovascular toxicity: from mechanisms to management.
    Lifeng Xiao, Weitong Liu, Yanchen Ji, Qiufeng Li, Junqing Pan, Renxian Xie.
      Cancer immunotherapy, including immune checkpoint inhibitors and CAR-T cell therapy, has revolutionized oncology but is associated with a broad spectrum of cardiovascular toxicities. This review comprehensively examines the current landscape of these adverse events, which range from myocarditis, pericardial disease, and arrhythmias to heart failure. We delve into the underlying pathophysiological mechanisms, such as T-cell-mediated cross-reactivity via molecular mimicry and cytokine-mediated injury in cytokine release syndrome. The article critically appraises strategies for risk stratification, vigilant monitoring using biomarkers and advanced imaging, and management protocols that encompass immunosuppression, targeted biological therapies, and supportive care. Furthermore, we explore the complex interplay with vaccinations and infections and highlight promising future directions, including novel therapeutic targets, preventive strategies, and advanced monitoring technologies. Ultimately, this review underscores the necessity of a proactive and multidisciplinary cardio-oncology framework to mitigate cardiovascular risks while preserving the anticancer efficacy of immunotherapies.
    Keywords:  cardio-oncology; cardiotoxicity; cytokine release syndrome; heart failure; immune checkpoint inhibitors; immune-related adverse events; myocarditis
    DOI:  https://doi.org/10.3389/fphar.2026.1762011
  18. J Immunother Cancer. 2026 Feb 18. pii: e013665. [Epub ahead of print]14(2):
    Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2Rα.
    Heydar Moravej, Taha Rakhshandehroo, Radia M M Khan, Victoria Marie Rivet, Elodie Marcandalli, Shreya R Mantri, Pegah Taklifi, Uk-Jae Lee, Benjamin B V Louis, Leila A Munaretto, Kathryn Regan, Zoe Farkash, Lea Berland, Zeina Gabr, Alexandra N Wolff, Antonia Kowalewski, Harris H Allen, Ali Nili, Jessika Baral, Dayna Mercadante, Mariateresa Fulciniti, Caron A Jacobson, Adam S Sperling, Omar Nadeem, Hadi T Nia, Michael Hemann, Nikhil C Munshi, Mohammad Rashidian.
       BACKGROUND: Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T persistence and function. It remained unclear whether CAR-Es are effective across distinct tumor contexts, when using patient-derived T cells, or in preventing exhaustion and sustaining persistence. It was also unknown whether CAR-Es can selectively expand CAR-Ts in humanized mice with pre-existing T cells, and to what extent their efficacy depends on IL-2Rβγ vs IL-2Rα engagement. While IL-2Rα (CD25) has been classically linked to potent antitumor responses and memory formation, it also drives IL-2-associated toxicities, including vascular leak and preferential regulatory T cell expansion.
    METHODS: We systematically dissected CAR-E signaling requirements by engineering IL-2 variants with selective receptor affinities. Multiple CAR-E constructs were developed and tested across a range of in vitro and in vivo models.
    RESULTS: We demonstrate that CAR-E activity is entirely independent of IL-2Rα and critically dependent on IL-2Rβγ signaling. A next-generation IL-2Rα-sparing CAR-E maintained full potency, driving robust CAR-T expansion, persistence, and tumor clearance, even at low doses and when using CAR-T cells derived from previously treated multiple myeloma patients. These CAR-T cells not only resisted exhaustion but also re-expanded months later to eradicate tumor rechallenges. In humanized mice with pre-established T cells, CAR-Es selectively expanded CAR-Ts to dominate the circulating T-cell pool. CAR-E exerted a dominant influence on CAR-T fate, overriding tumor-derived cues and enforcing consistent phenotypes across diverse preclinical models.
    CONCLUSIONS: These findings nominate a lead B-cell maturation antigen (BCMA)-IL-2 CAR-E candidate with strong translational potential for clinical development and establish IL-2Rβγ as a key driver of CAR-E activity. The results also identify IL-2Rα as dispensable and provide a mechanistic framework for designing safer, IL-2Rα-sparing CAR-Es.
    Keywords:  Chimeric antigen receptor - CAR; Cytokine; Multiple Myeloma
    DOI:  https://doi.org/10.1136/jitc-2025-013665
  19. Cancer. 2026 Feb 15. 132(4): e70317
    Second-line chimeric antigen receptor T-cell therapy versus standard of care in relapsed or refractory large B-cell lymphoma: A systematic review and meta-analysis.
    Lingrong Tang, Dali Cai, Xiaojing Yan, Wenbin Mo.
       BACKGROUND: CD19-directed chimeric antigen receptor (CAR)-T-cell therapy has emerged as a second-line option for relapsed/refractory large B-cell lymphoma (R/R LBCL). However, its long-term benefits over standard of care (SOC) remain a matter of debate.
    METHODS: A systematic review and meta-analysis was performed of three randomized controlled trials (ZUMA-7, TRANSFORM, BELINDA) and one real-world comparative study evaluating second-line CAR-T versus standard-of-care chemoimmunotherapy (±autologous stem cell transplantation) in adults with early R/R LBCL. Hazard ratios (HRs) and 95% CIs for overall survival (OS), event-free survival (EFS), and progression-free survival (PFS) were pooled. Individual patient data were reconstructed to generate pooled Kaplan-Meier survival curves. Subgroup analyses and long-term safety outcomes were also evaluated.
    RESULTS: A total of 1199 patients were included. Pooled analyses demonstrated a significant benefit of CAR-T over SOC in OS (HR = 0.75; 95% CI, 0.62-0.92), EFS (HR = 0.51; 95% CI, 0.33-0.78), and PFS (HR = 0.47; 95% CI, 0.39-0.58). Three-year OS and PFS estimates from reconstructed data were 53.59% and 44.08% in the CAR-T group, compared to 41.46% and 17.82% with SOC, respectively. Subgroup analyses confirmed consistent EFS across subgroups, including age, disease subtype, and relapse status. Long-term toxicities indicated more frequent hypogammaglobulinemia with CAR-T cell therapy, with no excess in secondary malignancies.
    CONCLUSIONS: Second-line CAR-T therapy significantly improves long-term survival and disease control in R/R LBCL, with consistent benefit across subgroups and real-world settings. These findings support early CAR-T use as a standard strategy in high-risk LBCL, while emphasizing the importance of timely delivery and long-term monitoring.
    Keywords:  CAR‐T; LBCL; meta‐analysis; second‐line therapy; standard‐of‐care
    DOI:  https://doi.org/10.1002/cncr.70317
  20. Gut Microbes. 2026 Dec 31. 18(1): 2631224
    The gut microbiome in graft-versus-host disease: mechanisms of immune modulation and therapeutic approaches.
    Adonai Blessington Moses, Albert C Yeh.
      Graft-versus-host disease (GvHD) remains a major complication of allogeneic hematopoietic stem cell transplantation and occurs when T cells from the donor graft target recipient-derived antigen on host tissue. The involvement of the gastrointestinal (GI) tract drives morbidity and mortality-not coincidentally, the GI tract also harbors the most complex and abundant human microbial reservoir. In this review, we first revisit how the microbiota initiates, propagates, and protects against GvHD in the context of both innate and adaptive immunity. Historically, the impact of the microbiota on GvHD has been ascribed primarily to the activation of innate immunity, setting the stage for donor alloreactivity. Although established models of GvHD focus on donor-host genetic disparity as the principal driver of donor T-cell activation, commensal microbes in the GI tract, whose collective gene content exceeds that of the human genome by more than two orders of magnitude, constitutes an immense and poorly understood source of potential T-cell antigens. We next discuss the evolution of therapeutic approaches aimed at modifying the microbiota to improve GvHD outcomes, incorporating over 40 clinical studies spanning the last 40 years, from broad decontamination strategies to pre/probiotic approaches and targeted ecosystem replacement, including fecal microbiota transplantation.
    Keywords:  GVHD; Graft-versus-host disease; bone marrow transplantation; gut microbiota; microbiome; stem cell transplantation
    DOI:  https://doi.org/10.1080/19490976.2026.2631224
  21. Int Immunopharmacol. 2026 Feb 17. pii: S1567-5769(26)00217-1. [Epub ahead of print]174 116373
    From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy.
    Ying Wang, Yu Yu, Siyu Wang, Jiangyong Qu, Yizhe Song.
      Natural killer (NK) cells are pivotal effector cells of the innate immune system. Their capacity to recognize and eliminate malignant cells without requiring antigen priming has attracted considerable interest in tumor immunotherapy. While NK cell therapy has shown relatively consistent clinical activity across various hematologic malignancies, its efficacy in solid tumors remains highly variable, posing significant challenges for clinical translation. This review summarizes the biological characteristics and antitumor mechanisms of NK cells. Based on published clinical evidence, it describes and synthesizes the heterogeneity in therapeutic efficacy across both solid tumors-including breast cancer (BC), ovarian cancer (OC), and melanoma (MEL)-and hematologic malignancies. The findings indicate that NK cell efficacy heterogeneity arises primarily from multiple factors: immunosuppression within the tumor microenvironment (TME), inadequate tumor infiltration capacity, heterogeneity in target antigen expression, and inhibitory receptor signaling. In addition, product-related attributes-including cell source, genetic engineering strategies, ex vivo expansion protocols, pretreatment regimens, and dosage-substantially influence therapeutic outcomes. Moving forward, the development of NK cell immunotherapy should focus on mechanism-informed patient selection and the rational design of combination therapy to facilitate sustained translation into precision oncology practice.
    Keywords:  CAR-NK cells; Hematological malignancies; Immunotherapy; Natural killer cells; Solid tumors
    DOI:  https://doi.org/10.1016/j.intimp.2026.116373
  22. J Transl Med. 2026 Feb 18.
    CAR-T cell immunotherapy in rhabdomyosarcoma.
    Pooria Safarzadeh Kozani, Setareh Dashti Shokoohi, Pouya Safarzadeh Kozani.
      
    Keywords:  Adoptive cell therapy; Cancer immunotherapy; Chimeric antigen receptor; Rhabdomyosarcoma; Soft tissue sarcoma
    DOI:  https://doi.org/10.1186/s12967-026-07773-3
  23. Immunol Res. 2026 Feb 20. 74(1): 17
    Efficacy of chimeric antigen receptor natural killer cells in treatment of ovarian cancer. A meta-analysis of pre-clinical studies.
    Nabeel Ahmed, Jawaria Jabeen, Malja Rehman, Safa Noor, Sana Tahseen, Asmaa Qamar, Muhammad Anas, Muhammad Muneeb Khalid, Taseer Ahmad, Weiqun Wang, Lechun Lyu.
      Chimeric antigen receptor (CAR) therapies have expanded beyond T-cells with addition of natural killer (NK) cells. In ovarian cancer, long-term survival remains poor with the rising need for new therapies. Therefore, this meta-analysis evaluated the pre-clinical efficacy of emerging CAR-NK therapies in ovarian cancer models. Following PRISMA-guidelines and registered protocol (PROSPERO, CRD420251131530), literature from PubMed, Web of Science, and Scopus was retrieved till 30-06-2025 for pre-clinical in-vivo studies of CAR-NK therapy in ovarian cancer. Studies without in-vivo components or human CAR-NK were excluded. Primary outcomes were ratio of means (ROM) for tumor burden and median survival ratio (MSR). Data was analyzed in JASP™ and risk of bias (RoB) was determined using SYRCLE's RoB tool for animal studies. Fourteen experiments (21 CAR-NK groups) were included. CAR-NK significantly reduced tumor burden versus untreated controls (ROM 0.09 [0.03-0.32], p < 0.001) and unmodified/mock NK-cells (ROM 0.18 [0.08-0.42], p < 0.001). Survival was significantly prolonged (MSR 1.67 [1.31-2.14] vs. control; 1.40 [1.08-1.83] vs. unmodified/mock NK, both p < 0.05). Subgroup analyses revealed no significant modifiers, though trends favored mesothelin-targeted and NK-92-based CARs. Limited safety data indicated no cytokine release syndrome or graft-versus-host disease. Small sample size in subgroup analyses and unclear RoB in certain areas are some limitations of this study. However, the pooled estimates were robust to sensitivity analyses and relatively insignificant heterogeneity in survival outcomes could be important for poor long-term survival in ovarian cancers. CAR-NK demonstrates potential pre-clinical efficacy in ovarian cancer models, outperforming naive NK-cells with a consistent survival benefit.
    Keywords:  CAR-NK; Cell therapy; Chimeric antigen receptor therapy; Immunotherapy; Meta-analysis; Ovarian cancer
    DOI:  https://doi.org/10.1007/s12026-026-09750-w
  24. Int J Biol Macromol. 2026 Feb 17. pii: S0141-8130(26)00875-5. [Epub ahead of print] 150949
    The adenylyl cyclase activator forskolin pretreatment reprograms CAR-T cells toward a stem-like state to enhance solid tumor therapy.
    Jialu Hong, Muya Zhou, Shichu Xu, Zhengling Wang, Yuting Liu, Xiaoyu Li, Luxia Xu, Wenwen Chen, Jinhua Hu, Shengjing Xu, Feiyan Pan, Zhigang Guo.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies; however, its efficacy against solid tumors remains limited, primarily due to T cell exhaustion. Enhancing memory-like properties and stemness of T cells has emerged as a promising strategy to overcome this barrier. In this study, we demonstrate that Forskolin, a stem cell-inducing compound, reprograms CAR-T cells toward a memory-like state characterized by elevated stemness. Forskolin-pretreated CAR-T cells exhibited enriched memory phenotypes, reduced exhaustion, and enhanced anti-tumor activity both in vitro and in vivo. Transcriptomic profiling further revealed upregulation of CXCR4 and BCL6 following Forskolin treatment, and functional blockade of these pathways attenuated the beneficial effects of Forskolin, underscoring their critical roles in reinforcing CAR-T cell stemness. Our findings highlight a novel strategy that integrates stem cell-reprogramming agents to enhance CAR-T cell stemness and provide potential therapeutic targets to improve the efficacy of CAR-T cell therapy against solid tumors.
    Keywords:  Chimeric antigen receptor (CAR)-T cell therapy; Forskolin; Solid tumor; Stem cell-reprogramming, memory T cell
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150949
  25. Br J Cancer. 2026 Feb 18.
    Tumour-infiltrating lymphocyte therapy in melanoma: ready for prime time?
    Rachel Woodford, Paul Lorigan, Deemesh Oudit, Ahmed Abdulgawad, Fiona Thistlethwaite, Kok Haw Jonathan Lim.
      Tumour infiltrating lymphocyte (TIL) therapy offers the potential for durable clinical benefit in select patients with advanced melanoma, especially after progression on treatment with immune checkpoint inhibitors and/or targeted therapies. The 2024 FDA approval of Lifileucel (Amtagvi), a commercially manufactured autologous TIL product, marks a key milestone in integrating advanced therapy medicinal products (ATMPs) into routine care for solid tumours. Health Canada has since approved Lifileucel, with regulatory and funding decisions across the UK and Europe still pending. In this Perspective, we review the evidence base and outline key considerations for national adoption of TIL therapy. Despite promising results from clinical trials, TIL therapy requires complex coordination, including patient selection, tumour procurement, manufacturing logistics, lymphodepletion, and IL-2 administration; all contingent on specialised infrastructure and well-considered integrated care pathways. While commercial centralisation may ease logistical barriers, the high cost of TIL therapy necessitates careful health economic evaluation. A nationally coordinated effort is required to harmonise clinical prioritisation strategies, maintain oversight by multidisciplinary specialist tumour boards, and consider investment in future-proof decentralised manufacturing capacity. Collaborations and peer support such as through the Advanced Therapy Treatment Centre (ATTC) Network will facilitate phased, experience-led rollout with equity-focused service design.
    DOI:  https://doi.org/10.1038/s41416-026-03350-z
  26. Front Immunol. 2025 ;16 1649313
    Interleukin-15 and innate effector cells as predictors of outcome in allogeneic hematopoietic cell transplantation.
    Marie Warny, Sisse Rye Ostrowski, Søren Lykke Petersen, Lone Smidstrup Friis, Brian Thomas Kornblit, Niels Smedegaard Andersen, Ida Schjødt, Margit Hørup Larsen, Janne Amstrup Møller, Eva Kannik Haastrup, Henrik Sengeløv, Lia Minculescu.
       Introduction: Immune reconstitution is a critical parameter in successful hematopoietic cell transplantation (HCT) and involves different cell types and a microenvironment including cytokines. Natural killer (NK) cells and γδ T cells are known to repopulate early after HCT and are proposed to have the intriguing capacity of mediating graft-versus-leukemia (GVL) effects without accompanying graft-versus-host-disease (GVHD). Interleukin-15 (IL-15) and interleukin-7 (IL-7) are key homeostatic cytokines, with effects on both T and NK cells, making these cytokines especially interesting in an HCT setting.
    Methods: In this prospective study, we investigated associations between IL-15 and IL-7, NK cells and γδ T cells, including activated subtypes, and clinical outcomes. We included 105 patients undergoing allogeneic HCT at a single-center institution. IL-15, IL-7, and extended T and NK cell phenotyping were measured longitudinally at fixed time points following HCT.
    Results: We found high IL-15 concentrations early post-transplant to be significantly associated with reduced overall survival, reduced relapse-free survival, and excess acute GVHD. Furthermore, IL-15 showed significant inverse correlations with NK cells and γδ T cells, including activated subtypes early after HCT, and with conventional T cells at later time points. IL-7 was significantly inversely correlated not only with conventional T cells but also with γδ T cells early after HCT.
    Discussion: These findings may suggest that early immune reconstitution of NK cells and γδ T cells is influenced by the bioavailability of IL-15 after HCT and that IL-15 could have a mechanistic effect in the activity of these innate effector cells. NK cells and γδ T cells are currently being investigated in several promising treatment settings, and IL-15 here may offer a potential benefit.
    Keywords:  allogeneic stem cell transplantation; cytokines; gamma delta T cells; innate immunology; natural killer cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1649313
  27. APMIS. 2026 Feb;134(2): e70175
    Lymphocyte Suppression and Exhaustion, Conventional, and Accelerated.
    Kevin Roe.
      The essential mammalian immune system lymphocytes include T cells, B cells, and natural killer cells. Any impairments of their functionalities can have severe consequences, since these lymphocytes each contribute as an interactive team in responding to pathogen infections or cancers. Such impairments include lymphocyte exhaustion, such as T cell, B cell, or natural killer cell exhaustion, or lymphocyte suppression impairing one or more of these cells. Lymphocyte exhaustion can have any intensity from mild to severe, having a severity scale worsened by various exposures and time periods of constant antigenic activation. Lymphocyte exhaustion can potentially have a conventional timing pathway or a hypothesized accelerated (pipelined) timing pathway. Lymphocyte suppressions initiated from pathogen infections are also possible, and this can also impair multiple types of lymphocytes. Finally, accelerated T cell exhaustion is possible, and this can explain several puzzling characteristics of virulent viral pandemics, especially in individuals having pathogen or cancer comorbidities. For instance, accelerated T cell exhaustion can explain a substantial percentage of the SARS-CoV-2 pandemic fatalities and also explain the relatively small, but significant, numbers of hyperinflammatory diseases or autoimmune diseases which were initiated in small percentages of individuals by SARS-CoV-2 infections.
    Keywords:  B cell exhaustion; NK cell exhaustion; T cell exhaustion; accelerated exhaustion; lymphocyte suppression
    DOI:  https://doi.org/10.1111/apm.70175
  28. Health Econ Policy Law. 2026 Feb 19. 1-29
    Cost-effectiveness thresholds in policy and practice: do HTA guidelines align with estimates of health opportunity cost?
    Peter Murphy, Susan Griffin, Simon Walker, Laura Vallejo-Torres, Oscar Espinosa, Mac Ardy J Gloria, Jessica Ochalek.
      Health technology assessment (HTA) processes provide evidence to inform the supply of healthcare, often comparing results from economic evaluation to a policy threshold to judge cost-effectiveness. However, recommended policy thresholds may not always align with empirical estimates of the opportunity costs of health care expenditure, captured by marginal productivity of healthcare expenditure ('k'). Such estimates are needed to inform the net health impact of funding decisions. We map policy thresholds in HTA guidelines against published estimates of k. We extract information from HTA guidelines identified in a previous literature review, including recommended perspective, relevant costs and outcomes, and justification for the threshold. Studies estimating k were obtained from a separate review. Of the 47 included HTA guidelines, 20 state an explicit policy threshold and 12 justify their choice. Estimates of k were available for 13 countries. Among the eight countries with explicit policy thresholds and k estimates, three matched. The recommended perspective influences whether k alone is sufficient or appropriate to inform cost-effectiveness judgements. It is important that guideline setters are aware of empirical estimates of k; and that economic evaluations consider k to reflect health opportunity costs even where the policy threshold is justified on other grounds.
    Keywords:  cost-effectiveness threshold; health technology assessment; marginal productivity; opportunity cost
    DOI:  https://doi.org/10.1017/S1744133126100395
  29. APMIS. 2026 Feb;134(2): e70159
    The Role of Human Microbiota in Autoimmune Diseases: Exploring Dysbiosis and Mechanisms.
    Shangyu Liu, Sarvin Sanaie, Hamed Abdollahi, Fatemeh Yazdanfar, Shakiba Khaki, Siavash Vadaye Kheiri, Ahmad Mobed.
      Humans host between 10 and 100 trillion microbial cells, engaging in a mutually beneficial relationship with their microbiota. This intricate ecosystem supports both the microbes and their hosts, provided the body remains in good health. Estimates indicate that the human microbiota comprises over 1000 unique species of microorganisms, which play a crucial role in maintaining immune balance. They help modulate responses to harmless antigens and maintain the integrity of the intestinal mucosal barrier. When the gut microbiota becomes disrupted, a condition known as dysbiosis, it can lead to a range of immune disorders, including autoimmune diseases. Dysbiosis can influence the development and progression of inflammatory and autoimmune conditions by affecting immune system function and inflammatory responses. The present study aims to provide a comprehensive analysis of the relationship between microbiota and autoimmune diseases. It delves into how microbiota imbalances can contribute to autoimmune conditions and explores the underlying mechanisms involved. By integrating recent research and data, this study seeks to enhance our understanding of the microbiota's impact on autoimmune disease mechanisms and offer insights into potential therapeutic strategies.
    Keywords:  autoimmune diseases; gut microbiota; immune homeostasis
    DOI:  https://doi.org/10.1111/apm.70159
  30. Recenti Prog Med. 2026 02;117(2): e47-e51
    [CAR-T: an effective option in primary refractory patients].
    Maria Chiara Tisi, Michele Wieczorek, Marcello Riva.
      Chimeric Antigen Receptor T-cell (CAR-T) therapy has significantly improved the prognosis of patients with diffuse large B-cell lymphoma (DLBCL), setting as the new standard of care. Below, we describe the case history of a 69-year-old female patient diagnosed with DLBCL, treated in 2024 with axi-cel for refractory disease to first-line with R-CHOP, after bridging therapy with PolaBR and associated radiotherapy. 18F-FDG-PET scan performed one month after CAR-T therapy showed complete remission of the lymphoma, and the patient is still in remission, at more than one year after the infusion. Patient treatment after infusion required the management of a CRS and ICANS requiring tocilizumab for CRS and subsequently dexamethasone for the ICANS, with rapid resolution of symptoms. This experience confirms the potential efficacy of axi-cel in a very extensive, symptomatic, and chemorefractory disease, and is very informative due to the specific immuno-effector T cell toxicities that occurred, both for the importance of their recognition and for the importance of their early treatment. These factors now ensure that safety considerations are no longer a barrier to offering the most effective treatment to this group of patients.
    DOI:  https://doi.org/10.1701/4649.46637
  31. Hematol Oncol. 2026 Mar;44(2): e70179
    Efficacy and Safety Comparisons of Four Approved Chimeric Antigen Receptor T-Cell Therapies in Multiple Myeloma.
    Zhiqiang Song, Qingcheng Fu, Juan Du.
      Despite significant advances in novel therapies, multiple myeloma (MM) remains incurable due to inevitable relapse. Chimeric antigen receptor (CAR) T-cell therapy is an innovative immunotherapy that has demonstrated remarkable efficacy in patients with relapsed/refractory (R/R) MM. To date, four B-cell maturation antigen (BCMA)-targeting CAR T-cell therapies have been approved in the United States and China for the treatment of R/R MM: idecabtagene vicleucel, ciltacabtagene autoleucel, equecabtagene autoleucel, and zevorcabtagene autoleucel. Although these four CAR T-cell therapies have achieved encouraging response rates in R/R MM, a comprehensive comparative analysis of their efficacy and toxicity profiles is still lacking. In this review, we compare the efficacy and safety of these four approved BCMA-directed CAR T-cell therapies. We also discuss potential factors underlying the observed differences and highlight strategies that may further improve the clinical outcomes of this revolutionary therapy.
    Keywords:  chimeric antigen receptor T‐cell therapy; efficacy; multiple myeloma; relapsed/refractory; toxicity
    DOI:  https://doi.org/10.1002/hon.70179
  32. Clin Cancer Res. 2026 Feb 20.
    Repurposing Tumor Cells: A Paradigm Shift in Cell-Based Therapies for Cancer.
    Kok-Siong Chen, Laura Y Lin, Yi-Ching Chen, Khalid Shah.
      Conventional cancer therapies emphasize eradication, often at the expense of harming healthy tissue and immune compromise. This article explores a paradigm-shifting concept: repurposing tumor cells not merely as targets, but as active therapeutic agents. By harnessing their self-homing ability, antigen diversity, and adaptive survival mechanisms, these engineered tumor cells can be repurposed to deliver therapeutic payloads, remodel the tumor microenvironment, and even function as antigen-presenting cells. We begin by critically analyzing the mechanistic failures of early whole-cell vaccine approaches, highlighting how their limited efficacy stemmed from underestimating both the tumor's potent adaptive resistance and the deeply immunosuppressive nature of its microenvironment. We then discuss next-generation strategies designed to overcome these hurdles, with approaches ranging from "killer vaccines" and APC-like reprogramming to Trojan horse delivery of oncolytic viruses. The translational challenges, ranging from multi-layered safety engineering, GMP manufacturing, regulatory navigation, patient selection, and ethical considerations, are examined in depth, with key insights drawn from the clinical evolution of CAR-T cell therapy. We conclude by outlining a clinical roadmap and rational combinatorial strategies, proposing that if these barriers are overcome, tumor cell-based therapies could emerge as complements to immune checkpoint inhibitors and adoptive cell therapies, thus transforming the tumor from an adversary into a catalyst of its own defeat.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3438
  33. Nat Commun. 2026 Feb 17.
    Adoptive γδ T cell therapy controls cytomegalovirus infection in preclinical transplantation models.
    Gabriel Marsères, Coline Gentil, Claire Tinevez, Maxime Courant, Anaïs Cosentino, Selma Cornillot-Clément, Victor Bigot, Vincent Pitard, Atika Zouine, Julien Izotte, Isabelle Garrigue, Valérie Prouzet-Mauleon, Béatrice Turcq, Dany Anglicheau, Edouard Forcade, Hannah Kaminski, Bruno Silva-Santos, Pierre Merville, Myriam Capone, Julie Déchanet-Merville, Lionel Couzi.
      γδ T cells show promise for anti-tumoral therapies but have yet to be evaluated to treat infectious diseases. In this preclinical study, we assess a Vδ1 + γδ T cell-based adoptive cell therapy, named Delta One T cells, to treat cytomegalovirus (CMV) infection in high-risk transplant recipients. Even when expanded from CMV-naïve healthy donors, Delta One T cells efficiently control CMV dissemination in vitro. CMV recognition is independent of the γδTCR but requires LFA-1 co-stimulation. In an in vivo model, adoptive transfer of mouse γδ T cells recapitulating Delta One T cell features protects mice against lethal murine CMV infection. Importantly, CMV-reactive Delta One T cells can be successfully generated from kidney transplant recipients undergoing refractory CMV infections and maintain their functionality in the presence of immunosuppressive drugs. These findings broaden the scope of γδ T cell therapies to infectious diseases and uncover a universal adoptive T cell therapy to treat refractory CMV infections.
    DOI:  https://doi.org/10.1038/s41467-026-69538-2
  34. Eur J Immunol. 2026 Feb;56(2): e70149
    Charting Bird Tregs.
    Lingling Wu, Jingxia Wu, Guoliang Cui.
      Regulatory T cells (Tregs) are fundamental to immune homeostasis, maintaining peripheral tolerance and preventing pathological autoimmunity across vertebrate species. The recent publication, "Beyond FoxP3: Identification of a Chicken Regulatory T Cell Signature," in the European Journal of Immunology by Naumann et al., addresses a critical gap in comparative immunology by providing a comprehensive phenotypic and transcriptional characterization of chicken Treg cells. This commentary will situate the study within the historical context of Treg research, underscore the specific challenges in avian Treg characterization, and highlight the work's transformative implications for both basic immunology and applied poultry science.
    DOI:  https://doi.org/10.1002/eji.70149
  35. Br J Clin Pharmacol. 2026 Feb 20.
    Do drugs approved via expedited approval pathways have therapeutic advantages? A systematic review and meta-analysis.
    Ashleigh Hooimeyer, Eliza J McEwin, Zhicheng Wang, Joel Lexchin, Barbara Mintzes.
      Regulators use expedited approval pathways to speed market approval and patient access to promising new drugs. However, there is uncertainty about whether these pathways are successful in approving drugs with significant therapeutic advantages. This systematic review aims to examine the safety, effectiveness and cost-effectiveness of drugs approved via expedited pathways. Searches were conducted in Medline, Embase and Scopus up to July 2024. Cross-sectional and cohort studies assessing effectiveness, safety and cost-effectiveness of drugs approved via expedited pathways in any jurisdiction were included. Risk of bias was assessed using Joanna Briggs Institute checklists. Where possible, results were meta-analysed; otherwise, narrative synthesis was used. The protocol for this review was registered with PROSPERO: CRD42023444180. Forty-one studies met the inclusion criteria: 36 investigated conditional approval pathways, 16 priority review (14 assessed both pathways) and 3 other pathways. Nineteen studies assessed drug effectiveness, 12 safety and 9 cost-effectiveness. Conditionally approved drugs were no more likely to be of high added clinical value (odds ratio [OR] 1.02; 95% confidence interval [CI] [0.57, 1.82]) but had more post-approval safety concerns (risk ratio [RR] 1.89; 95% CI [1.30, 2.76]) than standard approval drugs; more priority review drugs were of high added clinical value (OR 5.39; 95% CI [3.44, 8.44]) and had more post-approval safety concerns (RR 1.50; 95% CI [1.06, 2.12]). Cost-effectiveness outcomes varied. Study limitations include title and abstract screening conducted by single reviewer, English language only and the lack of published research in low- and middle-income settings. Although these pathways may have successfully sped up the regulatory process, their success in approving drugs that are therapeutic advances is less clear.
    Keywords:  conditional approval; cost‐effectiveness; drug regulation; effectiveness; expedited approval; priority review; safety
    DOI:  https://doi.org/10.1002/bcp.70486
  36. Immun Inflamm Dis. 2026 Feb;14(2): e70363
    Human Leukocyte Antigen (HLA) and Tumor Immunity: A Critical Link in Cancer Immunotherapy.
    Donath Damian.
       BACKGROUND: Malignant tumors pose a serious threat to human health and survival, with profound economic consequences worldwide. Human leukocyte antigens (HLAs), encoded by the human major histocompatibility complex, represent one of the most polymorphic genetic systems and play a vital role in immune regulation. This review summarizes the structural and functional characteristics of HLA molecules, their polymorphism and expression in tumor tissues, their involvement in tumor progression and immune responses, and their emerging applications in tumor immunotherapy.
    METHODS: A thorough literature review was conducted focusing on HLA molecules, their genetic variability in tumor tissues, and their impact on tumor immunity and cellular proliferation. The potential clinical utility of targeting HLA molecules in tumor immunotherapy was also evaluated.
    RESULTS: HLA polymorphisms and expression patterns have been closely associated with tumor initiation, progression, and immune modulation. These molecules influence tumor cell growth and regulate antitumor immune responses, either enhancing or suppressing immunity. HLA molecules are therefore critical in shaping the immune system's capacity to detect and eliminate cancer cells.
    CONCLUSION: This review underscores the pivotal role of HLA molecules in cancer immunology. A deeper understanding of HLA-tumor interactions offers promising avenues for the development of HLA-based immunotherapies, potentially improving clinical outcomes in cancer treatment.
    Keywords:  cancer progression; human leukocyte antigen (HLA); immune regulation; polymorphism; tumor immunity; tumor immunotherapy
    DOI:  https://doi.org/10.1002/iid3.70363
  37. Cancer Res Commun. 2026 Feb 21.
    Nanobody-Engineered CLL-1 CAR-T Cells: Optimizing Tumor-Specific Cytotoxicity and Minimizing Off-Tumor Toxicity.
    Chakrapani Tripathi, Sergey Zolov, John Nguyen, Frank Luh, Yun Yen.
      Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the rapid expansion of undifferentiated myeloid progenitors, leading to impaired hematopoiesis and poor patient prognosis. Although chimeric antigen receptor (CAR) T-cell therapy using single-chain variable fragments (scFvs) has revolutionized immunotherapy, clinical application in AML remains limited by on-target, off-tumor toxicities, largely due to shared antigen expression on normal hematopoietic stem and progenitor cells. To address this challenge, we developed a nanobody-based CAR-T cell platform directed against CLL-1, a myeloid-restricted surface antigen minimally expressed on healthy hematopoietic stem cells but consistently enriched on AML blasts and leukemic stem cells. Leveraging the high specificity, solubility, and reduced immunogenicity of llama-derived VHH antibodies, we engineered both CLL-1 and CD33 nanobody CAR constructs and compared their functional activity. Functional validation included real-time cytotoxicity monitoring using IncuCyte imaging of mKate2-labeled AML cells, serial tumor re-challenge assays to assess sustained killing, and NSG xenograft models to evaluate in vivo efficacy under conditions of high leukemic burden. CLL-1 and CD33 CAR-T cells demonstrated rapid and durable cytotoxicity. Unlike CD33 CAR-T cells, CLL-1-directed CARs spared normal hematopoietic progenitors, preserving colony-forming capacity. Importantly, CLL-1 CAR-T cells retained a favorable memory phenotype with stable proliferation and viability, while cytokine release assays confirmed effective yet antigen-specific immune activation. Together, these findings establish CLL-1-targeted nanobody-based CAR-T cells as a precision-engineered immunotherapy with potent anti-leukemic activity, reduced off-target toxicity, and enhanced translational potential. This platform provides a promising therapeutic avenue to overcome current barriers in AML CAR-T development and improve patient outcomes.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0521
  38. Nature. 2026 Feb;650(8102): 527
    CAR-T therapy provides relief for children with autoimmune diseases.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-026-00412-3
  39. Soc Sci Med. 2026 Jan 30. pii: S0277-9536(26)00098-5. [Epub ahead of print]395 119023
    Disrupting the information order in health care: Institutions, policy regimes, and the value of data.
    Denise Anthony, Amanda Stanhaus.
      This study analyzes how U.S. healthcare organizations view regulatory changes to the accessibility of patient health information as part of the 21st Century Cures Act. Rulemaking for the Cures Act recommended a technical change that would enable vendors in the consumer marketplace outside the institutional context and special data protections of health care to gain access to private patient data. We examine organizational stakeholders' comments during the Notice of Public Rulemaking to show how organizational actors both inside and outside of health care use the institutional values and relationships of health care versus the market to evaluate the impact of the technical change. Healthcare insiders use professional ethics and doctor-patient relationships to defend the status quo of data protections in health care. Outsiders, such as consumer health apps, use the logic and relationships of the marketplace to challenge clinical control of patient information as well as data protections and property rights over patient health data. Technical change alone does not alter the information order of health care, but it creates an opening to challenge the existing meaning and management of information and thereby potentially disrupt established institutions in health care in the United States.
    Keywords:  Health service organizations; Information technology; Institutions; Privacy; Professions
    DOI:  https://doi.org/10.1016/j.socscimed.2026.119023
  40. J Nanobiotechnology. 2026 Feb 20.
    Engineered nanovesicles as a DC vaccine to enhance the antitumor efficacy of CAR-T cells against solid tumors.
    Shaolong Ju, Tianchuan Zhu, Shoudeng Chen, Yongjian Wu, Xi Huang.
       BACKGROUND: Despite the success of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, its efficacy against solid tumors like non-small cell lung cancer (NSCLC) remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient T-cell infiltration. Dendritic cell (DC) vaccines offer potential to remodel the TME but face challenges with targeted antigen delivery. Therefore, we want to develop a DC-targeted nanovesicle (NV) vaccine to enhance the antitumor activity of CAR-T cells against lung cancer.
    RESULTS: We engineered CD205-targeted nanovesicles (aCD205 NVs) derived from LLC cells displaying anti-CD205 single-chain variable fragments. These NVs were evaluated for DC targeting, maturation induction, and T cell priming in vitro and were injected intravenously with Poly(I: C) as a DC vaccine to reprogram the TME in vivo. The combinatorial effect with mesothelin (MSLN)-targeted CAR-T cells (CAR-T + Vac therapy) was assessed in subcutaneous and orthotopic murine LLC models. We found that CAR-T + Vac therapy significantly enhanced tumor infiltration of CAR-T cells and endogenous T cells, substantially elevated cytotoxic molecules (Granzyme B and Perforin), and pro-inflammatory cytokines (IFN-γ and TNF-α), while reducing immunosuppressive cell populations (M2 macrophages, MDSCs, and Tregs) and IL-10. This synergistic remodeling resulted in potent tumor suppression and markedly prolonged overall survival, with no observable short-term toxicity.
    CONCLUSIONS: This study establishes a novel combinatorial strategy utilizing CD205-targeted, tumor cell-derived NVs as a DC vaccine to effectively reprogram the immunosuppressive TME. CAR-T + Vac therapy significantly enhances CAR-T cell infiltration and antitumor efficacy against lung cancer, providing a versatile and promising platform for advancing solid tumor immunotherapy.
    Keywords:  CAR-T cell; Dendritic cells; Lung cancer; Nanovesicles; Tumor microenvironment; Vaccine
    DOI:  https://doi.org/10.1186/s12951-026-04213-8
  41. Immunol Rev. 2026 Mar;338(1): e70110
    The Thymus Regeneration Paradox: The Search for Stemness in an Involuting Organ.
    Roberta Ragazzini, Paola Bonfanti.
      The thymus is emerging as a model for studying organ regeneration and stem cell biology. While research has long focused on how antigen-presenting cells shape the T cell repertoire, recent discoveries unveil a far richer cellular landscape that challenges long-held views of thymus structure and function. This review traces the history of early thymic reconstitution assays, the paradigm of clonal stem cells and serial transplantation, assessing evidence for "stemness" within the thymus. A key focus is the paradox that an involuting thymus retains cells able to expand in culture and reconstitute organ function. We differentiate embryonic/fetal thymus development from postnatal homeostasis, emphasizing how the potency of epithelial progenitor/stem cells shifts with age or upon injury. The role of mesenchymal/interstitial cells and the extracellular milieu is considered alongside advances in organ reconstruction. We outline major unsolved questions in the field: thymus regeneration after childhood; the minimal components required to generate functional naïve T cells outside the body; and the potential of next-generation humanized mouse models to interrogate immune tolerance and novel immunotherapies. We argue that thymus research is entering a new era, one in which understanding and harnessing thymus regenerative potential could yield transformative advances in both basic science and clinical applications.
    Keywords:  epithelial stem cells; extracellular matrix; in vitro clonal assay; involution and regeneration; thymus; whole‐organ reconstruction
    DOI:  https://doi.org/10.1111/imr.70110
  42. J Nanobiotechnology. 2026 Feb 19.
    Artificial intelligence-driven nano-enhanced stem cell therapy for neurodegenerative diseases: from rational design to clinical translation.
    Nan Chen, Shichan Wang, Jiyong Liu, Xiaoting Zheng, Huifang Shang.
      Neurodegenerative diseases (NDs) are progressive and incurable central nervous system disorders characterized by the accumulation of pathological proteins and the loss of neurons. Although stem cell transplantation offers a new treatment option, its clinical application is severely hindered due to imprecise delivery, low survival rate, and undirected differentiation. Many studies have used nanomaterials to enhance stem cell therapy. However, the rational design of these multifunctional nanomaterials often requires a large number of experiments and calculations to determine the optimal parameters. Meanwhile, the diagnosis of NDs and the design of nanomaterials are being profoundly influenced by artificial intelligence (AI) and data-driven modeling. Based on these advancements, we propose that AI can guide personalized nano-enhanced stem cell therapies. This review explores how machine learning (ML) and deep learning (DL) can address the current challenges in stem cell therapy and nano-enhanced stem cell therapies. More importantly, it provides a systematic framework for integrating AI across the entire nano-enhanced stem cell therapy. We analyzed how AI can optimize the design of nanobiological materials, thereby enhancing the survival rate of stem cells, targeted delivery, directing differentiation, and controlling the release of loaded drugs. Additionally, we proposed that AI can be used for post-transplant tracking and prognosis management. Beyond summarizing parallel advancements, this review proposes a closed-loop system that integrates patient-specific data, AI-driven design, and real-time monitoring, aiming to advance truly personalized medicine for NDs.
    Keywords:  Artificial intelligence; Nanomaterials; Neurodegenerative diseases; Stem cell transplantation
    DOI:  https://doi.org/10.1186/s12951-026-04154-2
  43. Front Immunol. 2026 ;17 1749911
    Rewriting the RNA code: an m6a-centric framework to classify tumors and guide combination therapies.
    Yi Sun, Jinliang Wu, Guanhao Chen, Haojun Ma, Wenshuya Li, Hongyu Tan, Kerong Yang.
       Background: The epitranscriptome, particularly N6-methyladenosine (m6A), represents a dynamic layer of post-transcriptional regulation fundamentally implicated in cancer. However, the clinical translation of this knowledge is hampered by profound context-dependency, where the same m6A regulator can exert opposing roles in different tumors. To overcome this barrier, we propose a novel, clinically actionable taxonomic framework that classifies tumors based on their dominant dysregulated m6A component.
    Methods: We synthesized current evidence through systematic reviews of primary research and high-impact papers from PubMed and Google Scholar, focusing on the mechanistic role of m6A modifications in cancer biology, therapy resistance, and therapeutic targeting. This synthesis was used to integrate pan-cancer molecular data including regulator expression, genetic dependency scores, and modification landscapes to define and characterize m6A-driven molecular subtypes.
    Results: We classify tumors into Writer-Dominant (METTL3/14-high, Eraser-High (FTO/ALKBH5-high), Reader-Amplified (IGF2BP/YTHDF-high), and Immune-Modulatory subtypes, each with distinct oncogenic programs, therapy resistance mechanisms, and, crucially, actionable therapeutic vulnerabilities. We provide explicit, evidence-based molecular and functional inclusion criteria for each subtype and acknowledge that tumors can exhibit hybrid features, which directly inform rational combination strategies. Furthermore, we detail a diagnostic-therapeutic roadmap that integrates liquid biopsy-based m6A biomarker detection with subtype-specific treatment assignment.
    Conclusion: Targeting the m6A epitranscriptome represents a paradigm shift in oncology; our framework provides the essential strategic approach needed to overcome context-dependency, offering a logical structure for tumor classification, vulnerability prediction, and the translation of epitranscriptomic insights into patient benefit through personalized, biomarker-guided combination therapies.
    Keywords:  N6-methylAdenosine (m6A); RNA modification; cancer immunotherapy; epitranscriptome; targeted therapy; therapeutic resistance
    DOI:  https://doi.org/10.3389/fimmu.2026.1749911
  44. Am J Clin Oncol. 2026 Feb 17.
    Relevance of Chemokines in Mobilizing γδ T Cells in the Biliary Tract Cancer Microenvironment: Potential for γδ T-Cell-Based Adoptive Cell Therapy.
    Saikat Mandal, Arkadeep Dhali, Manideepa Maji, Guruprasad Aithal.
       OBJECTIVE: Biliary tract cancer (BTC) has a poor prognosis with limited therapeutic options. γδ T cells represent an MHC-independent immune cell population; however, their therapeutic efficacy in solid tumors is constrained by insufficient tumor infiltration. Chemokine-mediated trafficking is fundamental to T lymphocyte recruitment; however, the chemokine landscape of the BTC tumor microenvironment (TME) remains uncharacterized. Using single-cell RNA sequencing of BTC tissues, we delineated chemokine ligand expression patterns, stratified chemokine producers by lineage, assessed γδ T-cell recruitment mechanisms, and identified chemokine-mediated immune escape.
    METHODS: We analyzed single-cell RNA sequencing data from 3 independent GEO cohorts (GSE210066, GSE201425, and GSE213452; 19 patients) to comprehensively delineate γδ T-cell mobilization-related chemokine expression across the BTC TME using the Seurat v5.0 pipeline in R.
    RESULTS: Analysis identified a multiaxis chemokine profile within the BTC TME. High expression of CCL5, CCL4, and CCL3 established predominant CCR5-mediated recruitment axes supporting Vγ9Vδ2 T-cell infiltration, whereas CCL2 and modest CXCL8 supported CCR2+ and CXCR1+ Vδ1 T-cell recruitment. Notably, CXCL16 expression supported epithelial γδ T-cell homing through CXCR6. However, critical deficiencies in CXCL9 and CXCL10 suppress the IFN-γ-driven immunity. Paradoxically, chemokine axes supporting γδ T-cell recruitment (CCL2-CCR2, CXCL8-CXCR1, CXCL12-CXCR4) simultaneously recruit immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs).
    CONCLUSION: Comprehensive single-cell analysis identified selective chemokine recruitment signatures supporting γδ T-cell infiltration but revealed paradoxical corecruitment of immunosuppressive populations. Patient stratification through chemokine profiling, combined with γδ T-cell enrichment and targeted chemokine antagonism, represents a rational therapeutic strategy.
    Keywords:  adoptive cell therapy; biliary tract cancer; chemokines; cholangiocarcinoma; gallbladder cancer; γδ T-cell
    DOI:  https://doi.org/10.1097/COC.0000000000001306
  45. Health Econ Rev. 2026 Feb 17.
    Value of information analyses for advanced cell therapies: a systematic review.
    Alexander Heaps, Sean P Gavan.
       BACKGROUND: Advanced cell therapies often face high parameter uncertainty at launch, prompting calls to collect further data about long-term effectiveness and safety. However, the value of collecting these data to support resource allocation decision-making is not known. Therefore, this study aimed to appraise all published value of information analyses for advanced cell therapies.
    METHODS: A systematic review (PROSPERO: CRD42023446874) identified value of information analyses for advanced cell therapies between inception and 14 May 2025 (databases: Medline; Embase). Included studies reported the expected value of perfect information (EVPI), expected value of partial perfect information (EVPPI), expected value of sample information (EVSI) or expected net benefit of sampling (ENBS). Study design and value of information results were summarised in a narrative synthesis. Quality of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards Value of Information (CHEERS-VOI) checklist.
    RESULTS: Three published value of information analyses were identified: tisagenlecleucel for relapsed/refractory acute lymphoblastic leukemia; tisagenlecleucel for relapsed/refractory diffuse large B-cell lymphoma, and tumor infiltrating lymphocyte cell therapy for advanced melanoma. The beneficiary populations were 6, 36, and 400 individuals per year, respectively. All studies reported EVPI; two studies reported EVPPI. Estimated base case population EVPI was: €314,455, €0, and €2,250,000, respectively. Estimated EVPPI indicated that input parameters for survival extrapolations were the most valuable targets for further research specifically during scenario analyses that explored a lower cost of treatment acquisition.
    CONCLUSIONS: Value of information analyses will help decision-makers, analysts, and manufacturers understand whether long-term data collection is worthwhile to reduce decision uncertainty for advanced cell therapies at launch. Current estimates indicated that the value of further research is likely to be low. The value of collecting additional data will likely increase if future advanced cell therapies are priced such that their corresponding incremental cost-effectiveness ratio aligns with a relevant cost-effectiveness threshold and if they are indicated for larger beneficiary populations.
    Keywords:  ATMP; Advanced therapy medicinal product; Cell therapy; Decision uncertainty; Expected value of perfect information; Systematic review; Value of information
    DOI:  https://doi.org/10.1186/s13561-026-00728-w
  46. Curr Opin Immunol. 2026 Feb 13. pii: S0952-7915(26)00017-8. [Epub ahead of print]99 102740
    Cell death pathways in graft-versus-host disease.
    Allison Pugel, Xue-Zhong Yu, Yongxia Wu.
      Regulated cell death, including apoptosis, necroptosis, and pyroptosis, as well as cell death arising from disrupted cellular homeostasis, such as ferroptosis and dysregulated autophagy, is implicated in cancer, autoimmunity, and transplantation biology. Graft-versus-host disease (GVHD), a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation, is driven by donor T-cell recognition of host alloantigens and effector response, leading to extensive tissue injury. Apoptotic pathways have been well studied in GVHD, and targeting apoptosis has shown therapeutic benefit. Emerging forms of cell death are now recognized to regulate immune and non-immune cells, providing new mechanistic insights into GVHD. Manipulating these pathways offers opportunities to alleviate GVHD through eliminating pathogenic alloreactive T cells or enhancing the survival of protective cell populations, such as regulatory T cells, innate lymphoid cells, and intestinal epithelial cells. We summarize recent advances on how diverse cell death pathways shape GVHD pathogenesis and their therapeutic implications.
    DOI:  https://doi.org/10.1016/j.coi.2026.102740
  47. Theranostics. 2026 ;16(8): 4245-4259
    CAR-T manufacturing reduces heterogeneity between CIDP and multiple myeloma patient-derived T cells.
    Xu Wang, Pu Wang, Qi Zhou, Xianzheng Wei, Yuhang Jin, Ying Liao, Xuan Zhao, Rui Hou, Sijin Li, Zhangchun Guan, Wen Ma, Dan Liu, Ming Shi.
      Rationale:​​ CAR-T cell therapy has demonstrated remarkable promise for managing specific autoimmune disorders. However, it remains unclear, whether long-term immunosuppressive therapy in autoimmune patients adversely affects the phenotype and function of patient-derived CAR-T products. This study aimed to compare the characteristics of T cells and manufactured CAR-T cells from patients with multiple myeloma (MM) and chronic inflammatory demyelinating polyneuropathy (CIDP). ​​Methods:​​ T cells isolated from MM and CIDP patients, as well as healthy volunteers (for baseline comparisons only), were analyzed. CAR-T cells were generated using an identical manufacturing process. A comprehensive analysis was conducted, including flow cytometry for phenotypic and functional assessment, transcriptomic profiling via RNA sequencing, and in vitro functional assays such as cytokine secretion and cytotoxicity tests. ​​Results:​​ T cells from CIDP patients showed phenotypes and functional profiles more comparable to those from healthy volunteers. In contrast, MM-derived T cells showed increased CD8⁺ T cell frequency, elevated exhaustion markers, reduced naïve and less-differentiated subsets, and enhanced effector molecule production upon non-specific stimulation. CAR-T manufacturing reduced these inherent differences, yielding similar differentiation states, transcriptomic profiles, and convergent cytotoxic capacities. However, distinct immunomodulatory features persisted, as CIDP-derived CAR-T cells displayed reduced activation markers and lower IFN-γ secretion upon antigen stimulation compared to MM-derived CAR-T cells. ​​Conclusions:​​ Our study reveals that CAR-T manufacturing process can reduce pre-existing T-cell heterogeneity across different patient populations. These findings support the feasibility of autologous CAR-T therapies in immunosuppressed autoimmune patients, demonstrating that critical cytolytic functions are preserved despite residual alterations in cytokine profiles.
    Keywords:  CAR-T cell therapy; CIDP; MM; T cell heterogeneity; autoimmune diseases; transcriptomic reprogramming
    DOI:  https://doi.org/10.7150/thno.125983
  48. Nat Commun. 2026 Feb 20.
    Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
    Lior Goldberg, Eric R Haas, Jiaqi Wu, Bryan Garcia, Ryan Urak, Vibhuti Vyas, Ruby Espinosa, Tamara Munoz, Shirley Bierkatz, Khyatiben V Pathak, Nathaniel P Hansen, Patrick Pirrotte, Jyotsana Singhal, James L Figarola, Ricardo Zerda Noriega, Zhuo Li, Dasol Wi, Erin Tanaka, Ramon Klein Geltink, Min-Hsuan Chen, Xiwei Wu, Jamie R Wagner, Jinny Paul, Mary C Clark, Dat Ngo, Ibrahim Aldoss, Stephen J Forman, Xiuli Wang.
      Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. Herein, we apply an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) have increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR have high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induces metabolic reprogramming and enhances anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.
    DOI:  https://doi.org/10.1038/s41467-026-69857-4
  49. J Med Internet Res. 2026 Feb 19. 28 e79052
    Securing Federated Learning With Blockchain in the Medical Field: Systematic Literature Review.
    Xudong Wang, Yi Xie, Xiaoliang Chen, Jiaming Yang, Ruiyuan Li, Weihang Gao, Zineng Yan, Hong Zhou, Zhewei Ye.
       Background: The exponential growth of medical data and advancements in artificial intelligence (AI) have accelerated the development of data-driven health care. However, the secure and efficient sharing of sensitive medical data across institutions remains a major challenge due to privacy concerns, data silos, and regulatory restrictions. Traditional centralized systems are prone to data breaches and single points of failure, while existing privacy-preserving techniques face high computational and communication costs.
    Objective: This study aims to provide a comprehensive review of the recent advances in blockchain-based federated learning (BCFL) within the medical field. By exploring the synergistic integration of federated learning and blockchain, this review evaluates how BCFL enhances data security, supports privacy-preserving cross-institutional collaboration, and facilitates practical applications in health care, including medical data sharing, Internet of Medical Things, public health surveillance, and telemedicine.
    Methods: We conducted a systematic literature review using databases such as PubMed, IEEE Xplore, Web of Science, and Google Scholar. Boolean logic and domain-specific keywords were used to retrieve studies from 2018 to 2025. After automated deduplication and multistage manual screening, over 100 high-quality papers were included. These works cover BCFL's theoretical foundations, system architectures, application domains, limitations, and future directions.
    Results: BCFL frameworks combine the decentralized trust and auditability of blockchain with the privacy-preserving collaborative learning capabilities of federated learning. This integration mitigates risks such as model tampering, data leakage, and a lack of incentives in federated systems. Applications span across cross-institutional medical data sharing, Internet of Medical Things, epidemic forecasting, and telemedicine. Architectures including fully coupled, flexibly coupled, and loosely coupled models offer varying trade-offs between efficiency, scalability, and security.
    Conclusions: BCFL represents a transformative paradigm for secure, collaborative, and privacy-preserving medical AI. By combining decentralized trust, incentive-driven participation, and privacy-enhancing machine learning, BCFL paves the way for next-generation smart health care systems. Despite current technical and practical challenges, BCFL demonstrates strong potential to support precision medicine, global health data collaboration, and large-scale AI deployment in health care.
    Keywords:  COVID-19; Internet of Medical Things; IoMT; blockchain; federated learning; health care; health data; review
    DOI:  https://doi.org/10.2196/79052
  50. Eur J Public Health. 2026 Feb 05. pii: ckag009. [Epub ahead of print]
    Landscape analysis towards data quality and utility labelling in the European Health Data Space.
    Ángel Sánchez-García, Claudio Proietti Mercuri, Nienke Schutte, Francisco Estupiñán-Romero, Carlos Tellería-Orriols, Ascensión Doñate-Martínez, Juan M García-Gómez, Enrique Bernal-Delgado, Carlos Sáez, On Behalf Of Quantum.
      The European Health Data Space (EHDS) promotes health data sharing and secondary use across Europe. The QUANTUM project focuses on labelling data quality (DQ), utility, and maturity to support EU-wide standards within this context. This study examines current DQ assessment practices in European Data Holder institutions to inform the design of a labelling tool for the EHDS. The study explored institutional practices for DQ assurance and assessment through a survey of EU-wide Data Holders and a literature search on open-source health DQ tools with potential for labelling. The survey targeted QUANTUM partners and external institutions, addressing DQ practices and tools. The literature review followed PRISMA guidelines and combined PubMed, AI-based queries, and known sources. We obtained survey responses from 27 Institutions across 13 European countries. The results showed a high variety and heterogeneity in DQ practices and tools used, including in-house developed tools, open-source tools, commercial products, and manual procedures. Most practices allowed customization of DQ dimensions and export of DQ analyses. The systematic review identified 66 DQ tools, 53% specific to data types such as electronic health records, omics or imaging, and 47% general-purpose. The diverse DQ institutional practices and tools emphasize the need for an interoperable self-assessment DQ labelling tool that guides the measurement and completion of consolidated metrics aligned with the EHDS regulations. Based on these findings, the QUANTUM project is developing this tool to support DQ labelling of Data Holders' datasets candidate to publication at EU Health Data Access Bodies.
    DOI:  https://doi.org/10.1093/eurpub/ckag009
  51. Front Immunol. 2025 ;16 1716916
    VNAR: shark single-domain antibodies for the new era of medical biotechnology.
    Richard A Olivares-Olivares, Angélica R Bravo, Carlos Garrido-Soto, Jonatan J Carvajal, Augusto Manubens, Mariella Rivas, Carlos Bustamente, Angello Retamal-Díaz, Alexis M Kalergis, Margarita K Lay.
      Shark-derived single-domain antibodies, known as VNARs, represent unique and advanced tools in medical biotechnology. Recognized for their small size, simple structure, and exceptional stability, VNARs can access cryptic epitopes that are inaccessible to traditional antibodies, making them valuable tools for next-generation diagnostic and therapeutic applications. Additionally, their evolutionary origin and structural diversity provide resistance to extreme pH, temperature, and proteolytic environments, making them especially suitable for demanding biomedical settings such as ocular and intestinal applications. Recent progress highlights their growing clinical potential: VNAR-based CAR-T cells targeting PD-L1 demonstrated strong anti-tumor effects in preclinical assays, with VNAR-B2 successfully blocking PD-L1/PD-1 interactions and reducing tumor growth in mouse models. Meanwhile, the TXB2 VNAR platform allows efficient, non-invasive transport of biologics across the blood-brain barrier. These developments emphasize VNARs' advantages over traditional antibodies and even camelid VHHs in targeting difficult-to-reach sites and environments. Additionally, commercial development in VNAR technologies is advancing, with companies like Elasmogen using its soloMER™ platform to develop shark-derived, humanized single-domain antibodies for challenging therapeutic environments. This review consolidates emerging insights into VNAR structural biology, display technologies (phage, ribosome, yeast, and bacterial), and library engineering strategies, emphasizing their growing role in immunodiagnostics, infectious disease detection, targeted therapies, and barrier-crossing biologics. It addresses key translational challenges such as humanization and half-life extension, which are crucial for clinical application, ultimately highlighting the transformative potential of VNARs in bridging vital gaps in modern medicine.
    Keywords:  IgNAR; VNAR; biomedical applications; display technologies; medical biotechnologies; shark antibodies; single-domain antibodies
    DOI:  https://doi.org/10.3389/fimmu.2025.1716916
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