bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–03–15
38 papers selected by
Luca Bolliger, lxBio
  1. Harnessing CAR-Extracellular Vesicles for Next-Generation Cancer Immunotherapy.
  2. Chimeric antigen receptor therapy for hepatocellular carcinoma.
  3. Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation.
  4. Current status and issues with CAR-T cell products in Japan: a regulatory perspective.
  5. From Ex Vivo to In Vivo: Advances in Lentiviral Vector Engineering for CAR-T Therapy.
  6. CAR-Cell Therapy for Autoimmune Diseases: From the Laboratory to Clinical Practice.
  7. Advances and challenges of chimeric antigen receptor T cell therapy in digestive system malignancies.
  8. Functional spectrum of γδ T cells in perinatal infectious diseases.
  9. Organizational impact in healthcare in France: a decade of insights but chicken and egg situation.
  10. Off-the-shelf CAR natural killer progenitor cell therapies are built to last.
  11. The European CAR-T map-Current status and future directions to improve access to CAR T-cell therapy for hematologic malignancies.
  12. Challenges and Potential Solutions to Advance Global Cancer Drug Development.
  13. CAR T cell therapy in autoantibody-mediated neurological disorders: a promising strategy.
  14. Antigen-binding affinity is a key determinant of the durable antitumor activity of CD5 CAR-T cells.
  15. Clinical trial landscape of CAR-based cell therapy for gastrointestinal malignancies.
  16. The Conflicting Role of Myeloid Cells in CAR-T Cell Therapy.
  17. γδ T Cells in Autoinflammatory Diseases.
  18. Integrative Roles of NK Receptors and γδ TCRs in γδ T Cell-Mediated Cancer Immunity.
  19. Stem-like T cells in cancer immunotherapy: biology, regulation and therapeutic targeting.
  20. Innate-like T Cell Biology in the Tumor Microenvironment Implications for Cancer Immunotherapy.
  21. Immune-mediated side effects of cancer immunotherapies.
  22. Experimental JAK inhibitors: the current, present, and future in graft-versus-host disease management?
  23. Hematopoietic Stem Cell Transplantation in Rheumatic Diseases.
  24. CAR-T therapy for autoimmune rheumatic diseases: navigating clinical frontiers between breakthroughs and uncertainties.
  25. Mechanisms of tumor cell evasion from NK cell-mediated killing and advances in NK cell-based cancer immunotherapy.
  26. Outcomes of point-of-care manufactured CAR T cell therapy for B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma in Vietnam.
  27. Securitization as a means to pay for cell and gene therapies for orphan diseases: a simulation study.
  28. Rethinking Immune Checkpoint Inhibition in Cancer.
  29. Nanobody-Based Drug Delivery: Emerging Strategies for Targeted Cancer Therapy.
  30. Use of synthetic data, a novel paradigm for immunopathology.
  31. The Virtual Biotech: A Multi-Agent AI Framework for Therapeutic Discovery and Development.
  32. Computational modeling and optimization of scFv-based receptors to support CAR-T design targeting CD19 for enhanced binding robustness and reduced off-target propensity.
  33. Charting the Current Landscape and Future Prospects of Cancer Therapy-Related Cardiovascular Toxicity in Cancer Survivors: From Bench to Bedside.
  34. Research Landscape of Stem Cell Applications in Musculoskeletal Tissue: A Scoping Review.
  35. The dual roles of natural killer cells in liver immunity and tolerance: Implications for health and disease.
  36. NIH-FDA Nutrition Regulatory Science Workshop: Advancing Research and Policy.
  37. Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion.
  38. Association between autoimmune diseases and the gut microbiome.
  1. Int J Mol Sci. 2026 Feb 25. pii: 2163. [Epub ahead of print]27(5):
    Harnessing CAR-Extracellular Vesicles for Next-Generation Cancer Immunotherapy.
    Sharenya Chelvaretnam, Kol Thida Mom, Carlos Andres Palma Henriquez, Quang Pham, Amirah Fitri, Sadman Bhuiyan, Mozhgan Shojaee, Kartini Asari, Hiba Rashid, Leearne Hinch, Ramin Khanabdali, Gregory Rice.
      Cancer immunotherapy has experienced substantial progress in recent years, particularly with the advancement of chimeric antigen receptor (CAR) technology, which enables immune cells to selectively target tumor-associated antigens. CARs, now in their fifth generation, are engineered by combining monoclonal antibody fragments with signaling and co-stimulatory domains and have been successfully applied to T cell, natural killer (NK) cell, and macrophage-based therapies. Notable clinical successes, such as tisagenlecleucel and lisocabtagene maraleucel underscore the therapeutic potential of CAR-T, CAR-NK and CAR-macrophages (CAR-Ms), which are currently being evaluated in numerous clinical trials. One promising extension of this approach involves the use of extracellular vesicles (EVs) derived from these immune cells. These nano-sized vesicles offer a cell-free platform to deliver diverse anticancer mediators, addressing the complex and dynamic nature of tumor environments. In this review, we examine the therapeutic potential and immunogenic properties of CAR-derived EVs, along with their role in modulating immune responses. Furthermore, we explore their application as targeted delivery vehicles for chemotherapeutic agents, with the goal of enhancing anti-tumor efficacy while minimizing systemic toxicity.
    Keywords:  cancer; chimeric antigen receptor; extracellular vesicles; immunotherapy
    DOI:  https://doi.org/10.3390/ijms27052163
  2. Semin Immunol. 2026 Mar;pii: S1044-5323(25)00072-7. [Epub ahead of print]81 102000
    Chimeric antigen receptor therapy for hepatocellular carcinoma.
    Lorenz Kocheise, Mohamed-Reda Benmebarek, Mitchell Ho, Tim F Greten.
      Adapting the success of chimeric antigen receptor T cell therapy from hematologic malignancies to solid tumors has become a major focus of ongoing research activities. However, the unique challenges posed by solid tumors, such as limited immune cell infiltration, reduced T cell persistence, and antigen loss, have led to only limited success in early clinical trials. Recently, combinatorial strategies incorporating next-generation armored CAR T cells along with various alternative immune cell types have rekindled optimism in the field. Hepatocellular carcinoma represents a distinct entity due to the unique characteristics of the liver microenvironment, including the influence of lipid metabolism, bile acids, and microbial compounds from the gut-liver axis. Furthermore, HCC is characterized by a variety of tumor-specific and tumor-associated antigens, enabling targeted approaches with minimal risk of on-target/off-tumor effects. The unique complexity of HCC, along with the underlying liver diseases that give rise to these tumors, presents both challenges and opportunities for cellular therapies. In this review, we examine the current landscape of CAR T cell therapy for HCC, highlighting recent clinical and preclinical developments. Furthermore, we discuss why HCC may be especially well-suited for tailored CAR-based strategies, given the liver's specific anatomical and immunological properties.
    Keywords:  CAR T cell; Cellular therapies; Chimeric antigen receptor; GPC3; HCC; Hepatocellular carcinoma
    DOI:  https://doi.org/10.1016/j.smim.2025.102000
  3. Ann Med. 2026 Dec;58(1): 2640457
    Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation.
    Yang Xiao, Long Liu, Shumei Liu, Lijing Wang, Jinfeng Tian, Ziyi Shao, Jingfei Shi, Chao Cui.
       INTRODUCTION: Relapsed/refractory acute myeloid leukaemia (AML) carries a dismal prognosis, primarily due to profound biological heterogeneity and the scarcity of effective targeted therapies. Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative investigational strategy for AML by genetically engineering T cells to specifically target tumour antigens; however, its clinical translation is severely impeded by target antigen scarcity and the immunosuppressive tumour microenvironment (TME).
    DISCUSSION: This review systematically summarizes the preclinical advances and mechanistic underpinnings of CAR-T therapy for AML, focusing on two core bottlenecks. First, it elaborates on the screening of candidate antigens (e.g. CD33, CD123) and cutting-edge target optimization strategies, including nanobody-based CARs, logic-gated systems, adapter-CAR technology and combinatorial approaches to mitigate antigen escape. Second, it dissects the inhibitory effects of the AML TME on CAR-T function and reviews corresponding intervention tactics, such as immune checkpoint blockade, cytokine arming and gene editing. Integrating key updates from the 2024 ASH Annual Meeting, the review also highlights emerging preclinical technologies, including off-the-shelf CAR-T, CAR-NK cells and γδ T cell therapy. Importantly, it acknowledges the prevalent preclinical-to-clinical translation gap, where promising lab efficacy has not yet translated into consistent clinical success.
    CONCLUSIONS: Multidimensional technological innovation and the synergistic optimization of combination therapies are critical to overcoming AML-specific barriers. These advances hold the potential to unlock the precise clinical application of CAR-T therapy, ultimately improving survival outcomes for patients with relapsed/refractory AML.
    Keywords:  CAR-T cells; acute myeloid leukaemia; immunotherapy; target optimization; tumour immune microenvironment
    DOI:  https://doi.org/10.1080/07853890.2026.2640457
  4. Int J Hematol. 2026 Mar 09.
    Current status and issues with CAR-T cell products in Japan: a regulatory perspective.
    Miki Nakamura, Shinich Noda, Atsushi Nishikawa, Jun Matsumoto.
      The development of chimeric antigen receptor (CAR)-T cell products is accelerating worldwide. CAR-T cell therapy represents one of the most significant therapeutic advances, as it elicits remarkably effective and durable clinical responses. Approved CAR-T cell products target one of two antigens on B cells: CD19 or B cell maturation antigen (BCMA). In Japan, all CAR-T cell products are approved for the treatment of relapsed or refractory hematologic malignancies, including acute lymphoblastic leukemia, B cell lymphomas, and multiple myeloma. Although CAR-T cell therapy is indisputably one of the most recommended therapies, it has faced scrutiny for its high cost and several unresolved issues. This article outlines issues with and important considerations for CAR-T cell products reviewed by the Pharmaceuticals and Medical Devices Agency. We describe the approval process for CAR-T cell products; differences in indications for their use, including optimal clinical use guidelines; and manufacture of CAR-T cells, especially out-of-specification products. We also describe key considerations in the regulatory review of CAR-T cell products, with a focus on clinical evaluation.
    Keywords:  CAR-T cell therapy; Hematologic malignancies; Out of specification; Pharmaceuticals and medical devices agency
    DOI:  https://doi.org/10.1007/s12185-026-04189-z
  5. Immune Netw. 2026 Feb;26(1): e13
    From Ex Vivo to In Vivo: Advances in Lentiviral Vector Engineering for CAR-T Therapy.
    Yejin Baek, Yu Ri Seo, Serin Kim, Sungmin Jung, Chan Hyuk Kim, Young-Ho Lee.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved substantial clinical success in hematological malignancies and has become a key modality in cancer immunotherapy. However, the current ex vivo autologous manufacturing model continues to face high costs, complex logistics, and prolonged production timelines, which collectively limit scalability and patient accessibility. Direct in vivo CAR-T generation could overcome these bottlenecks by bypassing ex vivo manipulation, but systemic administration must address significant safety and efficacy hurdles. In this review, we summarize core principles of lentiviral vector design, including essential genomic elements and the evolution of safety-enhanced, third-generation self-inactivating vector system. We then discuss emerging bioengineering strategies to optimize in vivo gene delivery, including pseudotype engineering for T cell targeting, immune-evasion strategies, transgene/payload engineering, and genetic armoring to enhance therapeutic performance and safety. Finally, we review the current clinical landscape and highlight early evidence supporting the feasibility of in vivo CAR-T generation from ongoing clinical-stage programs. Collectively, these advances are accelerating the maturation of in vivo CAR-T platforms toward scalable modalities with the potential to substantially broaden access to advanced cellular immunotherapies.
    Keywords:  Gene transfer techniques; Genetic vectors; Immunotherapy; In vivo CAR-T; Lentivirus
    DOI:  https://doi.org/10.4110/in.2026.26.e13
  6. J Immunol Res. 2026 ;2026(1): e6629562
    CAR-Cell Therapy for Autoimmune Diseases: From the Laboratory to Clinical Practice.
    Xiao-Peng Zhang, Yi-Dong Chen, Qi Yu, Fang Liu, Jia-Min Li, Shuang Li, Yi-Yu Cheng, Xiao-Yu Fu, Qian-Xi Xia, Jun-Rong Li, Xiao-Hua Hou, Liang-Ru Zhu.
      Autoimmune diseases (AIDs) are characterized by a breakdown in immune tolerance, wherein the patient's immune system fails to recognize self-tissues and subsequently attacks the body's organs and tissues. Although there are many therapeutic medicines targeting the pathogenic mechanisms, there is currently a lack of curative or long-term symptom control options. Chimeric antigen receptor (CAR) cells are engineered cells that express multifunctional synthetic receptors. These CAR cells specifically target killer pathogenic immune cells and offer a novel approach to treating AIDs by modulating the immune microenvironment. Recent studies have demonstrated satisfactory outcomes with this method in managing autoimmune conditions. In our review paper, we provide a comprehensive summary of previous cases utilizing CAR cell therapy for AIDs. We hope that our review will provide clinicians with more options for the treatment of AIDs.
    Keywords:  autoimmune diseases; cellular immunotherapy; chimeric antigen receptor cells
    DOI:  https://doi.org/10.1155/jimr/6629562
  7. World J Clin Oncol. 2026 Feb 24. 17(2): 114107
    Advances and challenges of chimeric antigen receptor T cell therapy in digestive system malignancies.
    Chen Wang, Jin Zhang, Zi-Ke Chen, Yu-Gang Wang, Min Shi.
      Chimeric antigen receptor T cell therapy (CAR-T) has revolutionized the treatment of hematologic malignancies, but its success in solid tumors, particularly those of the digestive system, remains limited. Tumors of the gastrointestinal system, including gastric, colorectal, esophageal, hepatic, and pancreatic malignancies, represent a significant global health burden with high morbidity and mortality. Recent advances in antigen selection, chimeric antigen receptor design, delivery techniques, and combinatorial approaches have sparked renewed interest in CAR-T immunotherapy for these cancers. This article discusses recent progress in CAR-T development across the major digestive system tumors, outlines tumor-specific targets and clinical trials, highlights prevailing challenges and potential solutions, and proposes strategic directions for the next generation of CAR-T therapies in solid tumors.
    Keywords:  Chimeric antigen receptor T cell therapy; Chimeric antigen receptor design; Digestive system tumors; Gastrointestinal cancers; Immunotherapy
    DOI:  https://doi.org/10.5306/wjco.v17.i2.114107
  8. Immunol Lett. 2026 Mar 10. pii: S0165-2478(26)00040-4. [Epub ahead of print]280 107167
    Functional spectrum of γδ T cells in perinatal infectious diseases.
    Ines Lorga, Ximena Léon-Lara, Sarina Ravens.
      γδ T cells represent one of the earliest T cell lineages to develop and persist as long-lived cells after birth. During gestation, distinct developmental waves generate γδ T cells with restricted TCR diversity and pre-set effector functions to mediate immune homeostasis and protection in early life. This review summarizes current knowledge on γδ T cell development, their postnatal maturation, and functional roles in utero and after birth. It highlights their robust and diverse effector responses, including cytotoxicity, cytokine production, and immune regulation, and their contribution to pathogen defense and tissue homeostasis. Together, these perspectives emphasize the functional diversity and developmental imprinting of γδ T cells, underscoring their importance for early-life immune competence and protection in vulnerable neonates.
    Keywords:  Development; Neonatal infection; Neonates; in utero infection; γδ T cells
    DOI:  https://doi.org/10.1016/j.imlet.2026.107167
  9. Int J Technol Assess Health Care. 2026 Mar 09. 42(1): e25
    Organizational impact in healthcare in France: a decade of insights but chicken and egg situation.
    Tess Martin, Giovanny Arbelaez-Garces, Christophe Roussel, Nicolas Martelli, Olivier Marcellin.
       OBJECTIVES: Over the past decade, organizational impact (OI) has gained recognition as a key dimension in health technology assessment (HTA) in France, particularly for medical devices. Despite the publication of a national framework by the Haute Autorité de Santé in 2020, the absence of standardized methodologies continues to hinder its integration into decision making.
    METHODS: This commentary article traces the evolution of OI in French HTA, highlights real-world examples, and analyzes existing methodological tools, many adapted from other disciplines, that could enhance OI assessment.
    RESULTS: It emphasizes the need for flexible, context-sensitive approaches and proposes recommendations to improve the robustness, reproducibility, and relevance of OI evaluations.
    CONCLUSIONS: The article also explores the implications for pricing and reimbursement decisions, as well as hospital-based HTA practices, aiming to support more structured and evidence-informed integration of organizational considerations into HTA processes in France and beyond.
    Keywords:  decision making; health technology assessment (HTA); medical devices (MDs); methodological frameworks; organizational impact (OI)
    DOI:  https://doi.org/10.1017/S026646232610347X
  10. Cell Stem Cell. 2026 Mar 05. pii: S1934-5909(26)00074-3. [Epub ahead of print]33(3): 366-368
    Off-the-shelf CAR natural killer progenitor cell therapies are built to last.
    Noor Radde, Max Jan.
      Induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cells are an emerging class of off-the-shelf cellular immunotherapy limited by short-term persistence. Wang et al.1 develop a platform for lineage-committed progenitor cell therapy to sustain in vivo CAR iNK cell lymphopoiesis and enhance tumor control.
    DOI:  https://doi.org/10.1016/j.stem.2026.02.004
  11. Hemasphere. 2026 Mar;10(3): e70306
    The European CAR-T map-Current status and future directions to improve access to CAR T-cell therapy for hematologic malignancies.
    Elise R A Pennings, Frederick W Thielen, Florence Broussais, Julio Delgado, Ulrich Jaeger, Carmen Sanges, Yolanda Cabrerizo, Lutgart Roux-Opstaele, Caroline Dreuillet, Eglys Gonzalez-Marcano, Olga Millán, Barbara Huber, Solène Clavreul, Natacha Bolaños, Samantha Nier, Jana Mihályová, Roman Hájek, Michaela Horňáková, Robin Doeswijk, Catherine Thieblemont, Michael Hudecek, Carin A Uyl-de Groot, Marie José Kersten.
      Despite its great promise, implementation of CAR-T therapy-a personalized, logistically complex, and expensive treatment-remains challenging, hampering patient access across and within countries. Since 2018, six products have been centrally approved in Europe (i.e., the European Economic Area; EU-approved) for 15 hematologic malignancy indications. To better understand patient access to EU-approved commercial CAR-T therapy, we evaluated the current status in all 30 countries where EU-approval is valid plus the UK, addressing economic, clinical, and organizational aspects, and identifying challenges and strategies for improvement. A two-step approach was used, complementing data from marketing authorization holders (4/4 responded) with country-specific insights from clinical experts obtained via an online survey (30/31 responded). In August 2024, 26% of the 31 countries had no CAR-T products commercially available, 74% ≥ 1 product for non-Hodgkin lymphoma and leukemia, and 16% ≥ 1 product for multiple myeloma. One-time payment was the most used reimbursement method. Time to access varied significantly, with medians ranging from 0 (France/Germany) to 53 months (Slovakia). The median number of qualified CAR-T centers per 10 million population per country was 5.0 (IQR: 3.0-6.1). In most countries, patient eligibility assessment was decentralized. Costs and logistical complexity were main factors restricting access in countries with and without commercially available products. Proposed solutions included cost reductions, improving reimbursement processes, and increasing healthcare resources. This study shows that patient access to commercial CAR-T therapy in Europe remains limited. Its insights into this multi-faceted problem can guide policy-making, advocacy work, and research to make this transformative treatment accessible to more patients in need.
    DOI:  https://doi.org/10.1002/hem3.70306
  12. Ther Innov Regul Sci. 2026 Mar 07.
    Challenges and Potential Solutions to Advance Global Cancer Drug Development.
    Axel Glasmacher, Kim Lyerly, Birgit Wolf, Pio Zapella, Lidia Zielinska, Emma Clark, Murielle Mauer, Bruno Paiva, Anja Schiel, Fergus Sweeney, Carin A Uyl-de Groot, Marie von Lilienfeld-Toal, Jaap Verweij.
      Despite recent advancements in oncology drug development, patient access to innovative cancer therapies remains inadequate. There is an urgent need for more patient-centric approaches, with meaningful patient input from trial design through to health technology assessment (HTA) consultation. Multi-stakeholder consensus calls for better representation of the diversity of the target population and integration of patients' preferences in clinical cancer research by systematically collecting patient-reported outcomes using standardized methods, and acknowledging trade-offs between survival and long-term wellbeing. Furthermore, the generation of insufficiently robust data for regulatory and HTA decision-making continue to delay patient access to innovation. This could be mitigated through smarter study designs, including smaller, fit-for-purpose randomized studies and prospectively designed trials. Finally, concerted efforts are required to develop and validate novel intermediate/surrogate endpoints that enable earlier assessment of treatment outcomes to facilitate timely, evidence-based decisions that improve the patient experience across the cancer care continuum.
    Keywords:  Health technology assessment (HTA); Innovative trial design; Patient access; Patient diversity; Patient-reported outcomes (PROs); Precision oncology
    DOI:  https://doi.org/10.1007/s43441-026-00936-w
  13. J Neuroinflammation. 2026 Mar 12. pii: 85. [Epub ahead of print]23(1):
    CAR T cell therapy in autoantibody-mediated neurological disorders: a promising strategy.
    Muzi Wen, Ruoyi Zheng, Hanqing Zhang, Sophia Y Goldberg, Zhiying Jian, Ye Gao, Ruogu Cheng, Linxin Wen, Yu Zhao, Saad S Kenderian, Pei Shang.
      
    Keywords:  Anti-NMDA receptor encephalitis; Autoantibody-mediated neurological disorders; CAR T cell therapy; Diacylglycerol lipase alpha antibody associated encephalitis; Lambert-Eaton myasthenic syndrome; MOG antibody-associated disease; Multiple sclerosis; Myasthenia gravis; Neuromyelitis optica spectrum disorder; Stiff person syndrome
    DOI:  https://doi.org/10.1186/s12974-025-03662-6
  14. Mol Ther Oncol. 2026 Mar 19. 34(1): 201158
    Antigen-binding affinity is a key determinant of the durable antitumor activity of CD5 CAR-T cells.
    Jeong-Hoon Jeong, Yu Ri Seo, Seung Rok Yu, Hyo Bhin Lee, Hyeong Ji Lee, Hyeon Jeong Cho, Hyung Cheol Kim, Young-Ho Lee.
      T cell fratricide in T cell antigen-targeted chimeric antigen receptor (CAR)-T cell therapies remains a critical barrier to achieving optimal antitumor efficacy. To address this challenge, we explored modulation of antigen-binding affinity as a simple yet effective strategy to mitigate fratricide. To this end, we aimed to develop low-affinity CD5-specific CAR-T cells and to test the hypothesis that low-affinity CD5 CAR-T cells can evade T cell fratricide, thereby alleviating T cell exhaustion and enhancing sustained antitumor activity. Our results demonstrate that CD5 CAR-T cells engineered with low-affinity monoclonal antibodies exhibit significantly reduced fratricide and diminished T cell exhaustion in the infusion product compared to high-affinity counterparts such as the standard H65 and A2 clones, which is assumed to correlate with improved long-term antitumor responses. These findings establish antigen-binding affinity modulation as a promising alternative to extensive gene editing approaches, potentially simplifying CD5 CAR-T cell manufacturing while improving therapeutic outcomes.
    Keywords:  CD5 CAR-T cells; MT: Regular; T cell malignancies; affinity tuning
    DOI:  https://doi.org/10.1016/j.omton.2026.201158
  15. J Immunother Cancer. 2026 Mar 10. pii: e014286. [Epub ahead of print]14(3):
    Clinical trial landscape of CAR-based cell therapy for gastrointestinal malignancies.
    Wenjie Li, Jiahui Yang, Qingyan Kong, Zheyu Chen.
      Gastrointestinal malignancies (GIM) impose a substantial global health burden, accounting for approximately 33% of cancer-related mortality worldwide. Although chimeric antigen receptor (CAR)-based cell therapy has achieved remarkable success in hematological malignancies, its application in solid tumors, particularly GIM, remains in its nascent stages. This comprehensive landscape analysis systematically examined the clinical trial ecosystem of CAR-based cell therapy for GIM by retrieving 179 eligible trials from the Trialtrove database as of October 2025 (hepatobiliary and pancreatic malignancies were excluded). The analysis revealed a predominantly early-phase landscape, with Phase I studies constituting 70.39% of all trials. Geographically, China (70.77%) and the USA (16.41%) dominated trial initiation, while academic institutions sponsored 54.92% of investigations. Claudin 18.2, NKG2D(L), mesothelin, and CEA emerged as the most frequently targeted antigens. Autologous therapy administered via peripheral intravenous infusion represented the predominant therapeutic modality. Combination strategies incorporating chemotherapy and immunotherapy demonstrated promising synergistic potential, suggesting that multimodal approaches may enhance therapeutic efficacy while potentially mitigating resistance mechanisms. The convergence of innovative preclinical developments with increasingly supportive regulatory frameworks portends transformative advances in the field, positioning CAR-based cell therapy as an emerging cornerstone modality in the therapeutic armamentarium against GIM.
    Keywords:  Chimeric antigen receptor - CAR; Combination therapy; Gastrointestinal Cancer
    DOI:  https://doi.org/10.1136/jitc-2025-014286
  16. Cancer Res. 2026 Mar 12.
    The Conflicting Role of Myeloid Cells in CAR-T Cell Therapy.
    Grace DeFranco, Elizabeth L Siegler, Saad S Kenderian.
      Chimeric antigen receptor T (CAR-T) cell therapy is revolutionizing cancer treatment in hematological malignancies, but challenges related to the tumor microenvironment have hindered CAR-T success, especially in solid tumors. Myeloid cells in particular have been implicated in CAR-T efficacy. In this review, we discuss the roles of myeloid cells in CAR-T-associated toxicities including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, along with strategies to treat these toxicities by modulating myeloid cells. The review also explores myeloid cell-mediated suppression or enhancement of CAR-T function. Finally, strategies employed to target myeloid cells in combination with CAR-T cell therapy will be investigated.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4817
  17. Cells. 2026 Feb 24. pii: 388. [Epub ahead of print]15(5):
    γδ T Cells in Autoinflammatory Diseases.
    Ilan Bank.
      Autoinflammatory diseases are characterized by inappropriate activation of innate immunity resulting in excessive or persistent inflammation in the absence of infection. γδ T cells possess innate-like properties, including rapid responsiveness to stress-induced self-molecules, phosphoantigens, and inflammasome-derived cytokines, while retaining adaptive effector functions. Neutrophils and macrophages are well-established drivers of autoinflammatory disease, but increasing evidence implicates γδ T cells as key intermediaries by linking innate immune activation to tissue-specific inflammatory pathology. Here, we review evidence that in both monogenic and multifactorial autoinflammatory diseases-including, for example, familial Mediterranean fever, hyper-immunoglobulin (Ig) D syndrome, gout, Behçet's disease, Still's disease, atherosclerosis, and neurodegenerative disorders-γδ T cells display altered frequencies, activation states, cytokine polarization, and tissue recruitment. In inflammasome-driven diseases, skewing of γδ T cells toward interleukin (IL)-17 production has been observed, often accompanied by reduced interferon (IFN)γ secretion, thereby amplifying neutrophilic inflammation and tissue damage. In other diseases, e.g., Behcet's disease, IFNγ and tumor necrosis factor (TNF)α producton predominate. Transcriptomic and tissue-based analyses support the accumulation and functional specialization of γδ T cells at sites of sterile inflammation. Collectively, these findings position γδ T cells as central amplifiers and modulators of inappropriate innate immune activation in the context of autoinflammatory diseases. Improved understanding of γδ T cell subset-specific regulation may inform novel therapeutic strategies targeting autoinflammatory diseases.
    Keywords:  Alzheimer’s disease; Behcet’s disease; T cells; atherosclerosis; autoinflammatory diseases; familial Mediterranean fever; gammadelta T cells; inflammasome; interferon gamma; interleukin-1; interleukin-17
    DOI:  https://doi.org/10.3390/cells15050388
  18. Immune Netw. 2026 Feb;26(1): e3
    Integrative Roles of NK Receptors and γδ TCRs in γδ T Cell-Mediated Cancer Immunity.
    Won Joon Oh, Haryoung Cho, Tilanka Kalanapriya Dahanayake, Tae Jin Kim.
      γδ T cells employ dual recognition strategies that integrate innate and adaptive immune sensing through NK receptors (NKRs) and γδ-TCRs in cancer immunity. Through the coordinated use of clonotypic γδ-TCRs and germline-encoded NKRs, γδ T cells recognize malignant cells in an MHC-unrestricted manner and exert potent cytotoxic and immunomodulatory functions. In this review, we discuss how activating and inhibitory NKRs-including NKG-2D, natural cytotoxicity receptors, CD16, NKG-2A, and killer cell immunoglobulin-like receptors-are expressed across major human γδ T cell subsets and how their signals are integrated with γδ-TCRs. We highlight subset-specific differential utilization of NKRs in circulating Vδ2 and tissue-resident Vδ1 γδ T cells, context-dependent integration of γδ-TCR and NKR signaling within the tumor microenvironment, and emerging implications for γδ T cell-based cancer immunotherapy.
    Keywords:  Cancer; Receptors, antigen, T-cell, gamma-delta; Receptors, natural killer cell; T lymphocyte subsets
    DOI:  https://doi.org/10.4110/in.2026.26.e3
  19. Front Immunol. 2026 ;17 1764549
    Stem-like T cells in cancer immunotherapy: biology, regulation and therapeutic targeting.
    Hui Wang, Zhuoran Yao, Ren Luo, Kai Kang, Feifei Na, You Lu.
      The identification of stem-like CD8+ T cells, also termed progenitor or precursor of exhausted T cells (TPEX), has reshaped our understanding of durable antitumor immunity. These cells exhibit progenitor-like properties, including self-renewal capacity and multilineage differentiation potential, giving rise to both effector-like and terminally exhausted CD8+ T cell subsets. Accordingly, the abundance of stem-like CD8+ T cells correlate strongly with improved clinical outcomes in patients receiving immune checkpoint inhibitors, adoptive cell therapy, or cancer vaccines across multiple tumor types. This review synthesizes recent advances in TPEX cells biology, highlighting interconnected research pillars, including: specialized niche microenvironments that sustain stemness of TPEX cells through coordinated chemokine signaling and antigen-presenting cell interactions; core molecular circuitry that dynamically balances self-renewal versus effector differentiation via transcription factors and cytokines; and therapeutic reprogramming strategies that harness TPEX cells as the primary driver of immunotherapy efficacy. Further, we explore strategies to augment the functionality of TPEX cells through niche modulation, stem-like CAR-T engineering, and combinatorial approaches, highlighting the trend that targeting TPEX cells thus emerge as a transformative future strategy to overcome immunotherapy resistance and achieve a durable response.
    Keywords:  cancer immunotherapy; self-renewability; stem-like T cells; therapeutic implications; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1764549
  20. Cells. 2026 Feb 26. pii: 402. [Epub ahead of print]15(5):
    Innate-like T Cell Biology in the Tumor Microenvironment Implications for Cancer Immunotherapy.
    Maryam Sanjari Pour, Ahmad Nasimian, Julhash U Kazi.
      Innate-like T cells (ILTCs) link innate immune responses with adaptive immune functions. This group includes invariant natural killer T (iNKT) cells, mucosa-associated invariant T (MAIT) cells, and γδ T cells. ILTCs detect transformed or stressed cells via non-classical antigen presentation pathways. For example, iNKT cells recognize CD1d-presented glycolipids, MAIT cells respond to MR1-presented metabolites from riboflavin pathways, and γδ T cells sense phosphoantigens through butyrophilin-dependent mechanisms and stress ligands. These features support early tumor control and shape downstream immunity by promoting dendritic cell activation, NK cell function, and priming of tumor-reactive CD8+ T cells. In established tumors, ILTC activity is frequently suppressed. Reduced antigen presentation, inhibitory cytokines, hypoxia, and metabolic constraints, including lactate accumulation and kynurenine production, limit effector responses and promote hyporesponsive states. Transcriptional regulators such as TOX, NR4A family members, and BATF are associated with these programs. This review discusses ILTC roles in tumor surveillance, immune escape, and therapeutic strategies to restore their function.
    Keywords:  MAIT; iNKT; immune evasion; immune surveillance; innate-like T cells; therapeutic reactivation; tumor microenvironment (TME); γδ T cells
    DOI:  https://doi.org/10.3390/cells15050402
  21. Blood. 2026 Mar 09. pii: blood.2025030059. [Epub ahead of print]
    Immune-mediated side effects of cancer immunotherapies.
    Lukas M Braun, Jarushka Naidoo, Robert Zeiser.
      Immunotherapies, such as allogeneic hematopoietic cell transplantation and infusion of chimeric antigen receptor T (CAR-T) cells have significantly extended our therapeutic armamentarium against several hematological malignancies. Blocking negative regulators of immunity with immune checkpoint inhibitors has significantly improved the survival of patients with mainly solid tumors. Despite their beneficial effects, these therapies are also associated with severe, immune-mediated side effects. Here, we discuss biological similarities and differences of acute graft-versus-host disease (GVHD), cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hemophagocytic lymphohistiocytosis like syndrome (IEC-HS), immune effector cell-associated hematotoxicity (ICAHT), local immune effector cell-associated toxicity syndrome (LICATS), and immune-related adverse events after immune checkpoint inhibition (irAEs). Recent data have led to a better understanding of the role of myeloid cells and T-cells, including tissue-resident T-cells, in the pathophysiology of GVHD, CAR-T-cell associated immunotoxicities and irAEs. Further, we summarize approved, currently evaluated and potential future therapies for immune-mediated toxicities of cancer immunotherapies. This review will help to understand how therapeutic strategies target communalities of different side effects to overcome immune-mediated side effects of cancer immunotherapies.
    DOI:  https://doi.org/10.1182/blood.2025030059
  22. Expert Opin Investig Drugs. 2026 Mar 12. 1-7
    Experimental JAK inhibitors: the current, present, and future in graft-versus-host disease management?
    M Abdullah Jamil, Salman Otoukesh, Haris Ali.
       INTRODUCTION: Graft-versus-host disease (GVHD) remains the primary barrier to successful allogeneic hematopoietic cell transplantation, contributing significantly to non-relapse mortality. With approximately 50% of patients developing GVHD despite prophylaxis, there is an urgent need for effective alternatives. Janus kinase (JAK) inhibitors have emerged as a promising class of targeted immunomodulators to address this clinical challenge.
    AREAS COVERED: This review examines the mechanistic rationale for JAK inhibition in GVHD and summarizes key preclinical and clinical data. We evaluate the efficacy and safety of selective and nonselective agents, including ruxolitinib, baricitinib, itacitinib, pacritinib, and rovadicitinib. Furthermore, the review analyzes recent advancements in peri-transplant prophylaxis, biomarker-driven strategies, and the comparative landscape of FDA-approved therapies for acute and chronic GVHD.
    EXPERT OPINION: The future of GVHD management is shifting from broad immunosuppression toward precision medicine. We anticipate a transition from the current 'steroid-first' paradigm to risk-stratified algorithms utilizing biomarker profiling and novel combination strategies. While ruxolitinib is the current cornerstone, the development of highly selective inhibitors and the resolution of financial access barriers will be crucial for establishing JAK inhibitors as the frontline standard of care over the next decade.
    Keywords:  Acute graft-versus-host disease; Janus kinase inhibitors; biomarkers; hematopoietic cell transplantation; immunomodulation; targeted therapy
    DOI:  https://doi.org/10.1080/13543784.2026.2643317
  23. Int J Rheum Dis. 2026 Mar;29(3): e70604
    Hematopoietic Stem Cell Transplantation in Rheumatic Diseases.
    Nandana Suresh, D R Spoorthy Raj, Harshwardhan Patil, Dyuksha Arora, Mahabaleshwar Mamadapur.
       BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an emerging therapeutic strategy for severe autoimmune rheumatic diseases (AIRD) where conventional therapies often fail to achieve long-term remission. This review focuses on the role of HSCT in specific AIRD, including systemic sclerosis (SSc), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), deficiency of adenosine deaminase 2 (DADA2), antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Takayasu arteritis (TA), and juvenile idiopathic arthritis (JIA).
    OBJECTIVE: The objective was to evaluate the efficacy, immunological mechanisms, patient selection criteria, conditioning regimens, and outcomes of HSCT in the management of these specific AIRD, with a focus on systemic sclerosis-associated interstitial lung disease (SSc-ILD).
    METHODS: A comprehensive literature review was conducted, analyzing clinical trials, observational studies, and preclinical research on HSCT in the following AIRD: SSc, SLE, RA, DADA2, ANCA-associated vasculitis, TA, and JIA. The review examined pulmonary outcomes, immune reconstitution, CD34+ cell selection, and post-transplant immunosuppression. Keywords used in the search included SSc, SLE, RA, DADA2, ANCA-associated vasculitis, Takayasu arteritis, and JIA.
    RESULTS: HSCT has demonstrated promising outcomes, particularly in diffuse cutaneous SSc with ILD improvement and in refractory cases of SLE, RA, and JIA. In DADA2, HSCT can reverse hematological, immunological, and vascular phenotypes. While effective in some cases of ANCA-associated vasculitis and TA, relapses and complications remain a concern. Immunological benefits include the regeneration of a self-tolerant immune system. However, early transplant-related mortality (TRM) necessitates careful patient selection and reduced toxicity conditioning.
    CONCLUSIONS: HSCT offers a transformative approach for select patients with refractory SSc, SLE, RA, DADA2, ANCA-associated vasculitis, TA, and JIA, achieving long-term, drug-free remission in some. Future research should optimize conditioning protocols, refine patient selection, and assess long-term outcomes to maximize HSCT benefits and minimize risks.
    Keywords:  autoimmune diseases; hematopoietic stem cell transplantation; juvenile idiopathic arthritis; rheumatic diseases; systemic lupus erythematosus; systemic sclerosis; treatment outcome
    DOI:  https://doi.org/10.1111/1756-185x.70604
  24. Clin Exp Med. 2026 Mar 07. pii: 177. [Epub ahead of print]26(1):
    CAR-T therapy for autoimmune rheumatic diseases: navigating clinical frontiers between breakthroughs and uncertainties.
    Juntao Cheng, Xiaohui Zhang, Yong Fan, Zhuoli Zhang.
      
    Keywords:  Autoimmune rheumatic diseases; B cell depletion; Chimeric antigen receptor T-cell therapy; Idiopathic inflammatory myopathy; Systemic lupus erythematosus; Systemic sclerosis
    DOI:  https://doi.org/10.1007/s10238-026-02076-9
  25. Pharm Sci Adv. 2026 Dec;4 100109
    Mechanisms of tumor cell evasion from NK cell-mediated killing and advances in NK cell-based cancer immunotherapy.
    Rulin Zheng, Zhuqing Wang, Baodi Zhang, Yiwei Li, Shan Gao, Yuhan Guo, Deping Meng, Xiaodong Mu, Liwei Shao.
      Natural killer (NK) cells represent a critical component of the innate immune system, capable of exerting potent cytotoxic activity against infected and transformed cells. However, tumor cells evolve diverse strategies to evade NK cell-mediated surveillance, including modulation of receptor-ligand interactions, secretion of immunosuppressive cytokines, metabolic disruption, and induction of NK cell exhaustion. In this review, we summarise the mechanisms by which tumors escape NK cell control and highlight recent advances in NK cell-based immunotherapies, including adoptive NK transfer, immune checkpoint blockade, and CAR-engineered NK cells. Ongoing efforts to improve NK cell persistence, infiltration, and functional resilience hold promise for optimising clinical efficacy.
    Keywords:  CAR-NK therapy; Cancer immunotherapy; Immune evasion; Natural killer cells; Tumor immunology; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.pscia.2026.100109
  26. Mol Ther Oncol. 2026 Mar 19. 34(1): 201156
    Outcomes of point-of-care manufactured CAR T cell therapy for B cell acute lymphoblastic leukemia and non-Hodgkin lymphoma in Vietnam.
    Liem Thanh Nguyen, Duy D Nguyen, Quoc Khanh Bach, Lan T M Dao, Trang Thi Kieu Phan, Hoang-Phuong Nguyen, Hong-Nhung Dao, Trang H Pham, Phuong T Pham, Hien T Mai, Viet Huong T Pham, Thanh Mai T Nguyen, Van Binh Le, Nam Lam Phung, Ngoc Quang Nguyen, Michelle L Hermiston, Quynh Lan Phan, Do Quang Trung Nguyen, Lan Mai, Quoc Nhat Nguyen, Van T Hoang.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL), but access remains limited in resource-constrained settings. This phase I study evaluated the safety and feasibility of point-of-care (PoC) manufactured CD19-targeted CAR T cell therapy in Vietnamese patients. Between August 2023 and June 2025, 16 patients, eight with R/R ALL and eight with R/R NHL, were enrolled. All received fresh CAR T cells produced on-site using the CliniMACS Prodigy system, with a median dose of 1.9 × 106 CAR T cells/kg (range, 0.83-2.17 × 106). Cytokine release syndrome (CRS) occurred in 13 patients (12 with grade 1-2, one with grade 3), and grade 1 neurotoxicity was observed in two patients. In ALL, the complete remission (CR) rates were 100% on day 30, 75% on day 90, and 62.5% on day 180. Patients with NHL showed CR rates of 87.5% on both day 90 and day 180. The estimated 1-year progression-free survival rates were 62.5% (95% confidence interval [CI]: 36.5%-100%) for ALL and 87.5% (95% CI: 67.3%-100%) for NHL. PoC manufactured CD19 CAR T cells demonstrated manageable toxicity and encouraging early efficacy in Vietnamese patients with R/R ALL and NHL. This model offers a cost-effective strategy for delivering advanced therapy in resource-limited settings.
    Keywords:  CAR T-cell therapy; CRS; ICANS; acute lymphoblastic leukemia; cell therapy; global health oncology; non-Hodgkin lymphoma; point-of-care manufacturing; resource-constrained settings
    DOI:  https://doi.org/10.1016/j.omton.2026.201156
  27. Gene Ther. 2026 Mar 11.
    Securitization as a means to pay for cell and gene therapies for orphan diseases: a simulation study.
    John M Lu, Avi J Cherla, Alexander W Carter, Elias A Mossialos.
      Cell and gene therapies may provide life-extending treatments for patients. However, paying for these therapies using a single upfront payment will be challenging because of uncertainty about long-term clinical effectiveness and affordability. Developers, recognizing the challenges of paying for these therapies, have offered payers 5-year outcomes-based installment plans. The short length of these plans, however, does little to address uncertainties about the cost-effectiveness of paying for these therapies. Instead, we propose to offer 30-year performance-based annuities that shift payments to match the expected accrual of clinical benefits more closely. Using securitization techniques combined with long-term performance-based annuities, we demonstrate that in the case of the gene therapy Zolgensma, this mechanism is effective at mitigating concerns over value and affordability for payers. In summary, our proposal for financing cell and gene therapies creates a viable incentive for developers, while also balancing long-term effectiveness and budget impact concerns from payers and access challenges for patients.
    DOI:  https://doi.org/10.1038/s41434-026-00604-6
  28. Scand J Immunol. 2026 Mar;103(3): e70106
    Rethinking Immune Checkpoint Inhibition in Cancer.
    Tibor Bakacs, Colin C Anderson.
      Immune checkpoint inhibitors (ICIs) have reshaped cancer treatment, offering durable remissions for a minority of patients. Yet their success has come with a difficult trade-off: a large proportion of patients develop immune-related adverse events (irAEs), sometimes severe, and often without gaining clinical benefit. These reactions signal a disruption of peripheral tolerance that is not easily explained by traditional models in which negative selection of autoreactive T cells maintains self-restraint. Under ICI therapy, patients' own T cells can behave in ways that resemble the alloreactive responses seen in chronic graft-versus-host disease (cGVHD), producing a pattern of tissue injury that mirrors this well-studied transplant complication. This parallel offers a fresh way to think about why irAEs occur and how they might be prevented. Despite arising from fundamentally different immunologic triggers, comparative transcriptomic analyses reveal that cGVHD and irAEs induced by ICIs converge on a common molecular ecosystem dominated by interferon-conditioned tissue states. Early clinical experience with ultra-low-dose ICI regimens supports this idea, showing that meaningful antitumor activity can be preserved while dramatically reducing toxicity. We suggest that viewing ICI-induced autoimmunity through a cGVHD-like lens may help guide safer dosing strategies and broaden access to immunotherapy worldwide.
    Keywords:  graft versus host disease; immune checkpoint inhibitors; ultra‐low dose ICI
    DOI:  https://doi.org/10.1111/sji.70106
  29. Int J Nanomedicine. 2026 ;21 584604
    Nanobody-Based Drug Delivery: Emerging Strategies for Targeted Cancer Therapy.
    Nandan Ghosh, Nasim Sepay, Mohuya Paul, Jungkyun Im.
      Traditional cancer treatments such as chemotherapy and radiotherapy remain effective but lack specificity, often causing collateral damage to healthy tissues. Antibody-drug conjugates (ADCs) using monoclonal antibodies (mAbs) have been developed to achieve advanced targeted delivery; however, preclinical and pharmacokinetic studies have indicated that factors such as large size, complex conjugation processes, high production cost, and immunogenicity can limit tumor penetration, pharmacokinetics, and broader translational applicability. Nanobodies (Nbs), or single-domain antibodies (sdAbs) derived from camelid heavy-chain-only antibodies (HCAbs), represent a promising alternative with smaller size, high aqueous solubility, stability, refolding capacity, and low immunogenicity. Preclinical studies have shown that Nbs retain high affinity and specificity while providing improved access to hidden epitopes on target antigens compared to conventional antibodies. These unique features have supported the development of Nb-drug conjugates (NDCs), which have been evaluated for the selective delivery of cytotoxic drugs to antigen-expressing cancer cells in vitro and in animal models, demonstrating improved target specificity. Furthermore, Nb-attached drug delivery vehicles (NDvs) functionalized with nanoscale carriers, such as liposomes, dendrimer-based nanoparticles, upconversion nanoparticles, and polymeric micelles, have expanded the scope of Nb-based drug delivery systems. This review summarizes the current progress in Nb-mediated drug delivery, compares different strategies, and discusses their translational potential in cancer therapy, highlighting opportunities and limitations based on available experimental data.
    Keywords:  drug delivery; nanobody; nanobody drug conjugate; single domain antibody; targeted cancer therapy
    DOI:  https://doi.org/10.2147/IJN.S584604
  30. Curr Opin Immunol. 2026 Mar 10. pii: S0952-7915(26)00030-0. [Epub ahead of print]100 102753
    Use of synthetic data, a novel paradigm for immunopathology.
    Antonio Tonutti, Saverio D'Amico, Suraj Timilsina, Merrill Eric Gershwin, Angela Ceribelli, Carlo Selmi.
      The complexity and heterogeneity of autoimmune diseases are only partially captured by current analytic tools, even when deep learning techniques are employed to intercept patterns beyond existing dogma. Synthetic data offer a newer paradigm through machine-generated reconstructions of real-world data that faithfully attempt to recapitulate biological and clinical patterns without creating duplicates and maintaining the privacy of the original ones. Synthetic data act as a magnifying lens, allowing predictions otherwise not possible on disease classification, progression, and therapeutic response. This approach has several advantages and is currently underutilized. Firstly, it provides cohort enrichment and equilibrates group imbalances. Second, it generates synthetic arms for both in vitro studies and human clinical trials, relevant to disentangle the rarity and heterogeneity of autoimmune diseases. Third, the platform allows applications beyond tabular registries, including medical images, genomics, and flow cytometry data. Last, 'digital twins' act through dynamic bidirectional links with the biological/clinical system counterpart, lending themselves to transformative opportunities for precision medicine. Herein, we discuss the current status of this fast-moving novel component of artificial intelligence and its implications for autoimmune diseases.
    DOI:  https://doi.org/10.1016/j.coi.2026.102753
  31. bioRxiv. 2026 Feb 23. pii: 2026.02.23.707551. [Epub ahead of print]
    The Virtual Biotech: A Multi-Agent AI Framework for Therapeutic Discovery and Development.
    Harrison G Zhang, Peter Eckmann, Jiacheng Miao, Andrew B Mahon, James Zou.
      Drug discovery and development requires integrating diverse evidence across biological scales and data modalities. However, relevant data, tools, and expertise remain fragmented across teams and organizations, making integration difficult. To address these challenges, we introduce the Virtual Biotech, a coordinated team of AI agents that mirrors the structure of human therapeutic research organizations to support end-to-end computational discovery. The Virtual Biotech is led by a Chief Scientific Officer agent that receives scientific queries, delegates them to domain-specialized scientist agents, and integrates their outputs through data-driven reasoning. Scientist agents leverage complementary tools and knowledge sources spanning statistical genetics, functional genomics, pathways and interactions, chemoinformatics, disease biology, and clinical data. We showcase the Virtual Biotech across three translational applications. First, the agents autonomously annotated and analyzed outcomes from 55,984 clinical trials to identify genomic features of drug targets associated with trial success. More than 37,000 clinical-trialist agents curated structured trial outcomes and linked targets to multi-omic annotations, including cell-type-specific features derived by the agents from single-cell RNA-sequencing atlases. The agents discovered that drugs targeting cell-type-specific genes were 40% more likely to progress from Phase I to Phase II and 48% more likely to reach market (Phase IV), while exhibiting 32% lower adverse event rates. Second, the Virtual Biotech evaluated B7-H3 as a lung cancer target, integrating statistical genetics, single-cell, spatial, and clinicogenomic evidence to propose an antibody-drug conjugate strategy while identifying key liabilities and differentiation opportunities. Third, the platform analyzed a terminated ulcerative colitis trial targeting OSMR β to infer potential failure mechanisms and proposed biomarker-guided enrollment strategies to address precision-medicine gaps. Together, these results illustrate how the Virtual Biotech can enable more transparent, efficient, and comprehensive multi-scale therapeutic analyses, helping to accelerate early-stage drug discovery workflows while keeping human scientists in the loop.
    DOI:  https://doi.org/10.64898/2026.02.23.707551
  32. Biochem Biophys Res Commun. 2026 Feb 13. pii: S0006-291X(26)00228-7. [Epub ahead of print]811 153464
    Computational modeling and optimization of scFv-based receptors to support CAR-T design targeting CD19 for enhanced binding robustness and reduced off-target propensity.
    Kadalmani Krishnan, Anita Chugh, Ravikrishnan Rajaram, Anagha S Setlur, Chandrashekar Karunakaran, Akshay Uttarkar, Vidya Niranjan.
      Chimeric Antigen Receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, with CD19 being a primary target due to its stable expression in lymphomas. However, current CAR-T therapies face challenges related to antigen escape, treatment resistance, and toxicity. In this study, we employed a computational approach to design and optimize scFv-based receptors to support CAR-T design with reduced predicted off-target interaction propensity. We utilized in-silico techniques, including PSI-BLAST sequence validation, molecular docking, machine learning-based toxicity prediction, and molecular dynamics simulations, to refine ScFv relevant receptor design. Our structural modeling and docking studies identified an optimized single-chain variable fragment (scFv) antibody (H8_L1) that demonstrated high binding affinity and stability with both wild-type and mutated CD19 variants. Toxicity assessments confirmed minimal off-target effects. Additionally, computational mutation docking studies revealed that the optimized scFv-based receptor for CAR-T design maintained stable interactions despite antigenic variations. These findings provide a robust prioritization study and framework to support the design of CAR-T receptors with enhanced computational efficiency and lower toxicity, paving the way for further experimental validation and clinical applications. However, this work is limited to computational scFv design and does not evaluate CAR expression, surface localization, or T-cell function.
    Keywords:  Antigen-antibody docking; CAR-T; CD19; Computational modeling; Immunotherapy; Molecular dynamics simulation; ScFv-based receptors
    DOI:  https://doi.org/10.1016/j.bbrc.2026.153464
  33. Drug Des Devel Ther. 2026 ;20 572304
    Charting the Current Landscape and Future Prospects of Cancer Therapy-Related Cardiovascular Toxicity in Cancer Survivors: From Bench to Bedside.
    Shiyi Tao, Lintong Yu, Lanxin Zhang, Jun Li, Ji Wu, Yuqing Tan.
      Cardio-oncology represents an emerging interdisciplinary discipline focusing on optimizing oncologic efficacy while mitigating treatment-related cardiovascular complications. The advent of novel anticancer agents such as targeted therapies, immune checkpoint inhibitors, and endocrine therapies has transformed cancer care, significantly improving survival rates. Nevertheless, prolonged patient survivorship has unmasked clinically significant cardiovascular sequelae, termed cancer therapy-related cardiovascular toxicity (CTR-CVT), which manifests as acute manifestations during therapy and delayed presentations persisting years post-treatment. This dual-onset toxicity profile necessitates rigorous longitudinal cardiovascular risk stratification integrating comprehensive pre-therapeutic assessment, multi-modal imaging, and biomarker-guided surveillance to detect subclinical dysfunction, prevent premature treatment cessation, and reduce cancer recurrence and mortality risks. Future research priorities include further elucidating pathophysiological mechanisms of CTR-CVT, developing cardio-protective strategies, implementing personalized therapeutic protocols, and reducing disparities in care to advance cardio-oncology and improve patient outcomes. This review synthesizes the development of CTR-CVT, existing evidence-based CTR-CVT risk surveillance approaches, and emerging innovative early-warning strategies, and the future development prospects.
    Keywords:  cancer therapy-related cardiovascular toxicity; cardio-oncology; cardiotoxicity; monitoring; prevention
    DOI:  https://doi.org/10.2147/DDDT.S572304
  34. Cells. 2026 Mar 04. pii: 456. [Epub ahead of print]15(5):
    Research Landscape of Stem Cell Applications in Musculoskeletal Tissue: A Scoping Review.
    Aiyarin Kittilukkana, Puwapong Nimkingratana, Dumnoensun Pruksakorn, Mingkwan Na Takuathung, Nut Koonrungsesomboon.
      Stem cell therapy represents an intrinsic part of regenerative medicine, with expanding applications in orthopedic and musculoskeletal research. Although studies span from small-animal models to early-phase clinical trials, the field remains fragmented, with wide variation in stem cell types, delivery methods, and target tissues. A consolidated overview is needed to inform future directions and bridge the gap between preclinical promise and clinical application. This scoping review synthesized evidence from 500 preclinical and clinical studies, identified through systematic searches and screened in accordance with PRISMA-ScR guidelines. Data were extracted on stem cell type and source, delivery approach, targeted tissue and organ, and disease indication. We found that autologous bone marrow-derived mesenchymal stem cells were the most used, with adipose- and perinatal-derived cells gaining prominence in recent years. Small-animal models such as rats and rabbits predominated, while large-animal and human studies focused mainly on knee osteoarthritis. Intra-articular injection was the principal delivery method across both preclinical and clinical settings. By mapping prevailing practices and emerging trends, this review provides a comprehensive reference for researchers, clinicians, and regulatory stakeholders. It highlights translational pathways, identifies critical gaps, and offers evidence to guide the design of safe, effective, and scalable regenerative therapies in orthopedics.
    Keywords:  cell-based therapy; mesenchymal stem cells; musculoskeletal diseases; orthopedics; regenerative medicine; scoping review
    DOI:  https://doi.org/10.3390/cells15050456
  35. Hepatol Commun. 2026 Apr 01. pii: e00923. [Epub ahead of print]10(4):
    The dual roles of natural killer cells in liver immunity and tolerance: Implications for health and disease.
    Zhongheng Li, Yihang Gong, Linsen Ye, Wei Liu.
      The liver, a pivotal organ in immunity, functions as a central site with dual roles in immune defense and tolerance. Natural killer (NK) cells, a key subset of hepatic lymphocytes, display significant heterogeneity, with varied phenotypic and functional traits that enable them to perform essential roles in immune surveillance, maintain tissue homeostasis, and defend against pathogens and tumors. NK cell activation is tightly controlled by a balance between activating and inhibitory receptors, which orchestrates their cytotoxic, cytokine-producing, and immunoregulatory functions. They are vital participants in antiviral responses, tumor surveillance, fibrosis regulation, and liver regeneration. In chronic liver diseases such as viral hepatitis, fibrosis, and hepatocellular carcinoma (HCC), NK cell dysfunction, characterized by diminished cytotoxic function and altered receptor expression, contributes to disease progression. Emerging therapies, including chimeric antigen receptor-engineered NK (CAR-NK) cells and cytokine-based treatments, aim to restore NK cell functionality and harness their therapeutic potential for liver disease management. This review highlights the dual roles of NK cells in liver health and disease, emphasizing their significance in immune regulation, disease progression, and therapeutic innovation.
    Keywords:  chronic liver disease; cytokines; hepatocyte; immunotherapy; phenotype
    DOI:  https://doi.org/10.1097/HC9.0000000000000923
  36. Am J Clin Nutr. 2026 Mar 10. pii: S0002-9165(26)00076-6. [Epub ahead of print] 101267
    NIH-FDA Nutrition Regulatory Science Workshop: Advancing Research and Policy.
    Andrew A Bremer, Samantha Adas, Alison G M Brown, Kellie O Casavale, Steven Hermansky, Kirsten Herrick, Claudine J Kavanaugh, Holly L Nicastro, Sheri D Schully, Jill Reedy, Ashley J Vargas, Krista A Zanetti, Robin A McKinnon.
      Nutrition plays a pivotal role in health, yet poor dietary habits are now the leading risk factor for illness and death. In the United States (U.S.), diet-related conditions such as heart disease, cancer, diabetes, and obesity cause more than one million deaths per year and are leading contributors to the nation's $4.5 trillion in health care spending. Addressing these issues requires coordinated efforts across multiple sectors and government agencies. The National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA) are essential partners in this endeavor. A strong foundation of scientific research, coupled with effective, practical, and real-world regulatory activities, is critical to inform consumers and support a healthier food environment. In December 2024, NIH and FDA convened a workshop to advance nutrition science for food-related policy decision-making. A diverse group of researchers, policymakers, and other experts participated in the event to identify research gaps, explore strategies for enhanced NIH-FDA collaboration, and highlight emerging technologies in nutrition science, with a particular focus on the topic of ultra-processed foods. The workshop objectives included: (i) identifying critical research gaps and priorities in nutrition regulatory science; (ii) enhancing scientific collaboration between NIH and FDA; (iii) exploring how scientific evidence informs food-related policies and regulations; and (iv) highlighting emerging technologies and data resource needs for nutrition research. This article summarizes the workshop proceedings and describes priority research gaps, opportunities, and suggested next steps that emerged from the discussions.
    Keywords:  Dietary habits; Food Regulation; Food environment; Health; Nutrition
    DOI:  https://doi.org/10.1016/j.ajcnut.2026.101267
  37. Sci Adv. 2026 Mar 13. 12(11): eadz1722
    Biodegradable targeted polymeric mRNA nanoparticles enable in vivo CD19 CAR T cell generation and lead to B cell depletion.
    Manav Jain, Savannah E Est-Witte, Sydney R Shannon, Sarah Y Neshat, Xinjie Yu, Sydney Dunham, Tina Tian, Leonardo Cheng, Jawaun Harris, Maximilian F Konig, Stephany Y Tzeng, Jonathan P Schneck, Jordan J Green.
      While chimeric antigen receptor (CAR) T cell therapies have demonstrated therapeutic efficacy against B cell malignancies, widespread implementation of these therapies is hindered by a cumbersome, ex vivo manufacturing process. Delivery of CAR-encoding messenger RNA (mRNA) to endogenous T cells can generate these therapeutic cells in vivo and streamline this manufacturing workflow. To accomplish this, T cell-activating ligands were conjugated to a biodegradable polymeric mRNA nanoparticle to form T cell-targeted particles. By conjugating multiple activating ligands, T cell transfection and stimulation in vitro was increased, and greater T cell transfection and selectivity in vivo was achieved compared to an untargeted particle. These nanoparticles can flexibly encapsulate mRNA cargos and were used to deliver anti-CD19 CAR mRNA in vivo, enabling depletion of 95% of B cells in the peripheral blood and 50% depletion of splenic B cells in healthy mice. These findings regarding nanoparticle tropism and their potential therapeutic efficacy highlight the importance of this nonviral, polymeric platform to address key limitations associated with current CAR T practices.
    DOI:  https://doi.org/10.1126/sciadv.adz1722
  38. Int Immunol. 2026 Mar 10. pii: dxag013. [Epub ahead of print]
    Association between autoimmune diseases and the gut microbiome.
    Yudai Hirano, Yoshihiko Tomofuji, Ryuya Edahiro, Toshihiro Kishikawa, Satoru Miyawaki, Yukinori Okada.
      The gut microbiome has emerged as an important environmental factor in the pathogenesis of autoimmune diseases. Advances in high-throughput sequencing technologies have enabled comprehensive characterization of the gut microbiome, providing detailed insights into its composition and functional potential. These approaches have been widely applied in autoimmune disease research, revealing disease-associated alterations in the gut microbiome of patients with conditions such as rheumatoid arthritis and systemic lupus erythematosus. In addition, microbiome sequencing data can be leveraged to investigate the gut virome, including viruses residing in the intestinal ecosystem. This review summarizes current evidence linking autoimmune diseases and the gut microbiome, with a particular focus on studies employing microbiome sequencing-based analyses.
    Keywords:  Gut virome; Microbiome sequencing; Rheumatoid arthritis; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1093/intimm/dxag013
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒15 at 10:10.