bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–05–24
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Targeting GD2 with CAR-T Cell Therapy in Neuroblastoma: Updates, Challenges, and Future Perspectives.
  2. The evolution of CAR therapies across oncology and autoimmunity: mechanistic insights and therapeutic innovations.
  3. Adapting CAR-T and CAR-Treg cancer therapies for autoimmunity: innovations and challenges.
  4. Chimeric antigen receptor-based cellular therapy in autoimmune diseases: A systematic review and meta-analysis of clinical, serological and safety outcomes.
  5. Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.
  6. Preclinical and clinical studies on CAR-NK cell therapy: latest update from 2025 ASH Annual Meeting.
  7. The in vivo revolution in CAR-T therapy medicinal products: challenges and regulatory prospects.
  8. Chimeric Antigen Receptor T-Cell Revolution Remodeling Immunity to Conquer Autoimmune Disease.
  9. Harnessing the potential of γδ T cells through engineering and combination treatment for cancer therapies.
  10. Chimeric antigen receptor T-cell (CAR-T) therapy and other cellular immunotherapy treatments for idiopathic inflammatory myopathies.
  11. The neurotoxic legacy of CAR-T cells: where do we stand?
  12. CAR-engineered neutrophils derived from induced pluripotent stem cells: a new frontier in cellular immunotherapy.
  13. T-cell engagers mediate deep cell depletion beyond autoimmunity.
  14. Next-generation CAR-T therapies: From personalized anti-cancer drugs to broadly applicable disease-modifying treatments.
  15. A new hope with CAR T-cell therapy for refractory idiopathic inflammatory myopathies: a systematic review.
  16. Bioengineering CAR-T cells to function in hostile tumor microenvironments.
  17. In vivo CAR-T therapy: latest updates from the 2025 ASH annual meeting.
  18. Imaging Immunotherapy.
  19. Frailty, Sarcopenia, and Functional Decline After CAR-T Therapy: The Case for Structured Rehabilitation.
  20. Resetting autoimmune disease with CAR cell therapies.
  21. Official Digital Health Technology Assessment Guidelines: An International Comparative Review and Analysis.
  22. [Chinese expert consensus on chimeric antigen receptor T-cell therapy for multiple myeloma (2026)].
  23. Induced pluripotent stem cells as platforms for engineering NK cell immunotherapies.
  24. A Novel Strategy to Produce CAR-γδ T Cells via Site-Directed Gene Integration by a Combination of CRISPR/Cas9 and AAV.
  25. Early results support base-edited anti-CD7 CAR T-cell therapy in T-cell ALL.
  26. Consensus Recommendations for CAR T-Cell Administration in Adult Acute Lymphoblastic Leukemia: a Modified Delphi Study.
  27. Rethinking The Role Of Health Technology Assessment: From Gatekeeper To Health System Shaper.
  28. Response to Methodological Concerns Regarding Eligibility Criteria and Study Selection in a Systematic Review and Meta-Analysis of CAR T-Cell Therapy for Hematologic Malignancies.
  29. Integrating Equity in Topic Selection for Orphan Medicinal Products: Policy Implications for Health Technology Assessment in Rare Diseases.
  30. Cellular Therapies in Solid Tumors: Are We Ready for Primetime?
  31. Regulatory approval of new oncology drugs, 2020-2024: A comparative analysis of FDA, EMA, and ANVISA.
  32. Immune tolerance versus cancer surveillance: an ongoing challenge.
  33. Current Status of Treg Therapy in Transplantation and Autoimmune Disease.
  34. CAR T-cell therapy-associated central hypothyroidism: a case of a novel onco-endocrine toxicity.
  35. Challenges and advances in CAR-T cell therapy for B-ALL.
  36. A Geographic Disparities Analysis Between Standard of Care and Clinical Trial CAR-T Patients in Kansas.
  37. Orchestration and Small World Governance in the European Health Data Space.
  38. Extracting adverse event nature, severity, timelines and resulting interventions from clinical notes of patients receiving CAR-T therapy using large language models.
  39. Interoperability Barriers in the European Health Data Space: A Scoping Review.
  40. Digital Twins in Healthcare: Enabling Predictive, Personalized, and Precision-Driven Transformation.
  41. Advancing precision oncology through innovative and adaptive master protocol designs: statistical, operational, and regulatory perspectives.
  42. Pharmaceutical Industry 5.0: The Role of Drug Discovery Technology, Innovation, and Digital Transformation in Economic Resilience.
  43. Cancer and Immune Cells: A Metabolic Battle in the Tumor Microenvironment.
  44. Adenoviral Vectors in Gene Therapy: A Detailed Overview.
  45. T Cell Dysfunction in the Acidic Tumor Microenvironment.
  46. T-cell mechanobiology: How molecular forces shape immune function.
  47. High incidence of cytomegalovirus infection in patients receiving standard of care CD19- or BCMA-targeted CAR T-cell therapies for hematologic malignancies.
  48. BaEV-pseudotyped lentiviral vectors enable stable CAR expression and cytotoxic function in NK cells.
  49. Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering.
  50. From Classical PKPD to Model-Informed Drug Development: Are "Digital Twins" a New Paradigm?
  51. Cell death pathways and targeting therapeutics in cancer therapy.
  1. Curr Oncol Rep. 2026 May 19. pii: 55. [Epub ahead of print]28(1):
    Targeting GD2 with CAR-T Cell Therapy in Neuroblastoma: Updates, Challenges, and Future Perspectives.
    Hortense Alliot, Pierre Machy, Marc-David Leclair, Stéphane Birkle, Sébastien Faraj.
       PURPOSE OF REVIEW: High-risk neuroblastoma remains a challenging pediatric cancer, with survival rates lagging despite advances in multimodal therapy. This review aims to critically synthesize recent advances in GD2-directed chimeric antigen receptor (CAR) T cell therapy for neuroblastoma and to highlight its potential to improve long-term outcomes.
    RECENT FINDINGS: In early-phase trials of GD2-directed CAR-T cell therapy for relapsed or refractory neuroblastoma, no dose-limiting toxicities were observed. Objective responses ranged from 6% to 33%, with durable complete remissions reported beyond 10 years. Stable disease occurred in up to 55% of patients. Cytokine release syndrome was reported in 0-90% of cases, generally mild, and neurotoxicity was rare. CAR-T cell expansion and trafficking to tumor sites have been demonstrated in several studies, although they remain variable and often limited in solid tumor settings. GD2-directed CAR-T cell therapy demonstrates limited but measurable clinical activity, particularly in minimal residual disease settings, with an overall acceptable safety profile. Continued innovation in CAR design and integration into multimodal strategies may improve long-term outcomes for this aggressive pediatric cancer.
    Keywords:  CAR-T cells; GD2; Immunotherapy; Neuroblastoma
    DOI:  https://doi.org/10.1007/s11912-026-01796-1
  2. Int Immunopharmacol. 2026 Aug 01. pii: S1567-5769(26)00713-7. [Epub ahead of print]182 116867
    The evolution of CAR therapies across oncology and autoimmunity: mechanistic insights and therapeutic innovations.
    Eslam E Abd El-Fattah, Rania Hamdy, Sameh S M Soliman, Mohamed I Husseiny.
      Chimeric antigen receptor (CAR)-engineered cellular therapies have progressed from early proof of concept into highly programmable platforms capable of mediating potent cytotoxicity and precise immune modulation. In oncology, successive CAR design has incorporated optimized costimulatory domains, cytokine-secreting modules, and gene-editing technologies to enhance efficacy and durability in hematologic malignancies. CD19- and BCMA-directed CAR-T cells induce deep and durable remissions in refractory B-cell leukemias, lymphomas, and multiple myeloma. Emerging strategies, including logic-gated CARs, synthetic Notch (SynNotch) circuits, and modular adaptor-based systems, aim to overcome antigen escape, reduce off-tumor toxicity, and extend efficacy to heterogeneous solid tumors. Concurrently, a conceptual shift has expanded CAR applications beyond cancer toward immune modulation in autoimmune diseases. CD19-directed CAR-T therapy has achieved deep B-cell depletion and clinical improvement in small early-phase studies (typically 5-18 patients) of systemic lupus erythematosus, inducing drug-free remission in some patients; however, randomized controlled trials are lacking and evidence remains preliminary. Antigen-specific approaches, including chimeric autoantibody receptor (CAAR)-T cells and CAR-engineered regulatory T-cells (CAR-Tregs), enable selective depletion of autoreactive B-cell clones or localized restoration of immune tolerance. These strategies are under investigation across systemic sclerosis, multiple sclerosis, myasthenia gravis, type 1 diabetes, inflammatory bowel disease, and rheumatoid arthritis. Collectively, advances in synthetic receptor engineering and translational application position CAR platforms as versatile, next-generation therapeutics across malignant and immune-mediated diseases.
    Keywords:  Autoimmune diseases; CAAR-T cells; CAR-T cells; CAR-Tregs; CD19; Immune tolerance; Malignancies
    DOI:  https://doi.org/10.1016/j.intimp.2026.116867
  3. Front Immunol. 2026 ;17 1737202
    Adapting CAR-T and CAR-Treg cancer therapies for autoimmunity: innovations and challenges.
    Michael D Lovelace, Kelly Barrett, Sarah Thomas Broome, Saparna Pai.
      The application of Chimeric Antigen Receptor T-cell (CAR-T), CAR-engineered regulatory T cell (CAR-Treg) and hematopoietic stem cell (HSC) therapies has grown in recent years, driven by an increasing demand for robust, antigen-specific T lymphocytes for the treatment of both cancer and autoimmune diseases. This review begins by examining existing cell-based therapies, its biological principles and mechanisms, that have helped achieve notable success in treating cancer. The review then discusses the applicability of these approaches to autoimmune diseases such as progressive and relapsing Multiple Sclerosis (MS) and Type 1 Diabetes Mellitus (T1D). We discuss the substantial promise of CAR-T and CAR-Treg therapies and highlight the role of HSCs, while detailing their mechanism of action, manufacturing processes and ongoing clinical trials. We also examine key challenges such as on and off-target effects, dependence on autologous cell sources, high production costs, and lengthy manufacturing timelines. Our review underscores the need for continued research to facilitate broader clinical implementation of these therapies across diverse healthcare settings.
    Keywords:  CAR-T therapy; T cells; autoimmune disease; cell therapy; diabetes mellitus; immune response; multiple sclerosis
    DOI:  https://doi.org/10.3389/fimmu.2026.1737202
  4. Autoimmun Rev. 2026 May 20. pii: S1568-9972(26)00104-7. [Epub ahead of print] 104090
    Chimeric antigen receptor-based cellular therapy in autoimmune diseases: A systematic review and meta-analysis of clinical, serological and safety outcomes.
    Hon Jen Wong, Ainsley Ryan Yan Bin Lee, Qai Ven Yap, Esther Chan, Georg Schett, Sen Hee Tay.
       OBJECTIVE: Chimeric antigen receptor (CAR)-T cell and natural killer cell therapies are emerging as treatments for autoimmune diseases (AIDs), capable of inducing immune reprogramming and drug-free remission. Their efficacy, safety, and durability across AIDs remain incompletely defined.
    METHODS: We performed a systematic review and meta-analysis of proportions to evaluate the efficacy and safety of CAR-based therapies in AIDs. PubMed, Embase, and CENTRAL were searched from January 1, 2010, to October 20, 2025. Primary outcome was medication-free remission (MFR); secondary outcomes included disease-specific remission indices, incidence of adverse events and their severity. Subgroup and meta-regression analyses were conducted.
    RESULTS: Of 3367 records screened, 56 studies met the inclusion criteria (15 eligible for meta-analysis; 41 synthesized qualitatively). For CAR-T cell therapies, among SLE patients, pooled MFR was 0·76 and DORIS remission 0·75. Subgroup analyses revealed a longer disease duration was associated with lower remission rates. Efficacy in other AIDs, including systemic sclerosis, myositis and myasthenia gravis showed consistent clinical improvement, though data was limited. Across all AIDs, CRS of any grade occurred in 0·63, but grade ≥ 3 CRS and any grade of ICANS were negligible (both 0·00). Hypogammaglobulinaemia of any grade occurred in 0·47, while grade ≥ 3 events were rare. Cytopenias were common: neutropenia and anemia of any grade were most frequent; severe cytopenias occurred in ≤0·3. Infection within 3 months occurred in 0·29.
    CONCLUSION: CAR-T cell therapies targeting CD19 or BCMA appear highly effective in inducing remission in refractory autoimmune diseases, with predominantly mild CRS and negligible neurotoxicity.
    Keywords:  Autoimmune disease; CAR-T; Cellular therapy; Chimeric antigen receptor; Rheumatology
    DOI:  https://doi.org/10.1016/j.autrev.2026.104090
  5. Acta Pharmacol Sin. 2026 May 18.
    Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.
    Ji-Zhao Cao, Wei Zhao, Xiao-Jun Xia.
      Cell-based immunotherapies have emerged as a transformative modality in modern cancer treatment, complementing conventional approaches such as surgery, chemotherapy, radiotherapy, and molecularly targeted therapies. This review provides an integrated and up-to-date synthesis of the rapidly evolving landscape of cellular immunotherapy, encompassing chimeric antigen receptor (CAR) T cells, T cell receptor (TCR)-engineered T cells, tumor-infiltrating lymphocytes (TILs), dendritic cell (DC) vaccines, natural killer (NK) cell-based therapies, and macrophage-directed strategies. We delineate the mechanistic foundations underlying each modality, summarize clinical outcomes across both hematologic malignancies and solid tumors, and critically evaluate therapeutic performance in the context of treatment-associated toxicities, resistance mechanisms, and barriers to durable response. Furthermore, we highlight emerging next-generation strategies designed to mitigate antigen escape, overcome immunosuppressive tumor microenvironments, and address challenges related to manufacturing, scalability, and accessibility. Collectively, these advances establish cell-based immunotherapies as a central component of precision oncology, with expanding potential to deliver durable and broadly accessible clinical benefit across diverse cancer types.
    Keywords:  TCR-engineered T cells (TCR-T); chimeric antigen receptor (CAR) T-cell therapy; dendritic cell (DC) vaccines; macrophage-based immunotherapy; natural killer (NK) cell therapy; tumor-infiltrating lymphocyte (TIL) therapy
    DOI:  https://doi.org/10.1038/s41401-026-01811-y
  6. Exp Hematol Oncol. 2026 May 18. pii: 46. [Epub ahead of print]15(1):
    Preclinical and clinical studies on CAR-NK cell therapy: latest update from 2025 ASH Annual Meeting.
    Hanxi Luo, Yiyang Ding, Xiangyu Zhao.
      Chimeric antigen receptor-engineered natural killer (CAR-NK) cells are emerging as an off-the-shelf immunotherapy for hematologic malignancies, supported by early clinical data and a favorable safety profile. Compared with CAR-T therapy, CAR-NK cells offer the potential for scalable allogeneic manufacturing with reduced toxicity while retaining antitumor activity. However, challenges such as limited in vivo persistence, immunosuppressive tumor microenvironments, and variable durability of responses remain. This summary highlights recent preclinical and clinical advances in CAR-NK cell therapy reported at the 2025 ASH Annual Meeting, focusing on engineering strategies to enhance NK-cell fitness and early trial results demonstrating efficacy with manageable toxicity.
    Keywords:  CAR-NK; Hematologic malignancies; Off-the-shelf immunotherapy
    DOI:  https://doi.org/10.1186/s40164-026-00780-6
  7. Signal Transduct Target Ther. 2026 May 22. pii: 192. [Epub ahead of print]11(1):
    The in vivo revolution in CAR-T therapy medicinal products: challenges and regulatory prospects.
    Jiaqi Lu, Jing Cui, Jing Dong, Liping Yan, Xue Wang, Di Zhou, Shuang Lu, Wei Wei.
      Chimeric antigen receptor T-cell (CAR-T) therapy, a groundbreaking advancement in cancer immunotherapy, has demonstrated remarkable efficacy in treating hematological malignancies and autoimmune diseases. However, conventional ex vivo CAR-T therapy medicinal products face multiple limitations, including complex manufacturing processes, high production costs, and challenges in quality control and risk management. In recent years, the emergence of in vivo CAR-T therapy medicinal products using viral vector or lipid nanoparticle platforms has provided a promising new direction by simplifying manufacturing, enhancing scalability, lowering costs, and increasing accessibility, though it may introduce elevated risks such as off-target effects and immunogenicity. From a regulatory perspective, this article reviews the progress, technological strengths, and regulatory landscape of in vivo CAR-T therapy medicinal products. We analyze their potential benefits in manufacturability, scalability, and discuss challenges including quality control, safety risks, and mitigation strategies in drug development. We propose adaptive regulatory strategies together with early regulatory engagement and international coordination to accelerate the clinical translation and standardized use of this emerging modality.
    DOI:  https://doi.org/10.1038/s41392-026-02633-4
  8. Research (Wash D C). 2026 ;9 1239
    Chimeric Antigen Receptor T-Cell Revolution Remodeling Immunity to Conquer Autoimmune Disease.
    Wenxia Shao, Jiayu Liu, Ming Sun, Daojun Yu.
      Chimeric antigen receptor T (CAR-T) cell therapy, a groundbreaking technology in tumor immunotherapy, has demonstrated unprecedented potential in the field of autoimmune diseases in recent years. This article provides a systematic review of the developmental trajectory and core concepts of CAR-T-cell therapy in autoimmune diseases, emphasizing its conceptual evolution from traditional "killing" strategies to "precision immune remodeling". Leveraging multitarget approaches (e.g., CD19 and B-cell maturation antigen) and chimeric autoantigen receptor technology, it achieves efficient elimination of pathogenic B cells, plasma cells, and autoreactive T cells, along with profound remodeling of the immune microenvironment, thereby inducing long-term disease remission and restoring immune tolerance. Nevertheless, unresolved challenges still exist in monotherapy strategies, such as antigen escape, nontumor toxicity of emerging targets, limited in vivo persistence, high production costs, and immune reconstitution imbalance. Future research ought to concentrate on the development of multitarget/logic-gated chimeric antigen receptor constructs, the optimization of chimeric antigen receptor architecture and nonviral delivery systems, the validation of the long-term safety of universal CAR-T cells, the customization of personalized treatment regimens, and the exploration of mechanisms for modulating the immune microenvironment. This review emphasizes that CAR-T-cell therapy shows potential for initiating a new era of personalized, mechanism-driven treatment for autoimmune diseases, offering crucial insights for clinical translation.
    DOI:  https://doi.org/10.34133/research.1239
  9. Nat Commun. 2026 May 22.
    Harnessing the potential of γδ T cells through engineering and combination treatment for cancer therapies.
    Jonathan Fisher, Yin Wu, Daniel Abate-Daga, Marta Barisa, Lawrence Lamb.
      γδT cells comprise 1-10% of circulating T cells, are further enriched in barrier tissues such as the gut and skin, and also form a critical component of lymphoid stress surveillance. γδ T cells have been gaining prominence as an alternative to αβ T cells for cancer immunotherapy. Such popularity may be attributed to multiple factors including the MHC-independent nature of γδ T activation, which differentiates them from αβ T cells and underlies their lack of alloreactivity. In this Review, we describe efforts to optimize the potential of γδ T cells as a cancer immunotherapeutic. We discuss the impact of disease burden on efficacy and the contexts in which unmodified γδ T cells have succeeded or failed to yield durable responses. Finally, we explore options for enhancing γδ T cell efficacy including combinations with other treatments and engineering strategies to capitalize on their potency.
    DOI:  https://doi.org/10.1038/s41467-026-73451-z
  10. Best Pract Res Clin Rheumatol. 2026 May 18. pii: S1521-6942(26)00025-2. [Epub ahead of print] 102140
    Chimeric antigen receptor T-cell (CAR-T) therapy and other cellular immunotherapy treatments for idiopathic inflammatory myopathies.
    Jisna R Paul, Prateek C Gandiga, Rohit Aggarwal.
      Idiopathic inflammatory myopathies (IIM), including immune-mediated necrotizing myopathy (IMNM), dermatomyositis (DM), anti-synthetase syndrome (ASyS), overlap myositis and polymyositis, are heterogeneous autoimmune diseases characterized by immune-mediated skeletal muscle injury and frequent extra-muscular organ involvement. Despite recent therapeutic advances, many IIM patients have persistent disease activity, medication toxicity, or steroid dependence with current treatments. Increasing evidence implicates autoreactive B cells and autoantibody-producing plasma cells as central drivers of disease activity in several IIM subtypes, providing a strong rationale for B-cell- targeted therapies. While monoclonal antibody-based B-cell depletion strategies such as rituximab have demonstrated variable efficacy, their inability to effect persistent, intense depletion of tissue autoreactive B-cell populations often limit their success. Chimeric antigen receptor T-cell (CAR-T) and related cellular immunotherapies were originally developed against hematologic malignancies, but have recently emerged potentially transformative therapeutic options for autoimmune diseases. CAR-T cells targeting CD19 and other B-cell antigens have demonstrated the capacity to induce deep and durable B-cell depletion, and may even lead to "immune reset" with long-lived autoimmunity remission in diseases such as systemic lupus erythematosus and systemic sclerosis. Early clinical experiences now suggest that CAR-T therapy may offer similar promise in refractory IIM, particularly in phenotypes that include pathogenic autoantibodies, such as ASyS, DM, IMNM. This review provides a synopsis of current knowledge on the immunopathogenesis of IIM relevant to CAR-T and other cellular immunotherapy, outlines CAR-T technology and the mechanistic rationale for its use in IIM, and critically appraises emerging clinical CAR-T treatment data in IIM. We also discuss safety considerations, practical challenges, and future directions, with a focus on how CAR-based immunotherapies may reshape treatment paradigms for refractory inflammatory myopathies.
    Keywords:  CAR-T therapy; Idiopathic inflammatory myopathies
    DOI:  https://doi.org/10.1016/j.berh.2026.102140
  11. Ther Adv Neurol Disord. 2026 ;19 17562864261440261
    The neurotoxic legacy of CAR-T cells: where do we stand?
    Simona Pagliuca, Caroline Jacquet, Marie Thérèse Rubio, Pierpaolo Sorrentino.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed outcomes for relapsed/refractory B-cell malignancies and is increasingly reshaping the therapeutic landscape of autoimmune disorders and solid tumors, offering curative potential where options were previously limited. Its broader deployment is, however, constrained by immune-mediated toxicities, chiefly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS spans a heterogeneous spectrum from mild aphasia and tremor to seizures, cerebral edema, coma, and death, and remains difficult to predict prospectively. As CAR-T platforms expand beyond CD19 malignancies, neurotoxicity phenotypes are also broadening beyond classical ICANS. In plasma cell dyscrasias, BCMA-directed CAR-T has been associated with delayed non-ICANS neurotoxicities, including movement and neurocognitive/behavioral symptoms, cranial nerve palsies, and peripheral neuropathic presentations. In parallel, early experiences with CAR-T and related immune effector therapies in autoimmune and neuroimmunologic diseases suggest distinct inflammatory contexts and potentially different neurotoxicity patterns, underscoring the need for indication-specific monitoring and attribution frameworks. Converging data implicate a multilayered pathophysiology involving systemic cytokine surges, disruption of the blood-brain barrier, endothelial dysfunction, and context-dependent trafficking of activated CAR-T cells and other immune effectors into the CNS with baseline neurological vulnerability and the peri-infusion inflammatory milieu likely modulating individual risk. Given the frequency of these complications, an active research effort is underway to identify clinical, functional, and biological signals that could predict and improve their management. However, most biomarkers remain investigational, lacking prospective validation and straightforward clinical utility. This review synthesizes current evidence on the epidemiology, mechanisms, and monitoring of ICANS and emerging non-ICANS syndromes, and offers a fresh perspective on integrated, multimodal risk models to enable more precise stratification and timely intervention across indications.
    Keywords:  CAR-T cell neurotoxicity; EEG; ICANS; MNT; neurological biomarkers; virtual brain twin
    DOI:  https://doi.org/10.1177/17562864261440261
  12. Clin Transl Oncol. 2026 May 17.
    CAR-engineered neutrophils derived from induced pluripotent stem cells: a new frontier in cellular immunotherapy.
    Elena A Nemilostiva, Olga A Paevskaya, Shuxrat Boymuradov, Baqodir Safoyev, Mirmukhsin Satov.
      Adoptive cell therapy has been revolutionized by chimeric antigen receptor (CAR)-based immunotherapy, but its applications are still mainly limited to T and natural killer (NK) cells. The FDA-approved seven CAR-T products in less than ten years, demonstrating the high capacity of this approach. However, given the limitations of CAR-T cell therapy, such as low tumor infiltration and clinical efficacy in solid tumors, there has been significant interest in recent years to engineer other immune cell types, including neutrophils, with CARs because they provide special advantages for cancer therapy, such as rapid infiltration into tumor sites, strong cytotoxic functions, and the ability to modify the tumor microenvironment (TME). However, the main barriers to the practical translation of CAR-neutrophils are their short lifespan, restricted ex vivo proliferation, and inherent resistance to genetic alterations, which calls for the availability of an infinite source for the ongoing supply of CAR-neutrophil therapy. These obstacles may be overcome by developments in induced pluripotent stem cell (iPSC) technology, which offers a consistent, renewable, and genetically changeable source of CAR-neutrophils (CAR-Neuts). The goal of this study is to present a comprehensive analysis of the state, gaps, and potential future directions of this recently developed topic.
    Keywords:  CAR-neutrophils; Chimeric antigen receptor; Immunotherapy; Induced pluripotent stem cells; Tumor
    DOI:  https://doi.org/10.1007/s12094-026-04396-4
  13. Kidney Int. 2026 Jun;pii: S0085-2538(26)00244-9. [Epub ahead of print]109(6): 1081-1084
    T-cell engagers mediate deep cell depletion beyond autoimmunity.
    Johanna T Kurzhagen, William Laqua, Mario Schiffer, Ricardo Grieshaber-Bouyer.
      Deep B-cell and plasma cell depletion is rapidly reshaping the therapeutic landscape. Initially developed for hematologic malignancies, T cell-redirecting therapies (chimeric antigen receptor T cells and T-cell engagers) are now demonstrating profound efficacy in autoimmune diseases. The first successful application of a B-cell maturation antigen-targeting T-cell engager to achieve human leukocyte antigen desensitization in a highly sensitized kidney transplant candidate marks yet another critical milestone: This success signals a "spillover" of deep cell depletion into nonmalignant, nonautoimmune indications and paves the way for novel strategies in transplantation tolerance, severe allergic diseases, and beyond.
    DOI:  https://doi.org/10.1016/j.kint.2026.03.010
  14. Transplant Cell Ther. 2026 May 18. pii: S2666-6367(26)00362-3. [Epub ahead of print]
    Next-generation CAR-T therapies: From personalized anti-cancer drugs to broadly applicable disease-modifying treatments.
    Mengru Wen, Jiayi Li, Shichu Xu, Wenying Li, Shuai Wang, Zhigang Guo, Jiannan Chen, Lingfeng He.
      Chimeric Antigen Receptor T (CAR-T) cell therapy is evolving beyond traditional autologous products. Two transformative directions are emerging: Allogeneic CAR-T and In vivo CAR-T. Allogeneic CAR-T addresses immune incompatibility through both gene editing (e.g., TCR/HLA knockout) and non-gene editing strategies (e.g., shRNA, protein expression blockers), overcoming graft-versus-host disease (GVHD) and host-versus-graft reaction (HvGR) to enable off-the-shelf production. In vivo CAR-T, leveraging engineered viral vectors and targeted lipid nanoparticles (tLNP), achieves in situ reprogramming of endogenous T cells, bypassing the need for ex vivo cell processing. These advancements are expanding CAR-T applications from hematological malignancies to autoimmune diseases (e.g., systemic lupus erythematosus, multiple sclerosis) and other conditions (e.g., fibrosis, HIV/AIDS). Despite challenges such as insufficient persistence of allogeneic CAR-T, imprecise delivery of In vivo CAR-T, safety concerns, ongoing advancements in targeted vectors, novel antigens, and combination therapies hold promise for enhancing efficacy and accessibility. This review summarizes the core strategies, clinical progress, cross-disease applications, and future directions, charting CAR-T's transition from a niche precision medicine toward a broadly applicable immunotherapy.
    Keywords:  Allogeneic CAR-T; Cross-Disease Applications; Gene Editing; In vivo CAR-T; Targeted Delivery
    DOI:  https://doi.org/10.1016/j.jtct.2026.05.019
  15. J Transl Med. 2026 May 18.
    A new hope with CAR T-cell therapy for refractory idiopathic inflammatory myopathies: a systematic review.
    Xueyan Shan, Fengtao Pang, Guochun Wang, Yongpeng Ge, Xin Lu.
       BACKGROUND: Treatment options for refractory idiopathic inflammatory myopathies (IIMs) remain limited, and sustained remission is frequently not achieved with conventional immunosuppression or biologic agents. Chimeric antigen receptor (CAR) T-cell therapy has been approved for multiple refractory hematologic malignancies and is increasingly being explored as an immune reset strategy for autoimmune diseases.
    MAIN BODY: This Review synthesizes all available clinical evidence on CAR T-cell therapy in adult and pediatric IIM, with the aim of raising awareness within the rheumatology community regarding its clinical application and providing an evidence-based framework to guide future therapeutic decision-making. Across 10 reports comprising 12 refractory IIM patients, CAR T-cell therapy was associated with rapid improvements in muscle enzymes and strength, meaningful treatment de-escalation with frequent drug-free remission. Safety was generally manageable, with predominantly grade 1-2 cytokine release syndrome, rare immune effector cell-associated neurotoxicity syndrome, and treatable infections. Pharmacokinetic and immunodynamic patterns were consistent, with early in-vivo expansion, rapid B-cell depletion, and reconstitution dominated by naïve and transitional phenotypes.
    CONCLUSIONS: Early clinical experience supports CAR T-cell therapy as a promising experimental approach for refractory IIM, but current evidence is limited by small sample sizes, heterogeneous endpoints, and short follow-up. Prospective studies with standardized outcomes, organ-specific assessments, and long-term safety monitoring are required.
    Keywords:  Antisynthetase syndrome; B-cell depletion; CAR T-cell therapy; Idiopathic inflammatory myopathy; Myositis
    DOI:  https://doi.org/10.1186/s12967-026-08262-3
  16. Trends Biotechnol. 2026 May 19. pii: S0167-7799(26)00177-0. [Epub ahead of print]
    Bioengineering CAR-T cells to function in hostile tumor microenvironments.
    Sara Mahajna, Raghad Barhoum, Asala Sabbah, Ilinca-Maria Igescu, Mohamed Mahameed.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies but remains largely ineffective in solid tumors. Accumulating evidence indicates that this limitation reflects not only suboptimal antigen recognition but also the inability of therapeutic cells to reach and function within the suppressive tumor microenvironment. This review synthesizes recent advances in CAR-T cell bioengineering aimed at overcoming physical barriers, immunosuppressive signaling, metabolic stress, and cellular exhaustion that characterize solid tumors, which are a leading cause of cancer-related mortality worldwide. We highlight in vivo-validated strategies that enhance tumor trafficking, intratumoral retention, stress resilience, and resistance to immunosuppression, while delineating key translational challenges and safety considerations required for clinical translation.
    Keywords:  CAR-T bioengineering; solid tumors; synthetic biology; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.tibtech.2026.04.023
  17. Biomark Res. 2026 May 22. pii: 51. [Epub ahead of print]14(1):
    In vivo CAR-T therapy: latest updates from the 2025 ASH annual meeting.
    Shule Wang, Ran Kong, Guangcai Zhong, Xinyu Yang, Xiangxiang Zhou.
      Chimeric antigen receptor (CAR)-T cell therapy has significantly improved outcomes in hematologic malignancies but remains constrained by complex ex vivo manufacturing and lymphodepleting chemotherapy. In vivo CAR-T therapy enables direct genetic programming of endogenous T cells through systemic delivery of CAR-encoding vectors, thereby bypassing ex vivo manipulation and simplifying treatment workflows. This strategy has the potential to reduce production timelines, lower costs, and broaden patient accessibility. In addition, in vivo CAR-T approaches may preserve more physiological T-cell states and offer improved scalability. Importantly, however, current in vivo CAR-T platforms differ substantially in delivery modality, persistence, reversibility, safety profile, and translational feasibility. Here, we summarize the latest advances in major preclinical approaches and early clinical studies presented at the 2025 ASH annual meeting, with emphasis on the comparative strengths, limitations, and translational trade-offs of viral vector-based, RNA/lipid nanoparticle-based, non-viral DNA, and gene-writing strategies.
    Keywords:  Anti-tumor therapy; Cellular therapy; In vivo CAR-T
    DOI:  https://doi.org/10.1186/s40364-026-00938-8
  18. Recent Results Cancer Res. 2026 ;225 911-943
    Imaging Immunotherapy.
    Egesta Lopci, Angelo Castello, Matteo Caracciolo, Luigi Mansi, Akram Al-Ibraheem.
      Cancer immunotherapy aims to enhance or reactivate immune system function by leveraging both adaptive and innate immunity mechanisms. Key approaches to stimulate tumor-specific immune responses include cytokine therapies, cancer vaccines, and immune checkpoint blockade. The field experienced transformative growth after the 2011 approval of ipilimumab (targeting CTLA-4), paving the way for subsequent inhibitors of PD-1 and PD-L1 pathways that demonstrated unprecedented survival benefits across multiple malignancies. These breakthroughs have catalyzed advancements in adoptive T cell therapies, particularly genetically modified CAR T cell infusions showing promising clinical efficacy, signaling a paradigm shift in oncology treatment approaches. Meanwhile, response assessment has faced new challenges. In fact, immunotherapy response patterns often contrast with conventional chemotherapy, particularly regarding phenomena like pseudoprogression, delayed clinical effects, and extended disease stabilization. To address these unique dynamics, revised response assessment guidelines have been established to enhance therapeutic development and clinical decision-making. This chapter examines the progression of immune-specific evaluation standards, their application in clinical trials, and their practical consequences, concluding with insights into future advancements in response classification systems.
    Keywords:  Immune-PET; Immunotherapy; Lymphoma; Metabolic response criteria; Response assessment; Solid tumors
    DOI:  https://doi.org/10.1007/978-3-032-21415-7_12
  19. Cardiol Rev. 2026 May 14.
    Frailty, Sarcopenia, and Functional Decline After CAR-T Therapy: The Case for Structured Rehabilitation.
    Jatin Thukral, Pyush Moudgil, Ninaad Sindhwani, Fnu Kudrat, Jairul Rohewal, Jashandeep Kaur, Riya Kaushal Shah, Harbir Kaur, Nikhil Thukral, William H Frishman, Wilbert S Aronow.
      Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment landscape of relapsed or refractory hematologic malignancies, offering unprecedented response rates and durable remissions in diseases such as B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. By genetically engineering autologous T cells to recognize tumor-associated antigens, CAR-T therapy enables targeted immune-mediated cytotoxicity against malignant cells. Although early clinical experience has largely focused on acute toxicities including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome improving survival has shifted attention toward the long-term health status of survivors. As the population of CAR-T recipients grows, a broader survivorship framework that incorporates functional outcomes and quality of life has become increasingly important. Emerging evidence suggests that frailty, sarcopenia, and progressive functional decline represent underrecognized complications in patients recovering from CAR-T therapy. These impairments may result from multiple converging factors including systemic inflammation, prior intensive chemotherapy, prolonged hospitalization, corticosteroid exposure, and physical inactivity during treatment. Such changes may have important cardiovascular implications, including reduced cardiorespiratory fitness, impaired exercise tolerance, and increased vulnerability to cardiovascular morbidity. Despite these risks, structured rehabilitation programs remain poorly integrated into CAR-T survivorship care.
    Keywords:  cancer survivorship; cardio-oncology; cardiovascular complications; chimeric antigen receptor T-cell (CAR-T) therapy; frailty; functional decline; rehabilitation; sarcopenia
    DOI:  https://doi.org/10.1097/CRD.0000000000001277
  20. Nat Med. 2026 May 21.
    Resetting autoimmune disease with CAR cell therapies.
    Georg Schett, Huji Xu.
      Pathogenic B cell activation underlies many autoimmune diseases (AIDs), and their depletion is an attractive therapeutic approach. Chimeric antigen receptor (CAR)-expressing cells-initially developed and successfully used to treat certain cancers-are increasingly being developed to selectively deplete B cells and 'reset' the immune system in AIDs. In this Review, we survey this fast-developing field, providing insights on the current unmet needs in the treatment of AIDs and how CAR T cells could address these needs. In particular, we explore the concept of deep B cell depletion, discuss the currently available technologies and review the key targets (CD19 and B cell maturation antigen) relevant for the treatment of AIDs. We summarize current evidence on the efficacy, safety, risks and limitations of autologous and allogeneic CAR T cells in this setting. Finally, we discuss the future outlook-from a technological and clinical standpoint-for development of engineered CAR-expressing cell therapies for AIDs.
    DOI:  https://doi.org/10.1038/s41591-026-04430-6
  21. Value Health. 2026 May 15. pii: S1098-3015(26)02419-8. [Epub ahead of print]
    Official Digital Health Technology Assessment Guidelines: An International Comparative Review and Analysis.
    Yuyan Fu, Yin Liu, Yashuang Luo, Ru Wang, Qian Xing, Haiyin Wang.
       OBJECTIVE: To systematically identify and comparatively analyze official digital health technology assessment (DHTA) guidelines worldwide, examining their methodological quality, domain coverage, and cross-national patterns to inform international standardization.
    METHODS: A systematic review was conducted in accordance with PRISMA 2020. Official DHTA guidelines issued by national authorities between 2019 and 2025 were identified through structured searches of PubMed and grey literature. Methodological quality was appraised using the AGREE II instrument, and domain coverage was analyzed based on the EUnetHTA Core Model to enable cross-country comparison.
    RESULTS: Twelve official DHTA guidelines from 10 countries across four continents were included. Overall methodological quality was moderate (mean AGREE II score: 65%), with substantial cross-national variation (range: 53%-73%), particularly in Rigor of Development and Stakeholder Involvement. Guidelines covered an average of 61% of the 11 EUnetHTA domains. Clinical effectiveness (91.7%), patient and social aspects (91.7%), technical description (83.3%), and safety (83.3%) were widely incorporated, whereas legal (25%), organizational (41.7%), and ethical (41.7%) domains were less frequently addressed.
    CONCLUSION: Official DHTA guidelines are becoming increasingly institutionalized worldwide, but important heterogeneity remains, particularly in governance-related dimensions. Greater methodological rigor and stronger international alignment may support more consistent and policy-relevant DHTA frameworks.
    Keywords:  Digital Health Technologies; Guidelines/Documents; Health Policy and Standards; Health Technology Assessment; Quality and Methodology
    DOI:  https://doi.org/10.1016/j.jval.2026.04.010
  22. Zhonghua Xue Ye Xue Za Zhi. 2026 Apr 14. 47(4): 319-326
    [Chinese expert consensus on chimeric antigen receptor T-cell therapy for multiple myeloma (2026)].
    Chinese Medical Doctor Association, Hematology Branch
      Chimeric antigen receptor T-cell (CAR-T) immunotherapy has demonstrated favorable efficacy and reliable safety in relapsed/refractory multiple myeloma (MM). Since the publication of the first consensus, both the scope and depth of CAR-T clinical research and application in MM have significantly expanded. Notably, three novel B-cell maturation antigen (BCMA) -targeted CAR-T products have been approved by the National Medical Products Administration (NMPA) for clinical use. The development and application of CAR-T targeting novel targets such as GPRC5D have garnered significant attention. Breakthroughs have been achieved in salvage therapies for post-CAR-T relapse, while enhanced understanding has been gained regarding comprehensive management of the CAR-T treatment for MM. In light of these advancements, it is imperative to update the consensus guidelines on CAR-T therapy for MM to address evolving clinical requirements in this rapidly progressing field.
    DOI:  https://doi.org/10.3760/cma.j.cn121090-20260114-00023
  23. Front Cell Dev Biol. 2026 ;14 1810206
    Induced pluripotent stem cells as platforms for engineering NK cell immunotherapies.
    Anna Jezierski, Jez Huang, Lea Desbiens, Basma Benabdallah, Scott McComb, Christian Beausejour.
      Human induced pluripotent stem cells (iPSCs) are transforming adoptive cell therapy by combining unlimited self-renewal, broad differentiation potential, and high amenability to genome engineering. These attributes make iPSCs a versatile source for the development of standardized immune effector cells at industrial scale, enabling a shift from patient- or donor-restricted cell products toward true off-the-shelf immunotherapies that can be improved through iterative genome engineering. iPSC-derived natural killer (iNK) cells are the most clinically advanced and exemplify the platform's advantages over conventional autologous or donor-sourced approaches. Unlike autologous therapies, which require labor-intensive and expensive personalized clinical-grade manufacturing, and are constrained by variable quality and genetic intractability of donor products, iPSC technology supports the creation of renewable, clonally defined master cell banks as uniform starting material for NK-cell therapy products. Advances in CRISPR/Cas-based editing now permit multiplex introduction of functional traits, enhanced cytokine signaling, antibody-dependent cytotoxicity, checkpoint resistance, optimized trafficking, safety switches, and increasing signal complexity, directly at the pluripotent or progenitor stages; ultimately allowing for fully-programmable iNK cells with customizable potency and persistence. Early clinical studies of iNK products validate the feasibility, safety, and therapeutic potential of this approach, but also underscore the need for continued refinement of differentiation protocols, manufacturing pipelines, and regulatory standards to ensure efficacy, genomic stability, phenotypic maturity, and long-term safety. This review outlines current breakthroughs and future directions of iNK cell therapies, emphasizing how programmable iPSC chassis platforms are enabling modular and off-the-shelf targeted immunotherapies.
    Keywords:  chimeric antigen receptor (CAR); genome engineering; immunotherapy; induced pluripotent stem (iPS) cells; natural killer cells
    DOI:  https://doi.org/10.3389/fcell.2026.1810206
  24. Cancer Med. 2026 May;15(5): e71918
    A Novel Strategy to Produce CAR-γδ T Cells via Site-Directed Gene Integration by a Combination of CRISPR/Cas9 and AAV.
    Ruoyu Dong, Yixi Zhang, Guangxun Yuan, Xiaoyan Yue, Yingying Ding, Xun Zeng, Haowen Xiao.
      Chimeric antigen receptor (CAR)-αβ T cells are commonly employed in tumor therapy but hindered by some limitations. γδ T cells are promising substrates for CAR therapy for their major histocompatibility complex (MHC)-unrestricted recognition manner and innate immune function. Here, we established a novel method for generating CAR-γδ T cells. We utilized the clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) method to interrupt the TCR delta chain constant region (TRDC) sequence, followed by the site-directed insertion of the CAR sequence into the TRDC locus via homologous complementation mediated by adeno-associated virus (AAV) gene delivery. We optimized electroporation parameters for Cas9/ribonucleoproteins (RNP) delivery and infection conditions for CAR-gene carrying AAV in γδ T cells. These optimizations facilitated efficient TCR knockout and site-directed CAR insertion, ultimately yielding functional CAR-γδ T cells. In vitro experiments demonstrated that these newly prepared CAR-γδ T cells could stimulate cytokine production, kill tumor cells as well as exhibit robust proliferative potential and memory-like phenotype. These state-of-the-art CAR-γδ T cells could reduce tumor burden and extend the survival period of tumor-bearing mice.
    Keywords:  AAV; CAR‐γδ T cells; CRISPR/Cas9; TCR site‐specific knockout; electroporation; hematologic malignancies; knockin
    DOI:  https://doi.org/10.1002/cam4.71918
  25. Cancer. 2026 May 15. 132(10): e70388
    Early results support base-edited anti-CD7 CAR T-cell therapy in T-cell ALL.
    Leah Lawrence.
      
    DOI:  https://doi.org/10.1002/cncr.70388
  26. Blood. 2026 May 19. pii: blood.2026033559. [Epub ahead of print]
    Consensus Recommendations for CAR T-Cell Administration in Adult Acute Lymphoblastic Leukemia: a Modified Delphi Study.
    Lori Muffly, Noelle V Frey, Gregory W Roloff, Jae H Park, Bhagirathbhai Dholaria, Anjali S Advani, Veronika Bachanova, Ryan D Cassaday, Michael Daunov, Kaitlyn C Dykes, Vivian Irizarry Gatell, Michael R Grunwald, Talal Hilal, LaQuisa C Hill, Omer Jamy, Vamsi K Kota, Muthu Kumaran, Chenyu Lin, Aaron C Logan, Marlise R Luskin, Kristen M O'Dwyer, Caspian Oliai, Olalekan O Oluwole, Joshua P Sasine, Marc S Schwartz, Melhem M Solh, Wendy Stock, Stephanie B Tsai, Matthew L Ulrickson, Sumithira Vasu, Eunice S Wang, Fevzi Firat Yalniz, Stephen A Strickland, Jessica T Leonard, Bijal D Shah, Ibrahim Aldoss.
      The use of chimeric antigen receptor (CAR) T cell therapy is increasing in adult B-cell acute lymphoblastic leukemia (B-ALL), with three commercially available CD19 CAR T cell products. Several key clinical questions related to best practices for CAR T cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T cell therapy for adults with B-ALL. Consensus panelists (n= 9) included Principal Investigators (PIs) from Real World Outcomes Collaborative of CAR T Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n=27). Consensus topics included patient selection, bridging and pre-CAR T leukemia staging, lymphodepletion and CAR T treatment setting, specific toxicity prevention and management, post-CAR T response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies following CAR T cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After two panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but one recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T cell therapy in adult B-ALL.
    DOI:  https://doi.org/10.1182/blood.2026033559
  27. Int J Technol Assess Health Care. 2026 May 18. 1-14
    Rethinking The Role Of Health Technology Assessment: From Gatekeeper To Health System Shaper.
    Wija Oortwijn, Saudamini Vishwanath Dabak, Máirín Ryan, Christoph Glaetzer, Andres Pichon-Riviere.
      
    DOI:  https://doi.org/10.1017/S0266462326103833
  28. Am J Hematol. 2026 May 19.
    Response to Methodological Concerns Regarding Eligibility Criteria and Study Selection in a Systematic Review and Meta-Analysis of CAR T-Cell Therapy for Hematologic Malignancies.
    Charalampos Filippatos, Ioannis Ntanasis-Stathopoulos, Evangelos Terpos.
      
    DOI:  https://doi.org/10.1002/ajh.70356
  29. Appl Health Econ Health Policy. 2026 May 17.
    Integrating Equity in Topic Selection for Orphan Medicinal Products: Policy Implications for Health Technology Assessment in Rare Diseases.
    Fatemeh Hosseini, Mohammadreza Mobinizadeh, William V Padula.
      Health technology assessment (HTA) informs evidence-based decision-making for resource allocation in healthcare; however, the topic selection phase that determines which technologies proceed to full assessment is underexplored and often lacks fairness and transparency, particularly disadvantaging orphan medicinal products (OMPs) for rare diseases. We drew on selectively identified literature and illustrative HTA experiences to advance an opinion-driven argument about equity in topic selection for OMPs, grouping insights into three domains: structural challenges, conceptual frameworks and policy strategies. Structural barriers in topic selection include a lack of institutionalised, participatory processes, overreliance on prioritisation criteria implicitly aligned with population-wide impact and minimal engagement with stakeholders representing the rare disease community, resulting in the systematic under-prioritisation of OMPs. Procedural and value frameworks, including multi-criteria decision analysis (MCDA), evidence-informed deliberative processes (EDPs), accountability for reasonableness (A4R), equity weighting and Health Equity Impact Assessment (HEIA), can help agencies incorporate social value and fairness before formal appraisal, but remain unevenly operationalised. Policy strategies such as equity-oriented horizon scanning, open nomination systems, and special pathways for OMPs are highlighted as feasible approaches to promote fairness. Achieving equity in HTA topic selection for OMPs requires both policy and cultural change, and embedding pluralistic value frameworks, engaging stakeholders and adopting specific policy tools are essential steps towards ensuring that rarity is met with heightened ethical attention rather than exclusion.
    DOI:  https://doi.org/10.1007/s40258-026-01048-0
  30. JCO Oncol Pract. 2026 May 20. OP2600119
    Cellular Therapies in Solid Tumors: Are We Ready for Primetime?
    Giuseppe Maiocco, Vinicius Ernani, Michael P Gustafson, Salman R Punekar, Konstantinos Leventakos, Julian Molina, Yousef Zakharia, Mitesh Borad, Antonious Z Hazim.
      Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune-based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.
    DOI:  https://doi.org/10.1200/OP-26-00119
  31. J Cancer Policy. 2026 May 15. pii: S2213-5383(26)00053-6. [Epub ahead of print]48 100752
    Regulatory approval of new oncology drugs, 2020-2024: A comparative analysis of FDA, EMA, and ANVISA.
    Alciellen Mendes da Silva, Eduardo Frizzera Meira, Jéssica Barreto Ribeiro Dos Santos, Michael Ruberson Ribeiro da Silva.
       CONTEXT: Cancer remains a leading cause of global mortality, increasing demand for effective and accessible therapies. Regulatory agencies are central to evaluating and approving new oncological technologies.
    OBJECTIVES: To compare oncology drug approvals by the FDA, EMA, and ANVISA from 2020 to 2024, analyzing regulatory timelines, innovation profiles, therapeutic trends, and the interval between approval and incorporation into Brazil's Unified Health System (SUS).
    METHODS: A retrospective study was conducted using publicly available data from the FDA, EMA, ANVISA, and the National Commission for Health Technology Incorporation (CONITEC). All first-time oncology drug approvals during the period were included. Approval dates, developer origin, exclusivity status, and time to potential SUS incorporation were assessed.
    RESULTS: The FDA granted 73 approvals, followed by the EMA (56) and ANVISA (18). Regulatory convergence was high between the FDA and EMA, whereas ANVISA showed median approval delays of 353 days compared with the FDA and 336 days compared with the EMA. Relatively balanced distribution between biological and synthetic medicines was observed, with approvals concentrated among US-headquartered companies and primarily indicated for lung cancer, multiple myeloma, and breast cancer. FDA and EMA decisions relied on a more heterogeneous mix of trial phases and designs, whereas ANVISA more frequently required phase 3 randomized studies. Incorporation into SUS remained limited.
    CONCLUSION: Greater integration between regulatory evaluation and health technology assessment is needed to reduce asymmetries and improve timely access to oncological innovations within SUS.
    POLICY SUMMARY: Differences in oncology drug approvals across regulatory agencies contribute to delays in access to innovative cancer therapies in Brazil. Strengthening regulatory alignment and integration with health technology assessment may improve timely and equitable access within SUS.
    Keywords:  ANVISA; Drug incorporation; EMA; FDA; Oncology; Regulatory agencies; SUS
    DOI:  https://doi.org/10.1016/j.jcpo.2026.100752
  32. J Immunother Cancer. 2026 May 20. pii: e014602. [Epub ahead of print]14(5):
    Immune tolerance versus cancer surveillance: an ongoing challenge.
    Michael Agrez.
      Maintenance of anticancer immunity without compromising immune tolerance remains a challenge. Immunosuppressive regulatory T cells (Tregs) are the guardians of immune tolerance that underpin prevention of autoimmune responses. Tregs express checkpoint molecules that suppress autoreactive immune cells from being activated by endogenous (self) proteins. However, expression of these checkpoints on immune cells contributes to cancer cell evasion from the immune system while inhibition of checkpoint signaling in cancer immunotherapy induces autoimmune-related adverse events. Two instructive cytokines that regulate the opposing functions of immunosuppressive Tregs and anticancer responses mediated by cytotoxic natural killer cells include the interleukins, IL-2 and IL-12. An overview based on published data is described herein to highlight how manipulation of these cytokines may have dual action in oncologic and autoimmune models. This raises the possibility of exploiting mechanisms in cancer immunotherapy that could promote anticancer immunity while still maintaining immune tolerance. Given the role of peptides in protein-related interactions, it remains important in rational drug design to remain vigilant for potentially beneficial effects that could benefit both cancer surveillance and immune tolerance.
    Keywords:  Autoimmune; Cytokine; Immune Checkpoint Inhibitor; Immune related adverse event - irAE; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-014602
  33. Immunology. 2026 May 20.
    Current Status of Treg Therapy in Transplantation and Autoimmune Disease.
    Hongwen Li, Huimin Zeng.
      Regulatory T cells (Tregs) represent a critical subset of T lymphocytes essential for maintaining immune homeostasis. Through diverse molecular mechanisms, Tregs exert potent immunosuppressive effects that preserve self-tolerance and mitigate aberrant immune activation. Dysregulation in Treg frequency or function is closely associated with the development of various immune-mediated disorders. This has prompted extensive preclinical investigations and clinical trials evaluating the therapeutic potential of Tregs in conditions such as graft-versus-host disease, solid organ transplantation, and autoimmune diseases, which have yielded promising outcomes. This review provides a comprehensive overview of current preclinical and clinical applications of Treg-based therapies, including adoptive Treg transfer, low-dose IL-2, and CAR-Treg therapy, and discusses their effectiveness in modulating immune responses across diverse pathological contexts.
    Keywords:  CAR‐Treg; GVHD; Tregs; autoimmune diseases; transplantation
    DOI:  https://doi.org/10.1111/imm.70151
  34. JCEM Case Rep. 2026 Jun;4(6): luag122
    CAR T-cell therapy-associated central hypothyroidism: a case of a novel onco-endocrine toxicity.
    Maria Martinez-Cruz, Lauren Mozingo, Courtney Dominguez, Afreen Shariff.
      Chimeric antigen receptor T-cell (CAR T-cell) therapy is a cellular-based immunotherapy in which autologous T-lymphocytes are genetically modified to recognize tumor-associated antigens (TAAs). However, TAAs can also be present at low levels in normal tissues, resulting in off-target toxicities. We present a case of a 66-year-old male with relapsing mantle cell lymphoma (MCL) and no prior endocrinopathies who received brexucabtagene autoleucel CAR T-cell therapy. Ten days post-infusion, he developed cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), with severe symptomatic hypothyroidism with undetectable free thyroxine (free T4) and inappropriately low thyroid-stimulating hormone (TSH). Brain magnetic resonance imaging (MRI) with and without contrast did not reveal any pituitary abnormalities, and comprehensive CSF analysis was unrevealing. Levothyroxine therapy was initiated, with subsequent normalization of thyroid function. This report describes an exceedingly rare case of central hypothyroidism following CAR T-cell therapy. We hypothesize that, during CAR T-cell-related acute toxicities, both direct CAR T-cell trafficking to the central nervous system and secondary inflammatory mechanisms may occur, contributing to blood-brain barrier disruption and potential pituitary dysfunction. Baseline thyroid and adrenal function testing may be considered prior to CAR T-cell therapy. If central hypothyroidism is diagnosed, a comprehensive pituitary hormonal evaluation is recommended.
    Keywords:  CAR T-cell therapy; ICANS; central hypothyroidism; cytokine release syndrome; endocrine toxicity
    DOI:  https://doi.org/10.1210/jcemcr/luag122
  35. Biomark Res. 2026 May 18.
    Challenges and advances in CAR-T cell therapy for B-ALL.
    Chenyu Zha, Ying Wang.
      Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment landscape for hematological malignancies such as relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with several CAR-T products now approved globally for R/R B-ALL. Despite high initial response rates, major challenges remain, including disease relapse due to antigen escape and the limited persistence of CAR-T cells; treatment-related adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, hematologic toxicity, and infections; and limited access to CAR-T therapy. In this review, we discuss the limitations of CAR-T and strategies to overcome them, specifically in the context of B-ALL, including the use of allogeneic CAR-T, dual-targeted CAR-T, and combination strategies with novel technologies and agents. Furthermore, we explored the role of consolidative allogeneic hematopoietic stem cell transplantation after CAR-T therapy and the potential of integrating CAR-T into the first-line treatment for B-ALL. Future research should aim to increase the efficacy of CAR-T, reduce their toxicity, improve their accessibility, and expand their use to earlier lines of therapy for B-ALL.
    Keywords:  Acute B cell lymphoblastic leukemia; Chimeric antigen receptor T cell; Hematopoietic stem cell transplantation; Relapse
    DOI:  https://doi.org/10.1186/s40364-026-00933-z
  36. Cancer Med. 2026 May;15(5): e71974
    A Geographic Disparities Analysis Between Standard of Care and Clinical Trial CAR-T Patients in Kansas.
    Sam Pepper, Aliya Rashid, Carine Tabak, Isuru Ratnayake, Mohammod Mahmudur Rahman, Md Robiul Islam Talukder, Matthew McGuirk, Olivia Rippee, Joseph McGuirk, Marc Hoffmann, Anthony D Sung, Nausheen Ahmed, Dinesh Pal Mudaranthakam.
       BACKGROUND: This study compares demographics and geographic factors associated with access to chimeric antigen receptor (CAR)-T cell therapy for B-cell malignancies or multiple myeloma: individuals in clinical trials at the University of Kansas Cancer Center (KUCC) and those receiving standard-of-care (SOC) CAR-T at the University of Kansas Health System (TUKHS).
    METHODS: Data were collected from electronic medical records and the KUCC Clinical Trial Management System. We evaluated differences in CAR-T access across race, gender, age, rurality, and HPSA status. SOC patients received FDA-approved CAR-T between May 2021 and May 2023; clinical trial patients received investigational CAR-T between January 2015 and February 2023.
    RESULTS: Most patients (80%) were from urban areas; 54.1% lived within 50 miles of the University of Kansas Medical Center (KUMC). The cohort was 58.4% male, 86.7% white, 60.4% aged 19-64, and 57% lived outside a Health Professional Shortage Area (HPSA). Rural patients made up 20% of both cohorts. No significant demographic differences were observed between clinical trial and SOC recipients. However, rural residence was significantly associated with age 65 or older (OR = 1.80), white race, HPSA status, and living more than 50 miles from KUMC (OR = 27.01). HPSA status was also associated with greater odds of living beyond the 50-mile radius (OR = 2.29).
    CONCLUSIONS: Findings highlight important geographic disparities in CAR-T access. Targeted outreach to rural and HPSA-designated communities may improve equity and ensure broader access to advanced therapies.
    Keywords:  CAR‐T therapy; health professional shortage areas; myeloma; rurality
    DOI:  https://doi.org/10.1002/cam4.71974
  37. Stud Health Technol Inform. 2026 May 21. 336 2409-2414
    Orchestration and Small World Governance in the European Health Data Space.
    Simon Lewerenz, Henrique Martins.
      The European Health Data Space (EHDS) introduces a legally binding framework for sharing health data across the EU. While the Regulation provides hard control through obligations, institutions and standards, its effectiveness will likely depend on soft coordination among Member States and stakeholders. This paper interprets the EHDS through orchestration theory and network science, proposing that its mandated governance forms an "orchestrated small world". We argue that the EHDS represents a hybrid system combining legal authority and distributed agency, in which the European Commission orchestrates a networked ecosystem rather than managing a hierarchy. We map main bodies-the Commission, EHDS Board, Health Data Access Bodies (HDABs), Steering Groups and Stakeholder Forum-onto a multi-level network and hypothesise that intermediaries connect dense national or sectoral clusters, supporting diffusion and resilience. We foresee considering emerging ad-hoc structures such as the xShare Standards and Policy Hub (ESHIA in short). This paper adopts a conceptual-analytical approach and advances a conceptual mapping for applying network concepts such as clustering, path length, modularity and centrality as they offer a new analytical lens for EU digital-health governance. With this, it concludes by inviting quantitative validation by the biomedical-informatics community.
    Keywords:  European Health Data Space; governance; network theory; orchestration; small world
    DOI:  https://doi.org/10.3233/SHTI260702
  38. medRxiv. 2026 May 05. pii: 2026.04.28.26351782. [Epub ahead of print]
    Extracting adverse event nature, severity, timelines and resulting interventions from clinical notes of patients receiving CAR-T therapy using large language models.
    Jordan Guillot, Brenda Miao, Arvind Suresh, Madhumita Sushil, Christopher Yk Williams, Rohit Vashisht, Tomiko T Oskotsky, Marina Sirota, Atul J Butte.
      Chimeric Antigen Receptor T-cell (CAR-T) therapy, where genetically engineered patient T cells target tumor antigens, has transformed care for hematologic malignancies but requires careful tracking of adverse events (AEs) often documented only in unstructured EHR notes. We evaluated a Large Language Model (LLM)-based approach in UCSF's secure environment to extract AEs, dates, grades, and interventions within 30 days post-infusion for six commercial CAR-T products (2012-2023), benchmarking against two evaluators. Using GPT-4-0314 in a zero-shot setting with four prompts (prespecified AEs, non-prespecified AEs, CRS, ICANS), we compared outputs against dual annotations on a random sample of 50 notes using accuracy, precision, recall, F1, and Cohen's kappa. From 4,762 progress notes for 293 patients (median age 65.6), CRS occurred in 80.2% (median onset 4 days); neutropenia 70.0% (16 days); neutropenic fever 64.8% (4 days); ICANS in 34.8%. Interventions included tocilizumab and corticosteroids. Grades were frequently undocumented (CRS 62.3%, ICANS 56.1%); documented cases were mainly CRS grade 1 (59.4%) and ICANS grade 2 (28.0%). Performance was high on CRS and ICANS grading (accuracy of 0.97 and 0.91, respectively). Moderate performances were assessed for prespecified AE extraction (accuracies 0.62-0.76), and non-prespecified AEs (accuracies 0.76-0.84). Inter-rater reliability was strong to near-perfect for CRS/ICANS presence and grade (kappa 0.86-0.96), moderate for dates and interventions, and weaker for broader AE attributes. LLM-derived insights can augment AE monitoring and real-world evidence generation by unlocking unstructured clinical detail and characteristic timelines after CAR T. However, performance varied for broader AE attributes, warranting cautious use. Performance was highest for detecting the presence and grade of CRS and ICANS, with strong to near-perfect inter-rater reliability. While cautious use of LLMs for broad AE extraction is warranted due to the variable performance observed in this study, these results support integrating high-performing CRS/ICANS extraction into EHR workflows.
    Author summary: Chimeric Antigen Receptor T-cell (CAR-T) therapy has transformed care for blood cancer but requires careful tracking of adverse events (AEs). We asked whether a large language model could read routine clinical notes and extract AEs after CAR T-cell therapy. We analyzed de-identified notes from the first month after infusion. The model identified when two key side effects occurred-cytokine release syndrome (a whole-body inflammatory reaction) and neurotoxicity (brain and nerve symptoms)-and how severe they were, with accuracy similar to human reviewers. It also captured when side effects started and what treatments were given, though performance was more variable for the wider range of side effects beyond these two. In our data, these reactions often arose within the first week; blood count problems and infections were also common. Because many notes did not state severity explicitly, the model sometimes could not assign a grade. Our findings suggest that language models can help unlock important details hidden in clinical notes and could be incorporated into electronic records to support faster, more reliable side-effect monitoring and research. We recommend careful, supervised use and continued validation, especially for broader side-effect categories.
    DOI:  https://doi.org/10.64898/2026.04.28.26351782
  39. Stud Health Technol Inform. 2026 May 21. 336 1297-1301
    Interoperability Barriers in the European Health Data Space: A Scoping Review.
    Iiris Karppila, Manu Setälä, Laura-Maria Peltonen.
      The European Health Data Space (EHDS) is the EU's most ambitious attempt to standardize cross-border data sharing, yet implementation faces significant interoperability challenges. This scoping review synthesizes literature on EHDS readiness across EU Member States to identify key barriers to seamless data sharing. Using Arksey and O'Malley's five-stage framework, 11 sources addressing EHDS implementation, patient care pathway coordination, and interoperability requirements were analyzed. The findings reveal that while the EHDS addresses technical standardization through frameworks like the European Electronic Health Record exchange Format (EEHRxF), persistent disparities in national implementations create semantic, organizational, and social gaps. Member States show varying adoption of standards such as HL7 FHIR and OMOP, with few shared metadata catalogues. The study contributes a systematic categorization of EHDS interoperability barriers across technical, organizational, and legal dimensions, identifying which challenges the regulation directly addresses versus those requiring additional Member State coordination. These insights inform prioritization strategies for European health informatics standardization efforts.
    Keywords:  EHDS; European Health Data Space; cross-border healthcare; health data standardization; health information systems; interoperability; scoping review
    DOI:  https://doi.org/10.3233/SHTI260408
  40. Stud Health Technol Inform. 2026 May 21. 336 1746-1750
    Digital Twins in Healthcare: Enabling Predictive, Personalized, and Precision-Driven Transformation.
    David Manne.
      Digital Twin (DT) technology is redefining healthcare through dynamic, data-driven virtual replicas of patients, medical devices, and complex clinical systems that continuously learn and evolve. By integrating real-time physiological data, advanced imaging, multi-omics, and comprehensive clinical records, DTs enable sophisticated simulation, prediction, and optimization across the care continuum. This paper examines how DTs accelerate the transition toward precision medicine, predictive analytics, and value-based healthcare delivery. It explores emerging applications in clinical decision support, advanced surgical planning, hospital operations, and drug development through in silico trials. As the European Health Data Space (EHDS) enters its implementation phase in 2026, establishing secure, validated, and ethically governed DT frameworks is crucial to achieving personalized, preventive, and participatory healthcare across Europe.
    Keywords:  AI Integration; Clinical Simulation; Digital Health Transformation; Digital Twins(DT); Electronic Health Records (EHR); Ethical Governance; European Health Data Space (EHDS); Healthcare Innovation; Hospitals; Precision Medicine; Predictive Analytics
    DOI:  https://doi.org/10.3233/SHTI260524
  41. Chin Clin Oncol. 2026 Apr;15(2): 40
    Advancing precision oncology through innovative and adaptive master protocol designs: statistical, operational, and regulatory perspectives.
    Jun Yin, Susan Geyer, Qian Shi, Bryan McComb, Courtney Henry, Jonathan Metts.
      Master protocol trials-including basket, umbrella, and platform designs-have revolutionized precision oncology by enabling the simultaneous evaluation of multiple therapies, biomarkers, and tumor subtypes within a unified adaptive framework. They operationalize the core vision of precision oncology-delivering the right therapy to the right patient efficiently-through harmonized infrastructure and adaptive statistical learning. These designs can improve statistical efficiency and operational feasibility by sharing infrastructure, controls, and information across related substudies. However, their benefits are not automatic and depend critically on the rigor of implementation, calibration, and governance. In this review, we synthesize recent methodological, operational, and regulatory advances in master protocol design, with a focus on how these elements jointly enable reliable inference in molecularly heterogeneous oncology settings. Recent statistical innovations have enhanced information sharing across related cohorts while maintaining control of false-positive results under clinical heterogeneity. Platform trials may extend these principles through multi-stage calibration and latent-subgroup dose optimization, providing flexibility for adding or dropping arms while preserving inferential rigor. By explicitly examining the trade-offs, limitations, and practical constraints underlying these designs, this review clarifies when and how master protocols can fulfill their promise in precision oncology. Collectively, these advances establish master protocol trials as powerful and efficient engines for precision oncology, capable of integrating hierarchical modeling, adaptive learning, and real-world data to accelerate therapeutic discovery and regulatory translation. With continued progress in assay standardization, real-time data infrastructure, and adaptive governance, master protocols are poised to transform clinical development, advancing precision oncology from concept to scalable, executable reality.
    Keywords:  Master protocol; basket trial; platform trial; precision oncology; umbrella trial
    DOI:  https://doi.org/10.21037/cco-2025-aw-153
  42. Curr Drug Discov Technol. 2026 May 12.
    Pharmaceutical Industry 5.0: The Role of Drug Discovery Technology, Innovation, and Digital Transformation in Economic Resilience.
    Virendra S Gomase, Rupali Sharma, Suchita P Dhamane, Nisha S Tatkar.
       INTRODUCTION: The pharmaceutical industry is undergoing a profound transformation driven by digitalization, innovation, and cutting-edge emerging technologies. The concept of Pharmaceutical Industry 5.0 has emerged as the sector adjusts to a rapidly shifting global environment, with cutting-edge technologies like artificial intelligence (AI), blockchain, automation, and personalized medicine playing a crucial role in determining the future. This new phase integrates advanced technologies such as artificial intelligence (AI), blockchain, automation, and personalized medicine, which are shaping the future of drug discovery, manufacturing, and distribution. The objective of this study is to explore how the transition to Industry 5.0 is enhancing the pharmaceutical industry's resilience, innovation, and sustainability in the face of global crises such as pandemics, regulatory changes, and market disruptions.
    METHOD: This research study investigates the integration of emerging technologies in pharmaceutical processes and analyzes their impact on operational efficiency, supply chain optimization, personalized medicine, and global access to treatment. The concept of economic resiliency is used as a central framework to evaluate the industry's adaptive capacity.
    DISCUSSION: Emerging technologies are enabling faster and more efficient research and development (R&D), paving the way for personalized and targeted therapies. Pharmaceutical companies are leveraging innovation to explore new business models focused on sustainability, predictive analytics, and big data. Additionally, digital transformation is reshaping healthcare delivery through telemedicine, AI diagnostics, and remote monitoring, thereby expanding global access to medical treatments.
    CONCLUSION: The adoption of Industry 5.0 principles allows pharmaceutical companies to strengthen economic resilience, drive innovation, and achieve sustainable growth. By embracing digital tools and fostering collaboration, the industry can enhance patient outcomes and maintain long-term viability in an increasingly complex and uncertain global economy.
    Keywords:  Artificial Intelligence (AI); Big Data in Healthcare; Biotechnology; Digital Transformation; Economic Resilience; Innovation in Pharmaceuticals; Pharmaceutical Industry 5.0; Technology in Pharma.
    DOI:  https://doi.org/10.2174/0115701638432521260101061854
  43. Cancer Treat Res. 2026 ;195 221-235
    Cancer and Immune Cells: A Metabolic Battle in the Tumor Microenvironment.
    Sam Pournezhad, Ramyar Azar, Farzad Taghizadeh-Hesary.
      Immunometabolism has emerged as a critical field that links cellular energy regulation with immune function, including in the context of cancer. The tumor microenvironment (TME) is characterized by hypoxia, acidosis, and nutrient competition, all of which promote metabolic reprogramming in cancer cells while suppressing immune surveillance. Antitumor immune cells such as cytotoxic T lymphocytes, natural killer (NK) cells, and M1 macrophages rely on glycolysis and oxidative phosphorylation to sustain effector functions. In contrast, tumor-promoting cells, including regulatory T cells, myeloid-derived suppressor cells, and M2 macrophages, adopt oxidative metabolism and immunosuppressive pathways that reinforce immune escape. Cancer cells further evade immunity through immune checkpoint expression, reduced antigen presentation, secretion of suppressive cytokines, and mitochondrial hijacking, gaining bioenergetic superiority over immune cells. Current immunotherapies, such as checkpoint inhibitors, CAR-T cell therapy, cancer vaccines, and NK-cell-based therapies, have transformed cancer treatment but are often limited by TME-induced metabolic suppression. This chapter highlights the central role of metabolism in cancer-immune dynamics and introduces a novel therapeutic framework that integrates metabolic intervention with immune activation for improved cancer treatment outcomes.
    Keywords:  Cancer; Immune system; Immunometabolism; Mitochondria; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-3-032-21861-2_11
  44. Iran Biomed J. 2026 01 01. 30(1): 16-35
    Adenoviral Vectors in Gene Therapy: A Detailed Overview.
    Hamidreza Saber, Zahra Mousavipour.
      Adenoviral vectors (AdVs) represent one of the most extensively researched platforms in the realm of gene therapy, providing advantages such as high transduction efficiency, large transgene capacity, and broad tropism. This review provides a detailed and structured overview of AdVs, highlighting their biology, gene delivery mechanisms, clinical applications, and challenges limiting their broader therapeutic applicability. The study also explores recent progress in vector engineering, such as rare serotypes, capsid modifications, third-generation vectors, as well as strategies for immune modulation and toxicity reduction. AdVs are used in therapies for genetic disorders, oncology, and vaccinology, alongside innovations such as CRISPR-Cas9, nanotechnology, and artificial intelligence design. Nevertheless, persistent hurdles, including vector immunogenicity, hepatotoxicity, scalability, and the lack of durable expression, prevent widespread clinical use. This review consolidates current knowledge and presents a future perspective on how AdVs may evolve as powerful, adaptable, and precise tools in modern gene therapy. By contextualizing strengths and unresolved challenges, this work aims to give researchers and clinicians a balanced foundation for evaluating their future roles in translational medicine.
    Keywords:  Adenoviridae; Genetic therapy; Oncolytic virotherapy; Transgene
    DOI:  https://doi.org/10.61882/ibj.5062
  45. Acta Physiol (Oxf). 2026 Jun;242(6): e70260
    T Cell Dysfunction in the Acidic Tumor Microenvironment.
    F B Christiansen, E S Novella, A V Lindemann, J F H Cordes, S F Pedersen.
      Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the consequences of these conditions for cancer cell behavior have been extensively studied, their impact on anti-tumor immune responses-particularly T cell function-has only recently gained attention. In this review, we summarize and critically discuss current knowledge on how acidic TME conditions affect the cytotoxic CD8+ T cells which are essential for anti-tumor immunity, and the protumorigenic, regulatory T cells (Tregs). An emerging body of literature shows that TME acidosis restricts cytotoxic CD8+ T cell motility and tumor penetration, suppresses cytokine production and secretion despite preserved transcription, impairs proliferation, and reduces cytotoxic killing capacity. These effects are closely linked to acid-induced metabolic reprogramming, including inhibition of glycolysis, altered mTOR and MYC signaling, and a shift toward fatty acid-dependent oxidative metabolism. In contrast, Tregs, which are metabolically adapted to rely on oxidative phosphorylation and lactate utilization, are comparatively resilient to acidic stress, and acidosis can enhance their suppressive capacity, thereby further skewing the immune balance toward tolerance. We highlight emerging evidence that tumor acidosis modulates immune checkpoint pathways, including pH-sensitive signaling through VISTA and regulation of PD-L1 expression, with important implications for immunotherapy sensitivity. We posit that limiting tumor acidosis may enable restoration of anti-tumor T cell function and improve therapeutic response to immune checkpoint blockade and adoptive T cell therapies.
    Keywords:  CD8+; Treg; anticancer immune response; cancer; immune oncology
    DOI:  https://doi.org/10.1111/apha.70260
  46. J Cell Biol. 2026 Jul 06. pii: e202601058. [Epub ahead of print]225(7):
    T-cell mechanobiology: How molecular forces shape immune function.
    Judith Zubia-Aranburu, Lingxiao Zhang, Mingdong Dong.
      T cells are central to adaptive immunity, and continuously sense, generate, and respond to mechanical forces. Advances in mechanoimmunology show that T-cell behavior is tightly shaped by the physical properties of their environment, including stiffness, viscoelasticity, ligand arrangement, and tissue topography. T-cell activation depends not only on biochemical signals but also on forces transmitted through the T-cell receptor, coreceptors, and mechanosensitive ion channels, which converge on the cytoskeleton to regulate signaling and effector function. When these mechanical interactions are disrupted, as in cancer, autoimmune diseases, or aging, T-cell function is impaired. Despite recent progress, T-cell mechanobiology remains partially understood, limited by challenges in measuring forces at relevant spatial and temporal scales. Incorporating biophysical principles into the design of immunotherapies may enhance treatment efficacy, specificity, and safety. This review summarizes emerging concepts in T-cell mechanobiology and outlines key challenges and future directions toward integrating mechanical and biochemical regulation of adaptive immunity.
    DOI:  https://doi.org/10.1083/jcb.202601058
  47. Transplant Cell Ther. 2026 May 19. pii: S2666-6367(26)00358-1. [Epub ahead of print]
    High incidence of cytomegalovirus infection in patients receiving standard of care CD19- or BCMA-targeted CAR T-cell therapies for hematologic malignancies.
    Tamer Othman, John H Baird, Yan Wang, Stacy Pak, Hannah Zhong, Yi-Ping Wen, Geoffrey Shouse, Alex Herrera, Leslie Popplewell, Ahmed Aribi, Myo Htut, Joycelynne Palmer, Lihua E Budde, Sanjeet S Dadwal.
       BACKGROUND: Infections are a common source of non-relapse morbidity and mortality (NRM) following chimeric antigen receptor (CAR) T-cell therapy, but data regarding cytomegalovirus (CMV) are limited.
    OBJECTIVE: We aimed to report the incidence and the risk factors of CMV infection (CMVI) after CAR T-cells therapy and describe their clinical outcomes.
    STUDY DESIGN: We conducted a retrospective chart review study among patients who received commercial CAR T therapy between 05/01/2021 and 07/31/2023 with undetectable CMV by quantitative PCR prior to lymphodepletion (LD) and underwent at least one CMV PCR test post-CAR T. The primary endpoint was the cumulative incidence of CMVI at day 30 post-CAR T.
    RESULTS: In total, 239 patients were included. After CAR T, 50 patients (21%) had a positive CMV PCR at a median of 23 days (range: 3-602) post-infusion. The cumulative incidence of CMVI was 16% (95%CI: 12-21%) at day 30, and 20% (95%CI: 9-18%) at day 100. By fitting a multivariable Cox proportional hazards model, patients with a positive CMV IgG at pre-LD or received corticosteroid post CAR T were at higher risk of developing a CMVI, adjusted hazard ratio [aHR]: 8.3 [95%CI: 2.6-26.9]; p<0.001 and 2.2 [95%CI: 1.2-4.2]; p=0.013, respectively.
    CONCLUSION: CMVI is an under-recognized complication following CAR T cell therapy. Patients with positive CMV IgG prior to LD, of older age at LD, or who receive corticosteroids post-CAR T are at higher risk for CMVI.
    Keywords:  CAR T; CMV; Large B-cell lymphoma; cytomegalovirus; multiple myeloma
    DOI:  https://doi.org/10.1016/j.jtct.2026.05.016
  48. PLoS One. 2026 ;21(5): e0348674
    BaEV-pseudotyped lentiviral vectors enable stable CAR expression and cytotoxic function in NK cells.
    Minji Park, Yuree Lim, Yujung Jo, Dong-Hyeon Jo, Sang-Ki Kim, Hyun-Young Kim, Seung-Hwan Lee, Mijeong Lee, Duck Cho.
      Lentiviral vectors (LVs) pseudotyped with either vesicular stomatitis virus glycoprotein (VSV-G) or baboon envelope glycoprotein (BaEV) have been studied for chimeric antigen receptor (CAR) transduction in natural killer (NK) cells. However, the stability of CAR expression and the persistence of vector genomes following transduction remain underexplored. We generated CAR-NK92 cells using either VSV-G- or BaEV-pseudotyped LVs and evaluated CAR expression kinetics, cytotoxic function, and vector DNA persistence over time. Primary expanded NK (eNK) cells were further transduced with BaEV-LVs to assess applicability in primary cells. Although VSV-G-CAR-NK92 cells transiently yielded high surface expression of CAR, this expression rapidly declined. Genomic DNA analysis revealed marked degradation of transfer DNA and reduced integration stability of VSV-G-transduced cells. BaEV-LVs, however, supported more sustained CAR expression by NK92 cells, demonstrating persistent gDNA integration and durable cytotoxicity, which were also replicated in eNK cells. In conclusion, these findings support BaEV-LVs as a preferred platform for CAR-NK cell engineering.
    DOI:  https://doi.org/10.1371/journal.pone.0348674
  49. J Control Release. 2026 May 21. pii: S0168-3659(26)00446-3. [Epub ahead of print] 115043
    Rapid receptor internalization potentiates CD7-targeted lipid nanoparticles for efficient mRNA delivery to T cells and in vivo CAR T-cell engineering.
    Jianhao Zeng, Tyler Ellis Papp, Awurama Akyianu, Alejandra Bahena, Lanfranco Leo, Faris Halilovic, Hamideh Parhiz.
      Targeted lipid nanoparticles (tLNPs) enable efficient mRNA delivery to T cells, allowing for in situ generation of chimeric antigen receptor (CAR) T cells without ex vivo manipulation. This strategy has shown promising therapeutic efficacy in preclinical studies of cardiac fibrosis, cancer, and autoimmune diseases. While multiple T-cell surface receptors have been targeted across studies for tLNP-mediated in vivo CAR T-cell generation and exhibit diverse efficiencies, their comparative performance and the mechanisms underlying these differences remain unclear. Here, we systematically compared tLNPs with antibody-based moieties targeting T-cell receptors including CD2, CD4, CD5, CD7, CD8, or a CD4 + 8 dual-targeting combination under identical conditions, assessing their mRNA delivery efficiency in human T cells and PBMCs in vitro, and subsequently validating the best performer in vivo in humanized mice. Among all moieties tested, CD7-targeted tLNPs achieved the highest mRNA delivery to T cells and efficiently generated functional aCD20 CAR T cells in vivo. Mechanistic analysis revealed that receptor internalization, rather than the receptor abundance, is the primary determinant of delivery efficiency, a property intrinsic to each receptor and largely independent of antibody clone. These findings provide a rational framework for selecting optimal targeting moiety to enable highly efficient in vivo CAR T-cell engineering.
    Keywords:  CD7; In vivo CAR-T; Receptor internalization; T cells; Targeted lipid nanoparticles (tLNPs); mRNA delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115043
  50. Clin Pharmacol Ther. 2026 May 21.
    From Classical PKPD to Model-Informed Drug Development: Are "Digital Twins" a New Paradigm?
    Brett E Houk.
      Quantitative pharmacology has guided drug development for decades, turning concentration and response data into mechanistic models that support dosing, trial design, and regulatory decisions. Model-informed drug development (MIDD) did not replace pharmacokinetic and pharmacodynamic (PKPD) modeling so much as formalize it across the lifecycle. Today, "digital twins" are often promoted as a new paradigm, yet most proposed features mirror established pharmacometrics: individual-level simulation, sequential updating, and decision-focused uncertainty analysis. The fundamentals remain unchanged, and identifiability still sets hard limits.
    DOI:  https://doi.org/10.1002/cpt.70340
  51. Acta Pharmacol Sin. 2026 May 21.
    Cell death pathways and targeting therapeutics in cancer therapy.
    Bo Zhan, Hai-Liang Zhang, Ying Xiao, Wen-Qing Zhong, Yi-Qing Guo, Jia-Lu Shan, Jia-Hong Tang, Xiao-Feng Zhu, Rong Deng.
      Dysregulated cell death represents a cornerstone of cancer development and therapeutic resistance. This review systematically deciphers the molecular architecture underlying various regulated cell death modalities and their crosstalk. Moving beyond a mere catalog of mechanisms, it critically evaluates the translational landscape of agents that are designed to precisely trigger these pathways. We then critically evaluate the translational strategies that target their key components via diverse agents, from small molecules to PROTACs and nanomedicines. A key focus is the strategic induction of immunogenic cell death to convert tumor cell killing into durable antitumor immunity. This review synthesizes evidence on how distinct death pathways, such as ferroptosis, can be leveraged to remodel the immunosuppressive tumor microenvironment and potentiate immune checkpoint blockade. It further examines the contextual factors that determine the immunogenic outcome of cell death, providing a rationale for combination therapies (e.g., the synergistic effect between ferroptosis inducers and immune checkpoint inhibitors). By integrating mechanistic insights with therapeutic innovations, we provide a framework for developing next-generation therapies that precisely manipulate cell death to overcome treatment resistance and activate immune surveillance. Finally, the review outlines future directions, suggesting the need for the integration of multidisciplinary approaches to discover novel targets, develop selective inducers, and rationally combine cell death modulation with immunotherapy to achieve sustained clinical responses.
    Keywords:  cell death; drug development; immunogenic cell death; molecular targeted therapy
    DOI:  https://doi.org/10.1038/s41401-026-01803-y
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