bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–05–31
77 papers selected by
Luca Bolliger, lxBio
  1. Challenges and opportunities: CAR-T cell therapy in autoimmune diseases.
  2. Live-Cell Microscopy for quantitative analysis of CAR T Cell fratricide and immune synapse.
  3. CAR-T cell therapy in cancer immunotherapy - Biology, clinical successes, and emerging challenges: A review.
  4. CAR-iNKT cells for cancer therapy: a comprehensive review of engineering, mechanisms, and clinical progress.
  5. Toward equitable access to cell and gene therapies: rethinking co-payments.
  6. Characterization of CAR-T cell factors that contribute to myeloid cell activation.
  7. Why promising ATMPs fail to reach patients: a qualitative stakeholder-informed analysis of cell therapy access in Europe.
  8. Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy.
  9. Leveraging CRISPR/Cas9 for optimized adoptive T cell therapies: From molecular engineering to clinical manufacturing.
  10. Emerging Applications of CAR-T Cell Therapy in Overcoming Resistance and Expanding Targets in Hematologic Malignancies: Insights from Recent Research.
  11. The silent pharmacist: Harnessing the gut microbiome to improve therapy in hematologic malignancies.
  12. CAR-T cell therapy in non-Hodgkin lymphoma: a clinical trial landscape review.
  13. Adoptive T-Cell Immunotherapy.
  14. Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.
  15. Image analysis of mitochondria during T lymphocyte and chimeric antigen receptor (CAR) effector responses.
  16. Regulatory T cell therapy in solid organ transplantation: mechanisms, translational progress, and remaining barriers.
  17. Natural Killer (NK) Cells in Tumor Immunity: Limitations and Therapeutic Potential with a Focus on Nasopharyngeal Carcinoma and Comparison with T-Cell-Based Therapies.
  18. A new fully closed automated banking process for healthy autologous cells to standardize the starting material for CAR T manufacturing.
  19. Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.
  20. Engineering human T cells with antigen receptors for immune regulation in autoimmune disease and transplantation.
  21. Induced Pluripotent Stem Cell-Derived NK Cells as an Off-the-Shelf Platform for Cancer Immunotherapy: Opportunities, Challenges, and Clinical Translation.
  22. Beyond Hematology-Current Insights into Chimeric Antigen Receptor (CAR) T-Cell Therapy for Skin and Connective Tissue Disorders.
  23. Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges.
  24. Preconditioning determines engraftment and therapeutic efficacy of anti-CD19 CAR-T cells in murine lupus.
  25. Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.
  26. Clinical landscape and development of universal CAR-T cell therapies.
  27. Neoantigen-based TCR-T therapy in solid tumors.
  28. Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors.
  29. From Concept to Claim: An Integrated Lifecycle Roadmap (ILR) for Patient-Centric Endpoints in Clinical Trials and Real-World Evidence.
  30. Analysis of murine CAR-T cell-mediated cytotoxicity in solid tumor models.
  31. Therapeutic cancer vaccines: navigating clinical translation and multimodal synergy.
  32. Impact of Market Access Delays on Time to Patient Access: Multi-Country Comparative Analysis Assessing the First Commercial Launch Indications for Five Oncology Medicines Across Europe and Canada.
  33. Building sustainable multiple sclerosis registries in Latin America: A practical framework for real-world evidence generation and healthcare access.
  34. Between Rigor and Relevance: Why the EU HTA Guidelines on Indirect Comparisons Miss the Mark.
  35. Zero-Knowledge Process Verification: A Comprehensive Framework for a Distributed Healthcare System.
  36. Pre-emptive and Prophylactic Strategies to Prevent Cardiovascular and Neurotoxicity in Chimeric Antigen Receptor T-Cell Therapy: The Role of Tocilizumab, Anakinra, and Cytokine-Targeted Interventions.
  37. Artificial Intelligence Across the Drug Development Lifecycle.
  38. Evidence Synthesis via Indirect Treatment Comparisons in the European Framework of Joint Clinical Assessment.
  39. Boosting the Activity of Melanoma-Targeting CAR-T Cells in the Presence of Citrate by the Application of Gluconate.
  40. External controls for rare disease drug development: Lessons for emerging and advanced therapeutic modalities.
  41. Coverage with evidence development programs: a scoping review on characteristics and patient access.
  42. Efficient NK cell transduction with VSV-G-pseudotyped lentiviral vectors.
  43. Data-driven computational modeling of CAR-T cell function.
  44. Incorporating the Next Generation of Immunotherapies Into the Treatment of Multiple Myeloma.
  45. A Focused Comparative Review of Innovative Therapeutics Across Autoimmune and Chronic Inflammatory Diseases.
  46. Secondary T-cell lymphomas after CAR T-cell therapy in dermatology.
  47. Generation of therapeutic T cells from human induced pluripotent stem cells.
  48. Synthesis and Clinical Application of Small-Molecule Drugs Approved by FDA in 2025.
  49. Artificial intelligence in cancer immunotherapy: current trends in predicting response and personalizing treatment.
  50. The Landscape of Clinical Trials for TCR-T Cell Therapy.
  51. Navigating the regulatory landscape of herbal medicines: A global comparison of India, China, Europe, the United States and Japan.
  52. Drugs that boost immunity are making lung cancer less deadly.
  53. Efficacy and safety of durcabtagene autoleucel in a phase 1 trial for patients with relapsed/refractory multiple myeloma.
  54. Virtual cell: Current perspectives and future prospects.
  55. Emerging therapeutic opportunities for psychedelic and related drugs.
  56. Digital Twins in Neurology Care: Evidence, Limitations, and a Path Forward.
  57. Blockchain Technology to Enhance Clinical Data Management in Healthcare: A Systematic Literature Review.
  58. Gut microbiota and cancer immunotherapy: from dysbiosis to personalized immune checkpoint blockade optimization.
  59. Therapeutic effects of Lentinan in gastrointestinal inflammation and carcinogenesis - A scoping review of evidence from preclinical and clinical studies.
  60. Yeast surface display meets immunotherapy: unlocking the potential of T cells.
  61. T cell activity is boosted after meals.
  62. Delivery of mRNA Therapeutics Beyond Infectious Diseases: Design Innovations and Applications in Oncology, Cardiovascular, and Rare Genetic Diseases.
  63. Toward Precision Health in Autoimmunity and Immune-Related Adverse Events: The Autoantibody Reactome, Spatial Omics, and Multimodal Data Integration.
  64. Exploring Technological Solutions for Interoperability Between Patient Electronic Medical Records and Clinical Registries: Scoping Review.
  65. The governance of health data in the AI era: a scoping review and computational topic model of the global research landscape.
  66. Engineered Plant-Derived Extracellular Vesicles: A Novel Strategy for Tumor-Targeted Therapy.
  67. Science takes on the world's most lethal malignancy.
  68. AI-Enabled Inclusive Oral-Systemic Integrated Care (AI-IOC+): An Equitable, Learning Framework for Managing Polypharmacy, Multimorbidity, and Special Health Needs Throughout Life.
  69. Emerging trends impact drug expenditure.
  70. Optimizing the Efficacy-Toxicity Paradigm in Pediatric Oncology: A Narrative Review of Immunotherapy and Survivorship Outcomes.
  71. From Algorithms to Assets: A Comprehensive Review of AI's Role in Preclinical Drug Discovery and the Hurdles to Clinical Translation.
  72. Broadly neutralizing antibody-secreting CAR-T cells elicit Fc-mediated effector functions in vitro and suppress HIV in humanized mice.
  73. Machine Learning-Assisted Rapid Optical Imaging for Label-Free CAR T-Cell Detection in Whole Blood.
  74. Multiscale predictive cellular modeling: integrating hypothesis grammars, digital twins, and multi-omics for In silico oncology and precision theranostics.
  75. Advancing the systematic implementation of patient experience data in healthcare decision-making: multi-stakeholder insights on barriers, opportunities and policy ways forward.
  76. Functionalized Lipid Nanoparticles for Targeted RNA Delivery in Immune and Inflammatory Diseases.
  77. Pediatric Rheumatic Disorders Revisited: Integrating Imaging and Pathophysiologic Insights across the Autoinflammatory-Autoimmune Continuum.
  1. Cell Insight. 2026 Jun;5(3): 100327
    Challenges and opportunities: CAR-T cell therapy in autoimmune diseases.
    Ran Yan, Songying Ye, Huji Xu.
      Chimeric antigen receptor T (CAR-T) cell therapy is rapidly moving from hematologic malignancies into severe autoimmune disease, particularly B cell-mediated disorders such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and inflammatory myopathies. Recent autologous and allogeneic studies show that deep immune-cell depletion can induce drug-free remission or major clinical responses in the refractory patients. However, translating CAR-T cell therapy into autoimmune disease raises challenges that differ from oncology, including target selection in heterogeneous immune ecosystems, depletion of nonpathogenic immune compartments, control of cytokine release syndrome and infection risk, definition of the optimal degree of CAR persistence, and scalable manufacturing. In this review, we summarize the major obstacles and emerging opportunities for CAR-T cell therapy in autoimmune diseases, with emphasis on representative clinical studies, candidate targets beyond CD19, engineering strategies to improve safety and durability, and the specific promise and limitations of allogeneic platforms.
    Keywords:  Allogeneic CAR-T cells; Autoimmune diseases; CAR-T cell therapy
    DOI:  https://doi.org/10.1016/j.cellin.2026.100327
  2. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00019-1. [Epub ahead of print]207 75-94
    Live-Cell Microscopy for quantitative analysis of CAR T Cell fratricide and immune synapse.
    Álvaro Gómez-Morón, Celia Martín-Otal, Teresa Lozano, Noa Beatriz Martín-Cófreces.
      Chimeric antigen receptor (CAR) T cell therapy has redefined cancer immunotherapy, offering remarkable efficacy against hematologic malignancies and solid tumors. However, CAR T cell therapy targeting T cell malignancies is limited by fratricide, self-directed cytotoxicity caused by shared antigen expression on both therapeutic and endogenous T cells. This process impairs CAR T cell expansion, viability, and overall efficacy. In this study, we present a live cell microscopy-based methodology to visualize and quantify CAR T cell fratricide and immune synapse. Through fluorescent labeling, time-lapse imaging and automated analysis, we track dynamic T cell interactions, cytotoxic events, and synaptic structures. This protocol enables precise measurement of fratricide events kinetics, serial killing behavior, and immune synapse morphology, thereby offering valuable insights into CAR design optimization and underlying mechanisms. This imaging-based approach complements conventional assays by providing temporally and spatially resolved data, thereby enhancing our understanding of CAR T cell function and cytotoxic regulation in the context of fratricide.
    Keywords:  Actin; CAR-T; Golgi; Lysosome; immune synapse
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.019
  3. Biomol Biomed. 2026 May 26.
    CAR-T cell therapy in cancer immunotherapy - Biology, clinical successes, and emerging challenges: A review.
    Abdisa Tufa Bedada, Mohammed Mehdi, Ousman Mohammed.
      Cancer immunotherapy has transformed oncology by enabling targeted activation of antitumor immune responses in patients with relapsed or refractory malignancies. Among adoptive cell transfer (ACT) strategies, chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a pivotal therapeutic advancement, genetically redirecting T lymphocytes to recognize tumor-associated antigens independently of major histocompatibility complex (MHC) presentation. This review provides a comprehensive overview of the biological principles, design evolution, manufacturing platforms, clinical applications, resistance mechanisms, toxicities, and future directions of CAR-T cell therapy within cancer immunotherapy. Specifically, we examine the evolution of CAR architecture, spanning from first-generation constructs to advanced armored and fifth-generation platforms. Furthermore, we compare viral and non-viral gene delivery systems and discuss emerging approaches such as in vivo CAR engineering, allogeneic "off-the-shelf" products, logic-gated receptors, safety switches, and alternative immune-cell platforms, including natural killer (NK) cells and macrophages. CAR-T cell therapy has achieved its most profound clinical success in hematological malignancies, particularly in cluster of differentiation 19 (CD19)-positive B-cell acute lymphoblastic leukemia and B-cell non-Hodgkin lymphoma, reporting durable remission rates of approximately 60-90% in specific clinical contexts. However, broader clinical translation, particularly in solid tumors, remains constrained by challenges such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), antigen escape, tumor heterogeneity, poor trafficking, limited persistence, high manufacturing costs, and the immunosuppressive tumor microenvironment (TME). While next-generation strategies-including clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated editing, lipid nanoparticle (LNP)-based messenger ribonucleic acid (mRNA) delivery, bispecific CARs, and inducible suicide switches-hold promise for improving safety, specificity, scalability, and accessibility, a significant number remain in preclinical or early-phase clinical development. Overall, CAR-T cell therapy represents a transformative "living drug" platform in oncology; however, its broader clinical utility is contingent upon improving durability, reducing toxicity, overcoming solid-tumor barriers, and validating next-generation technologies through robust, long-term clinical studies.
    DOI:  https://doi.org/10.17305/bb.2026.14266
  4. Immunotherapy. 2026 May 25. 1-16
    CAR-iNKT cells for cancer therapy: a comprehensive review of engineering, mechanisms, and clinical progress.
    Ying Yang, Jiaqi Gu, Yujie Ding, Yuqin Li, Zhida Sun.
      Chimeric antigen receptor (CAR)-modified T cells, as a revolutionary cancer immunotherapy, have achieved remarkable success in hematologic malignancies. However, the therapy is hindered by severe toxicity, complex manufacturing, and suboptimal efficacy in solid tumors. Invariant natural killer T (iNKT) cells combine features of T cells and NK cells, bridging innate and adaptive immunity. Beyond direct cytotoxic functions, iNKT cells exert indirect antitumor effects through interactions with other immune cells while also modulating the tumor microenvironment (TME). Their exceptional TME infiltration capacity offers hope for solid tumor treatment. Leveraging their inherent major histocompatibility complex (MHC)-independent cytotoxicity, iNKT cells offer a viable strategy for developing "off-the-shelf" CAR cell products. Consequently, CAR-iNKT cell therapies developed by introducing CAR technology into iNKT cells demonstrate extraordinary potential as a next generation tumor immunotherapy. Despite being established and garnering attention, CAR-iNKT cell therapy remains nascent with numerous obstacles. This review comprehensively discusses CAR-iNKT cell therapy, from the fundamental biology of iNKT cells to the latest advances in engineering and clinical translation, offering new perspectives for its research, development, and application. A comprehensive literature search was conducted using [PubMed, Embase, and Web of Science] for articles published between [January 1900 and March 2026].
    Keywords:  CAR-iNKT cell; Chimeric antigen receptors (CAR); cancer immunotherapy; invariant natural killer T (iNKT) cell; tumor microenvironment (TME)
    DOI:  https://doi.org/10.1080/1750743X.2026.2674418
  5. Am J Manag Care. 2026 May;32(5): 257-259
    Toward equitable access to cell and gene therapies: rethinking co-payments.
    William H Shrank, Ellen Kelsay, A Mark Fendrick.
      Cell and gene therapies represent a transformative advance in the treatment of inherited disorders, hematologic malignancies, and progressive neuromuscular diseases, offering the potential for durable remission or cure. However, with onetime therapies now routinely priced above $3 million, their integration into the US health care system presents significant challenges related to affordability, access, and equity. Although patient cost sharing represents a small fraction of total cell and gene therapy spending, deductibles and coinsurance can expose commercially insured and Medicare beneficiaries to thousands of dollars in out-of-pocket costs, creating meaningful financial barriers for patients and families already burdened by illness-related economic strain. This article examines the role of co-payments in the context of high-cost, physician-administered, curative therapies and evaluates whether traditional cost-sharing rationales remain applicable. Drawing on emerging evidence from chimeric antigen receptor T-cell therapy utilization, we highlight persistent disparities in access by race, socioeconomic status, geography, and insurance type and discuss how patient cost sharing may exacerbate inequities in a category characterized by strict clinical eligibility, intensive oversight, and minimal risk of inappropriate use.
    DOI:  https://doi.org/10.37765/ajmc.2026.89933
  6. Gene Ther. 2026 May 26.
    Characterization of CAR-T cell factors that contribute to myeloid cell activation.
    Supreet Khanal, Md Kamal Hossain, Joseph Fischer, Santosh Panthi, Alan Baer, Nirjal Bhattarai.
      Chimeric antigen receptor (CAR) T cell therapies have shown remarkable success in the treatment of hematologic cancers; however, their use is often accompanied by inflammatory toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). These toxicities, ranging from mild to life-threatening, are partly driven by bystander myeloid cell activation (BMCA) and the subsequent release of pro-inflammatory cytokines such as IL-6 and IL-1β. Although previous studies have described the individual contributions of GM-CSF, IFN-γ, and TNFα secreted by CAR-T cells, a comprehensive characterization of CAR-T-derived inflammatory factors has been lacking. In this study, we characterized the soluble factors secreted by activated CAR-T cells derived from human peripheral blood and assessed their role in BMCA. Comparative cytokine analyses across human T cell subsets, including CAR-T cells, identified multiple candidates involved in BMCA. Antibody-mediated neutralization confirmed that four factors, GM-CSF, IFN-γ, TNFα, and GPIbα, play dominant roles in driving BMCA. Furthermore, siRNA-mediated knockdown of these factors in CAR-T cells significantly reduced BMCA without impairing their anti-tumor activity. These findings are consistent with prior reports on the inflammatory roles of GM-CSF, IFN-γ, and TNFα during CAR-T cell therapy and, importantly, identify GPIbα as a previously unrecognized contributor to CAR-T-associated inflammatory toxicities. Targeting these factors through antibody blockade or genetic modification may represent a promising strategy to mitigate inflammatory toxicities and improve the safety of CAR-T cell therapies.
    DOI:  https://doi.org/10.1038/s41434-026-00620-6
  7. J Transl Med. 2026 May 23.
    Why promising ATMPs fail to reach patients: a qualitative stakeholder-informed analysis of cell therapy access in Europe.
    Giuseppe Di Mauro, Maria Pachetti, Christian Ploner, Michele De Luca, Graziella Pellegrini, Elisa Gambini, Massimo Moretti, Antonio Sfiligoj, Teodor E Yordanov, Miomir Knezevic, Giulia Benedetta Sidoti, Giovanni Papa, Serena Zacchigna.
       BACKGROUND: Advanced therapy medicinal products (ATMPs) comprise gene therapies, somatic cell therapies, tissue engineered products (TEPs), and combined ATMPs. These modalities have the potential to deliver durable or curative benefit in oncological, genetic, chronic, and rare diseases with high unmet medical need. Yet in Europe, access remains limited, uneven, and often commercially unsustainable: clinically promising therapies frequently fail to progress beyond early development or are withdrawn after regulatory approval for reasons related to scalability and reimbursement rather than lack of clinical benefit.
    METHODS: This study was designed as a qualitative, interview-based analysis to identify the major barriers faced by ATMP stakeholders to the clinical translation and patient access of cell therapies in Europe. We collected structured oral and written questionnaire/interview input from six stakeholders operating in the European ATMP landscape and synthesized the material into cross-cutting themes related to health technology assessment, manufacturing, regulatory implementation, and market dynamics.
    RESULTS: Stakeholders consistently report that HTA approaches optimized for conventional pharmacological therapies often overemphasize short-term budget impact and insufficiently account for long-term clinical benefit, downstream healthcare and societal costs, and the durability of therapeutic effects. In parallel, substantial variability across donors, batches, manufacturing and delivery settings, together with fragmented GMP infrastructure, uneven national execution of clinical trial and access pathways, and chronic underinvestment, undermines reproducibility and scalability. Although the European Medicines Agency (EMA) offers facilitation instruments including early scientific dialogue and accelerated or supportive regulatory pathways, their potential to improve predictability is frequently attenuated by Member State heterogeneity and discontinuities across regional innovation ecosystems.
    CONCLUSION: From a stakeholder's perspective, key recommendations including revising HTA frameworks to better reflect long-term lifetime value, investing to improve the accessibility to GMP facilities, strengthening ATMP regulatory expertise and access to early scientific advice, enabling cross-border ecosystems, and addressing structural market failure through public risk-sharing mechanisms.
    Keywords:  ATMPs; Funding; GMP; HTA; Innovation; Manufacturing; Regulatory; Scalability; Tech transfer
    DOI:  https://doi.org/10.1186/s12967-026-08303-x
  8. Front Immunol. 2026 ;17 1843548
    Wnt signaling as a regulator of memory T cells: implications for CAR-T cell therapy.
    Tatiana Fourfouris, Ki Jun Lee, Samantha Hurwitz, Asher Ahdoot, Alexander Lee, Maiah Zarrabi, Michael Kahn, Yong-Mi Kim.
      Chimeric antigen receptor T-cell (CAR-T) therapy has achieved impressive remission rates in hematologic cancers, but long-term efficacy remains limited by insufficient CAR-T cell persistence. T cell factor 1 (TCF1) and lymphoid enhancer binding factor 1 (LEF1), transcription factors well known for their role in downstream Wnt/β-catenin signaling, have been found to regulate transcriptional and epigenetic memory programming important for CAR-T cell persistence and favorable patient outcomes. Activation of the Wnt/β-catenin in endogenous T cells was found to arrest effector differentiation and promote the formation of cluster of differentiation (CD) 8+ memory stem cells, characterized by strong proliferative and recall potential, key traits of persisting memory cells. Genetically engineered CAR-T cells are subject to the same transcriptional and epigenetic factors that govern memory development in endogenous T cells, providing a strong rationale for applying scientific findings from basic T cell biology to CAR-T cell engineering. With this in mind, recent studies have shown that there is clinical potential for Wnt-directed approaches to improve CAR-T cell memory phenotypes, persistence, and exhaustion. Here we review the role of Wnt/β-catenin signaling in T cell development and memory formation, examine clinical evidence linking Wnt/TCF1 activity to CAR-T cell persistence and patient outcomes, and discuss emerging genetic, epigenetic, and pharmacological strategies used to target this pathway in CAR-T cell manufacturing.
    Keywords:  CAR-T cell persistence; CAR-T cells; LEF1; T cells; TCF1 (TCF7); Wnt/β-catenin signaling; memory T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1843548
  9. Biochem Biophys Res Commun. 2026 May 20. pii: S0006-291X(26)00767-9. [Epub ahead of print]826 154003
    Leveraging CRISPR/Cas9 for optimized adoptive T cell therapies: From molecular engineering to clinical manufacturing.
    Ji-Hyeon Kim, Hyo Jung Cho, Hyang-Mi Lee.
      Cancer immunotherapy is rapidly evolving from pharmacologic immune modulation to adoptive cell therapy (ACT). In ACT, T cells are expanded and genetically engineered ex vivo to achieve long-lasting antitumor activity. The primary ACT platforms-tumor-infiltrating lymphocytes (TIL), chimeric antigen receptor (CAR) T cells, and T-cell receptor (TCR) T cells-rely on T-cell effector function but differ in their mechanisms of antigen recognition, HLA dependence, and engineering requirements, leading to unique clinical strengths and limitations. CRISPR/Cas9 genome editing provides precise knock-out (KO) and knock-in (KI) strategies, allowing for multiplex editing and functional modulation across the genome. In the context of ACT manufacturing, CRISPR/Cas9 addresses critical challenges such as T-cell exhaustion, graft-versus-host disease (GvHD), and ensuring product consistency and quality. This article explores how CRISPR/Cas9 can be utilized to overcome the limitations of ACT and summarizes the current clinical landscape of CRISPR-engineered ACT products. Finally, we discuss the ongoing challenges associated with CRISPR-based genome editing and propose potential solutions.
    Keywords:  Adoptive T cell therapy; CAR-T; CRISPR/Cas9; Multiplex gene editing; TCR-T; TIL
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154003
  10. Curr Treat Options Oncol. 2026 May 23. pii: 28. [Epub ahead of print]27(1):
    Emerging Applications of CAR-T Cell Therapy in Overcoming Resistance and Expanding Targets in Hematologic Malignancies: Insights from Recent Research.
    Iraj Alipourfard, Zahra Shafaghat, Saber Saharkhiz, Marzieh Ramezani Farani, Salar Bakhtiyari.
      Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment outcomes of patients with hematologic malignancies, including B-cell acute lymphoblastic leukemia (B-ALL), diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM). However, issues such as antigen escape, T-cell exhaustion, and the limited efficacy of CAR-T cells in acute myeloid leukemia (AML) and T-cell leukemias still persist. This review aims to summarize human trials and achievements from 2015 with a focus on the innovations within the last two years. We discuss strategies to overcome resistance, including multi-target CARs, next-generation constructs, and combination strategies to treat resistant cancers. We also explore the ways to increase safety and access, including allogeneic CAR-T options. In this article, we propose CRISPR-enhanced CARs and synthetic biology-based allogeneic systems to enhance the efficacy and accessibility of CAR-T therapy with the aim of moving the field of oncology towards durable cures.
    Keywords:  Allogenic CAR-T; CAR-T therapy; Hematologic malignancies; Multi-target CARs
    DOI:  https://doi.org/10.1007/s11864-025-01371-z
  11. Transl Oncol. 2026 May 25. pii: S1936-5233(26)00170-1. [Epub ahead of print]70 102833
    The silent pharmacist: Harnessing the gut microbiome to improve therapy in hematologic malignancies.
    Amr Ali Mohamed Abdelgawwad El-Sehrawy, Hamed Soleimani Samarkhazan.
      The gut microbiome, a complex ecosystem of microorganisms, is now recognized as a key determinant of drug efficacy and toxicity, giving rise to the field of pharmacomicrobiomics. This review decodes the profound influence of the gut microbiome on treatment outcomes for hematologic malignancies. We explore the tripartite mechanistic pathways through which gut microbes act: the direct enzymatic biotransformation of chemotherapeutic agents, the indirect immunomodulation of systemic and anti-tumor responses, and the preservation of mucosal barrier integrity to prevent devastating complications like graft-versus-host disease (GVHD). The manuscript details how the microbiome interacts with specific drug classes, from conventional chemotherapies like cyclophosphamide to cutting-edge immunotherapies like immune checkpoint inhibitors and CAR-T cells, shaping their clinical success. Furthermore, we discuss the translational potential of targeting this "silent pharmacist" through fecal microbiota transplantation, next-generation probiotics, and dietary interventions. Finally, we highlight the main translational opportunities, current limitations, and future clinical priorities for integrating microbiome science into hematology, paving the way for more personalized and improved cancer care.
    Keywords:  Gut microbiome; Hematologic malignancies; Immunotherapy; Personalized medicine; Pharmacomicrobiomics
    DOI:  https://doi.org/10.1016/j.tranon.2026.102833
  12. Front Immunol. 2026 ;17 1820425
    CAR-T cell therapy in non-Hodgkin lymphoma: a clinical trial landscape review.
    Jinyu Wu, Yun Liao, Wen Wang, Xin Zhang.
       Background: Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a transformative treatment modality for selected subtypes of non-Hodgkin lymphoma (NHL). While multiple CAR-T products have demonstrated remarkable clinical activity, the overall clinical development landscape remains heterogeneous, with substantial variation in trial design, target selection, geographic distribution, and endpoint prioritization. A comprehensive analysis of the global clinical trial landscape is essential to contextualize current progress and identify unmet needs in this rapidly evolving field.
    Methods: We conducted a systematic landscape analysis of CAR-T-related clinical trials for NHL using the Trialtrove database. Interventional trials registered up to December 18, 2025, were retrieved using predefined search criteria. Eligible studies were screened according to standardized inclusion and exclusion criteria. Key trial characteristics, including trial status, phase, geographic location, sponsor type, molecular targets, and reported clinical endpoints, were extracted and analyzed descriptively.
    Results: A total of 360 eligible clinical trials were included in the final analysis. The global CAR-T clinical trial landscape in NHL is characterized by rapid expansion and a predominant focus on early-phase development. Trial activity is highly concentrated in a limited number of countries, with academic institutions serving as the primary drivers of clinical investigation. CD19-directed CAR-T therapies dominate the current landscape, although emerging diversification toward alternative targets is evident. Reported study endpoints largely emphasize safety and short-term efficacy, whereas durable clinical outcomes remain less frequently assessed, reflecting the exploratory nature of most trials.
    Conclusion: CAR-T therapy development in NHL continues to advance rapidly, driven by academic innovation and expanding preclinical insights. However, persistent challenges related to antigen escape, treatment durability, and trial design remain. Future progress will require the integration of next-generation CAR engineering strategies, broader incorporation of long-term clinical endpoints, and alignment with evolving regulatory and policy frameworks to support sustainable clinical translation.
    Keywords:  chimeric antigen receptor T cell; clinical trial landscape; immunotherapy; molecular targets; non-Hodgkin lymphoma
    DOI:  https://doi.org/10.3389/fimmu.2026.1820425
  13. Curr Top Microbiol Immunol. 2026 May 28.
    Adoptive T-Cell Immunotherapy.
    Stephen Gottschalk, Catherine M Bollard, Cliona M Rooney.
      Epstein-Barr virus (EBV) contributes to diverse malignancies defined by distinct patterns of viral latent antigen expression, which shape tumor immunogenicity and influence responsiveness to T-cell therapies. Adoptive transfer of EBV-specific T cells (EBVSTs) has demonstrated exceptional efficacy in posttransplant lymphoproliferative disease (PTLD), particularly after hematopoietic stem cell transplantation (HSCT), when donor-derived EBVSTs restore antiviral immunity, persist long term, and induce high response rates with minimal toxicity. Advances in manufacturing and the development of multispecific virus-specific T cells (VSTs) have increased accessibility, while "off-the-shelf" third-party products now enable urgent treatment and have achieved regulatory approval in Europe. Type 2 latency tumors such as Hodgkin lymphoma, non-Hodgkin lymphoma, and nasopharyngeal carcinoma remain more challenging due to restricted antigen expression and immunosuppressive tumor microenvironments. Strategies that enrich T cells targeting the type 2 latency antigens, LMP1, LMP2, EBNA1, and BARF1 have improved outcomes, but many patients require enhanced approaches to overcome tumor immune evasion. Genetic engineering technologies-resistance to immunosuppressive drugs, providing cytokine support, dominant-negative TGFβ receptors, chemokine receptors, and chimeric antigen receptors-offer promising avenues to improve persistence, trafficking, and antitumor potency. Collectively, the clinical experience underscores the safety, durability, and therapeutic potential of EBVSTs across EBV-associated diseases. Continued innovation in engineering and antigen targeting is poised to broaden VST applicability and support development of widely available cell therapies for EBV-associated and other cancers.
    Keywords:  EBV; EBV-associated malignancies; Genetically engineered T cells; Immunotherapy; T-cell therapy; Virus-specific T cells
    DOI:  https://doi.org/10.1007/82_2026_345
  14. Cytokine Growth Factor Rev. 2026 May 17. pii: S1359-6101(26)00040-7. [Epub ahead of print]90 26-38
    Cytokine-mediated intrinsic and extrinsic regulation of anti-tumor adoptive T cell therapy.
    Jing Hu, Jiayue Qiu, Tommy Chen, Bingfei Yu.
      Adoptive T cell therapy has transformed the treatment of hematologic malignancies but fails to control solid tumors, where T cell dysfunction and an immunosuppressive tumor microenvironment (TME) remain the central barriers. Cytokines are essential regulators of both T cell fate and the TME, making cytokine engineering a key lever for overcoming these limitations. Here we review recent advances in intrinsic strategies that embed cytokine support directly into the engineered T cell product and extrinsic strategies that deliver cytokines to the tumor site to remodel the TME, providing a comprehensive analysis to guide rational strategy selection and combination. We further highlight synthetic cytokine and receptor designs that induce novel T cell states beyond the boundaries of natural T cell biology. Finally, we propose virtual cytokine networks as a framework for predicting patient-specific immune cascades triggered by any designed cytokine intervention, providing a path toward personalized cytokine-guided adoptive T cell therapy.
    Keywords:  Adoptive T cell therapy; CAR-T therapy; Cancer immunotherapy; Cytokine engineering; Synthetic cytokine receptor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.05.002
  15. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00022-1. [Epub ahead of print]207 19-51
    Image analysis of mitochondria during T lymphocyte and chimeric antigen receptor (CAR) effector responses.
    Javier Ruiz-Navarro, Víctor Calvo, Manuel Izquierdo.
      Mitochondria play a central role in cellular metabolism, ATP production, and redox homeostasis, all of which are essential for sustaining T lymphocyte and CAR-T cell effector functions. Mitochondrial dysfunction has been linked to T cell and CAR-T cell exhaustion, reduced cell expansion capacity, and impaired tumor clearance. To investigate the contribution of mitochondria to T lymphocyte and CAR-T cell functionality, this protocol leverages advanced imaging analysis techniques to assess different parameters related to mitochondrial dynamics, structure and function, which may serve as indicators of both metabolic activity and the exhausted state of T cells. Specifically, the protocol focuses on measuring mitochondrial morphology, energization state, and mitochondrial translocation in the three-dimensional space. The image-based methodologies described in this protocol will contribute to a deeper understanding of mitochondrial regulation during T-cell and CAR-T cell responses. This knowledge will facilitate the identification of key metabolic vulnerabilities and support the refinement of therapeutic strategies to enhance T lymphocyte cytotoxic potential, ultimately improving clinical outcomes in T cell-based adoptive cancer immunotherapy.
    Keywords:  Actin cytoskeleton; Chimeric antigen receptor; Immune synapse; Mitochondria; T lymphocytes
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.022
  16. Front Immunol. 2026 ;17 1823841
    Regulatory T cell therapy in solid organ transplantation: mechanisms, translational progress, and remaining barriers.
    Jie Yang, Xusheng Zeng, Ke Jiang, Xiangli Pang, Ai Huang.
      The long-term outcomes of solid organ transplantation are constrained by alloimmune rejection and the toxicities of lifelong immunosuppression; durable tolerance therefore remains an unmet goal. Regulatory T cells are central mediators of peripheral tolerance, capable of restraining cellular and antibody-mediated rejection while shaping the intragraft inflammatory and repair milieu, supporting a mechanistic rationale for immunosuppression minimization. This review integrates key mechanisms by which Tregs regulate transplant immunity and summarizes evidence for Treg-directed interventions from preclinical studies to early clinical translation across liver, kidney, heart, and lung transplantation. To address the persistent gap between biological promise and inconsistent clinical efficacy, we organize translational barriers using a failure-mode perspective across the therapeutic continuum, encompassing product attributes and manufacturing quality, in vivo delivery and persistence, phenotypic stability under inflammatory stress, target engagement, and endpoint sensitivity. In addition, we outline a biomarker-driven evaluation approach centered on quantifiable proof-of-biology and clinically meaningful surrogate endpoints to enable patient stratification, dose/regimen optimization, and risk-controlled immunosuppression minimization. Together, advances in precision engineering, harmonized CMC standards, and mechanism-linked immune monitoring may facilitate reproducible and verifiable tolerance-oriented immunotherapies in solid organ transplantation.
    Keywords:  Treg cell therapy; biomarkers; regulatory T cells; solid organ transplantation; translational barriers; transplant tolerance
    DOI:  https://doi.org/10.3389/fimmu.2026.1823841
  17. Cells. 2026 May 15. pii: 913. [Epub ahead of print]15(10):
    Natural Killer (NK) Cells in Tumor Immunity: Limitations and Therapeutic Potential with a Focus on Nasopharyngeal Carcinoma and Comparison with T-Cell-Based Therapies.
    Anna Makowska, Udo Kontny.
      Natural killer (NK) cells are increasingly recognized as a complementary platform to T-cell-based cancer immunotherapies. Their innate, MHC-unrestricted recognition, capacity to mediate antibody-dependent cellular cytotoxicity (ADCC) and comparatively favorable toxicity profile have given rise to a broad therapeutic pipeline that includes cytokine-supported regimens, adoptive NK products, bispecific and trispecific NK engagers, and chimeric antigen receptor (CAR)-engineered NK cells. Clinical data, particularly in hematologic malignancies, show that NK-cell-based strategies can be safe and biologically active, although limited persistence, suboptimal trafficking and immune escape remain key challenges. Nasopharyngeal carcinoma (NPC), an Epstein-Barr virus (EBV)-driven epithelial cancer, illustrates how a tumor microenvironment (TME) can simultaneously impair NK function and create specific vulnerabilities that NK-focused therapies can exploit. This review summarizes NK biology and current therapeutic platforms, analyzes major limitations, highlights the specific context of NK-cell-based strategies in NPC and compares NK- and T-cell-based therapies with an emphasis on clinical translation.
    Keywords:  NPC; nasopharyngeal carcinoma; natural killer cells; tumor immunity
    DOI:  https://doi.org/10.3390/cells15100913
  18. Mol Ther Adv. 2026 Jun 11. 34(2): 201745
    A new fully closed automated banking process for healthy autologous cells to standardize the starting material for CAR T manufacturing.
    Zenghui Xu, Yuanjian Xu, Wei Ding, Jieying Chen, Yi He, Jiangrui Chen, Yan Sun, Xiaoliang Guo, Qijun Qian.
      Diseases, aging, and pharmacological interventions can all cause severe damage to human cellular functions. Cell therapy has become one of the most promising therapeutic approaches, and the preservation of healthy cells offers unlimited possibilities for disease treatment. While current biobanks fail to meet cell therapy requirements for starting materials, and allogeneic chimeric antigen receptor T (CAR T) cells using healthy donor cells faces immune compatibility challenges. The strategy of banking one's own cells during healthy states for future autologous cell therapy presents a promising alternative. Thus, we engineered the Baize Xin system-a fully closed, automated, good manufacturing practice (GMP)-compliant healthy autologous cell biobank system. It meets the standards for cell therapy starting materials, with a 27% increase in efficiency and a 50% reduction in cost. Moreover, it has been validated across multiple therapeutic manufacturing processes: (1) Clinical-grade CAR T cells via non-viral electroporation achieved >95% viability, 96.20 ± 0.68-fold expansion, and 36.88% ± 4.14% CAR positivity; (2) Cryopreserved and fresh leukapheresis materials show functional equivalency in generating CAR T cells; (3) Non-genetically edited activated T cells over 14 days maintained >95% viability, >200-fold expansion, and approached 100% CD3+ T cell purity. Critically, the resulting standardized cellular materials comply with China's National Medical Products Administration (NMPA) regulatory requirements (acceptance number CXSL2200605). This achievement represents a comprehensive advancement over existing biobanking technologies, providing pharmaceutical companies with a source of regulatory-compliant cellular materials for future therapies. It thereby offers a validated strategy to overcome key limitations in patient-derived autologous cell therapy.
    Keywords:  GMP system; baize xin system; cell therapy; cell therapy starting materials; fully-closed automated; healthy autologous cell biobank
    DOI:  https://doi.org/10.1016/j.omta.2026.201745
  19. J Transl Med. 2026 May 27.
    Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.
    Yulin Yang, Yuanjie Sun, Haobo Kang, Enqi Guan, Rui Liu, Kun Yang, Dongbo Jiang.
       BACKGROUND: CAR-T cell therapy represents a major breakthrough in hematological malignancies. However, the trade-off between insufficient treatment persistence and treatment-related toxicities (especially cytokine release syndrome, CRS) still limits its wider clinical application.
    MAIN BODY: Our review aims to reframe the understanding of this central dilemma. It posits that the dynamic imbalance of intracellular signaling networks and external inflammation in the tumor microenvironment (TME) are the causes of insufficient persistence of CAR-T cells and the severe CRS. The intracellular signaling network and the influence of the external TME jointly regulate CAR-T cell persistence and inflammatory response. We explore strategies for designing CAR-T cells that simultaneously enhance persistence and mitigate severe CRS risk. The next-generation goal is to achieve an optimal therapeutic outcome in which CAR-T cells exhibit sustained antitumor efficacy alongside a favorable safety profile.
    CONCLUSION: The central thesis posits that persistence and safety do not have to be chosen one at the expense of the other. Rather, the relationship between persistence and CRS exists in harmony. Through the precise modulation, it is feasible to simultaneously enhance CAR-T cell persistence while effectively mitigating CRS. This review paints a blueprint for the next-generation CAR-T cell therapies that are both more persistent and inherently safer.
    Keywords:  CAR-T cell; Cytokine release syndrome; Immunotherapy; Intracellular signaling; Persistence; TME
    DOI:  https://doi.org/10.1186/s12967-026-08299-4
  20. Mol Ther. 2026 May 26. pii: S1525-0016(26)00404-1. [Epub ahead of print]
    Engineering human T cells with antigen receptors for immune regulation in autoimmune disease and transplantation.
    Sonya Mangat, Karoliina Tuomela, Megan K Levings.
      Engineered cell therapies have revolutionized the treatment of immune disorders; most notably, chimeric antigen receptors (CARs) have been used to generate antigen-specific T cells capable of targeting and eliminating tumours. Ongoing research extends similar principles to induce immune tolerance in autoimmune diseases and transplantation, by leveraging the immunosuppressive properties of regulatory T cells (Tregs) and co-opting conventional T cells for tolerogenic applications. In this review, we highlight the diverse use of engineered antigen receptors to generate human T cell-based therapies, spanning a variety of disease contexts and focussing primarily on CAR Tregs. We further summarize work that aims to improve therapeutic potency and safety, including approaches to enhance suppressive pathways and optimize antigen receptor design and regulation. Finally, as CAR Tregs and similar therapies move to the clinic, we discuss the practical implications of translation and methods that utilize off-the-shelf products and in vivo gene delivery.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.05.017
  21. Stem Cell Rev Rep. 2026 May 26.
    Induced Pluripotent Stem Cell-Derived NK Cells as an Off-the-Shelf Platform for Cancer Immunotherapy: Opportunities, Challenges, and Clinical Translation.
    Shiva Mosadegh Manshadi, Maryam Mehravar, Abbas Hajifathali, Elham Roshandel, Saeid Kaviani Jabali.
      In recent years, off-the-shelf cellular immunotherapies have attracted much attention as a practical alternative to autologous therapies. Within this landscape, induced pluripotent stem cell-derived natural killer cells (iPSC-derived NK cells; iPSC-NK) have emerged as a highly versatile platform because they combine renewable starting material, batch-to-batch uniformity, favorable intrinsic safety, and amenability to precise genetic engineering.This review places iPSC-NK cells within the broader field of NK cell-based immunotherapy by comparing them with peripheral blood-derived NK cells, umbilical cord blood-derived NK cells, and NK cell lines, including clinically explored NK-92-based platforms, and by outlining key distinctions between NK cell therapies and CAR-T approaches. We summarize current strategies for iPSC-to-NK differentiation, spanning feeder-based systems, feeder-free protocols, embryoid body approaches, and scalable GMP-compatible manufacturing methods. We further discuss genetic engineering strategies for NK cells, with particular emphasis on genetic tuning as a systems-level framework for coordinating CAR signaling, cytokine responsiveness, and activation-inhibition balance to improve antitumor efficacy while preserving functional stability and clinical safety. In addition, this review examines translational challenges that continue to limit broader NK-cell adoption, including incomplete functional maturation, limited persistence, donor- and source-dependent variability, manufacturing standardization, cryopreservation, and quality-control requirements. Early clinical studies of iPSC-NK products indicate a favorable safety profile and preliminary antitumor activity in selected hematologic malignancies, although durable efficacy and broader validation in solid tumors remain to be established. Importantly, iPSC-NK cells should be considered one of several complementary NK-cell platforms rather than a definitive or universally superior strategy. Overall, current evidence supports iPSC-NK cells as a promising programmable off-the-shelf platform, but their ultimate clinical impact will depend on achieving reproducible large-scale manufacturing, balanced genetic engineering, and consistent in vivo performance relative to other NK-cell sources and established CAR-T therapies.
    Keywords:  Cancer immunotherapy; IPSC-derived NK cells; Induced pluripotent stem cell (iPSCs); Natural killer cells; Off-the-shelf cell therapy
    DOI:  https://doi.org/10.1007/s12015-026-11156-y
  22. Cells. 2026 May 12. pii: 874. [Epub ahead of print]15(10):
    Beyond Hematology-Current Insights into Chimeric Antigen Receptor (CAR) T-Cell Therapy for Skin and Connective Tissue Disorders.
    Agata Ciosek, Julia Hofmann, Kacper Galant, M Peter Marinkovich, Agnieszka Wierzbowska, Magdalena Ciążyńska, Natalia Bień, Joanna Narbutt, Aleksandra Lesiak.
      Chimeric antigen receptor (CAR) T-cell therapy represents a major advance in modern immunotherapy. This narrative review summarizes evidence from the past five years, including case reports, case series, and clinical trials, on its application beyond hematologic malignancies, focusing on autoimmune diseases such as systemic lupus erythematosus (SLE), systemic sclerosis (SSc), as well as solid tumors including melanoma and primary cutaneous lymphomas. CD19-directed CAR T-cells have demonstrated clinical benefits in SLE and SSc, with sustained immune reset, reduced autoreactive antibody levels, and clinical improvement. In melanoma, CAR T-cells targeting GD2, cMET, and CD20 have shown in vivo expansion and tumor infiltration; however, clinical efficacy remains limited, with transient stabilization or disease progression in most patients. In primary cutaneous lymphomas, early-phase studies with anti-CD70 and anti-CCR4.30 CAR T-cells indicate partial tumor regression and disease stabilization, often requiring additional therapy. Key challenges include limited durability of immune reset due to persistent plasma cells in autoimmune disorders, tumor heterogeneity, antigen loss or overlap, infiltration barriers, resistance mechanisms, and T-cell depletion in solid tumors, collectively reducing response durability and safety. The main toxicities include grade 1-2 cytokine release syndrome and rare hematologic complications, while immune effector cell-associated neurotoxicity syndrome is uncommon. Clinical translation remains limited and requires larger studies to improve efficacy and define safety profiles.
    Keywords:  CAR T-cell therapy; CD19; adoptive cell therapy; autoimmune diseases; chimeric antigen receptor T cells; cutaneous lymphoma; cytokine release syndrome; immunotherapy; melanoma; systemic lupus erythematosus; systemic sclerosis; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15100874
  23. Front Oncol. 2026 ;16 1810903
    Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges.
    Wenfang Hu, Zhongyu Zhang, Mengyao Pan, Weiye Wang, Zibing Wang.
      T-cell receptor-engineered T-cell (TCR-T) therapy has emerged as a promising strategy for solid tumors because it enables recognition of intracellular antigens presented by human leukocyte antigen (HLA) molecules, thereby extending targetability beyond cell-surface proteins. However, its clinical activity remains inconsistent because of HLA restriction, heterogeneous antigen expression, unstable antigen presentation, and an immunosuppressive tumor microenvironment. In this review, we summarize the biological basis of TCR-T therapy in solid tumors, including peptide-HLA recognition, target selection, antigen-presentation barriers, and mechanisms of tumor-cell killing. We then review current clinical progress across major solid tumor types, highlighting meaningful responses in selected biomarker-defined settings while noting that efficacy in many epithelial cancers remains limited. Current evidence further indicates that target recognition alone is insufficient for durable tumor control; sustained benefit also depends on preserved antigen presentation, effective tumor trafficking, resistance to suppressive signals, and maintenance of T-cell fitness. We also discuss emerging strategies to improve therapeutic performance, including precision receptor engineering, multi-HLA target development, microenvironment-focused armoring, and manufacturing optimization. Overall, TCR-T therapy provides a compelling framework for solid-tumor treatment, but broader and more durable benefit will require integrated advances in target selection, safety design, and cellular engineering.
    Keywords:  TCR-T therapy; adoptive cell therapy; antigen presentation; peptide–HLA; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1810903
  24. J Immunol. 2026 May 14. pii: vkag112. [Epub ahead of print]215(5):
    Preconditioning determines engraftment and therapeutic efficacy of anti-CD19 CAR-T cells in murine lupus.
    Jorge Romo-Tena, Shouvonik Sengupta, Carmelo Carmona-Rivera, Shuichiro Nakabo, Gyeong Min Kim, William G Ambler, Eduardo Patino-Martinez, Luz P Blanco, Victoria Hoffmann, Shairaz Shah, Jennifer Zeng, Ashley Mahne, Joseph K Cheng, Tom Van Blarcom, Mariana J Kaplan.
      Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as a promising therapeutic strategy for autoimmune diseases, including systemic lupus erythematosus. An unresolved question is how immunosuppressive preconditioning regimens influence CAR-T cell engraftment and therapeutic efficacy. In murine models, whole-body irradiation is required for optimal CAR-T cell engraftment. However, irradiation alone can ameliorate lupus disease, confounding attribution of CAR-T-specific effects. To delineate the contribution of CAR-T cells beyond irradiation, we investigated how conditioning intensity shapes immunologic and physiological outcomes in lupus-prone New Zealand Black/New Zealand White (NZB/W) F1 mice. We generated murine anti-CD19 CAR-T cells incorporating a CD28 costimulatory domain and compared their efficacy following low-, intermediate- and high-dose irradiation. High-dose irradiation induced disease improvement that limited mechanistic discrimination between irradiation- and CAR-T-mediated effects, whereas low-dose irradiation failed to support durable CAR-T cell engraftment. In contrast, an intermediate-dose irradiation regimen in 22-week-old mice achieved consistent CAR-T cell engraftment in lymphoid organs while minimizing irradiation-driven disease modulation. Under these conditions, CAR-T cell treatment induced significant depletion of B cells in blood and spleen, including naïve B cells, marginal zone B cells, and plasma cells, accompanied by reduced anti-double-stranded DNA antibody levels and prevention of renal disease progression. Collectively, these findings demonstrate that intermediate-intensity conditioning enables mechanistic separation of CAR-T-mediated immune remodeling from irradiation effects in murine lupus and provide a preclinical framework that aligns with the pressing need for reduced-intensity lymphodepletion strategies in human CAR-T therapy for autoimmune diseases.
    Keywords:  B cells; CAR-T cell therapies; lupus nephritis; murine lupus; systemic lupus erythematosus
    DOI:  https://doi.org/10.1093/jimmun/vkag112
  25. Front Immunol. 2026 ;17 1772001
    Regulatory T cell therapy in autoimmune and immune-mediated diseases: from basic research to clinical practice and future perspectives.
    Shihao Duan, Junyan Zhang, Zhongxiu Chen, Yong He, Yingzhi Zhang, Hong Guo.
      Regulatory T cells (Tregs) are pivotal immune modulators essential for maintaining immune homeostasis and preventing aberrant immune responses. In recent years, Treg-based therapies have emerged as a promising strategy for treating a variety of non-malignant diseases, including autoimmune disorders, transplantation-related complications, and allergic conditions. This review provides a comprehensive overview of the discovery and evolution of Tregs, detailing their immunoregulatory mechanisms that underpin their therapeutic potential. We systematically evaluate current clinical applications of Treg therapy in diverse non-tumor pathologies, highlighting both the efficacy and safety outcomes reported in ongoing clinical trials. Additionally, the review addresses the challenges faced in translating Treg therapies from bench to bedside, such as cell stability, expansion methodologies, and functional heterogeneity. Finally, we explore future directions in Treg research, including innovative therapeutic approaches, advances in gene engineering technologies, and improvements in cell expansion techniques, all aimed at enhancing the clinical translation and therapeutic efficacy of Treg-based interventions. This article aims to provide a thorough theoretical foundation and practical guidance to advance the application of Treg therapy in non-malignant diseases.
    Keywords:  CAR-Treg; adoptive cell therapy; autoimmune diseases; immune-mediated diseases; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1772001
  26. Cancer Gene Ther. 2026 May 28.
    Clinical landscape and development of universal CAR-T cell therapies.
    Jincai Zhou.
      
    DOI:  https://doi.org/10.1038/s41417-026-01043-6
  27. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00157-1. [Epub ahead of print]402 143-185
    Neoantigen-based TCR-T therapy in solid tumors.
    Wenjie Feng, Daichao Wu, Yukun Li.
      T-cell immunotherapy is an appealing cancer immunotherapy that consists mainly of modified T cells based on chimeric antigen receptors (CARs) and engineered T-cell receptors (TCRs). TCR-T cells have significant advantages over CAR-T for solid tumor treatment, with the ability to recognize antigens expressed on the cell surface and in the intracellular compartment, and have a lower risk of adverse effects due to the normal physiological T cell activation architecture of the TCR. This study aims to provide an overview of novel TCR-related cancer therapeutic targets to expand the application of TCR-T cell therapy, focusing on methods to identify novel antigens in patients and novel TCRs, and discusses the main current challenges of TCR-T, describing potential solutions to improve its safety and efficacy. Finally, we discuss the latest clinical research status of its above studies, providing new ideas to promote further development of TCR-T in the future.
    Keywords:  Neoantigen; Prediction algorithms; Solid tumor; TCR; TCR-T therapy
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.11.001
  28. Front Immunol. 2026 ;17 1822668
    Supercharging the metabolic engine: mitochondrial engineering strategies for CAR-T persistence in solid tumors.
    Soohyun Chun, Sanghyeon Yu, Hyun Gu Lee, Man S Kim.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in hematological malignancies, yet its efficacy in solid tumors is severely limited by the metabolically hostile tumor microenvironment (TME). Within this landscape, CAR-T cells undergo rapid functional exhaustion driven by mitochondrial dysfunction and metabolic insufficiency. This mini-review synthesizes emerging mitochondrial engineering strategies designed to restore metabolic fitness and persistence. We first examine the newly identified metabolic-epigenetic axis, where the pathological mitochondrial translocation of P4HA1 and the concomitant accumulation of oncometabolite succinate lock T cells in an exhausted state, and discuss how targeting this pathway restores progenitor subsets. Furthermore, we explore genetic reprogramming approaches, including "Envirotune" platforms that couple hypoxia-sensing elements (HRE) with enhanced glutamine transport (SLC38A2), and CRISPR-identified targets such as RHOG and FAS that prevent fratricide and apoptosis to preserve effector pools. Finally, we highlight the frontier of organelle medicine, focusing on intercellular mitochondrial transfer via tunneling nanotubes (TNTs) mediated by Talin-2, and emerging computational strategies to detect mitochondrial hijacking risk. By integrating these metabolic interventions, next-generation CAR-T cells can be engineered to overcome the TME's metabolic barriers, transforming them from transient effectors into long-lived, highly effective therapeutic agents.
    Keywords:  CAR-T cell therapy; T cell exhaustion; immunometabolism; metabolic reprogramming; metabolic-epigenetic axis; mitochondrial engineering; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1822668
  29. Healthcare (Basel). 2026 May 11. pii: 1299. [Epub ahead of print]14(10):
    From Concept to Claim: An Integrated Lifecycle Roadmap (ILR) for Patient-Centric Endpoints in Clinical Trials and Real-World Evidence.
    Moustafa Kardjadj.
      Background: Patient-centric endpoints increasingly influence clinical development, regulatory evaluation, and health technology assessment, yet the relevant methodological guidance remains distributed across separate domains. Estimands, digital health technologies, and real-world evidence are often addressed independently, making it difficult for sponsors to apply them within a single endpoint development strategy. This review synthesizes existing guidance and framework literature to organize these elements into a coherent lifecycle perspective for endpoint development. Methods: This semi-structured narrative review used a structured search of PubMed, Embase, and regulatory databases (FDA and EMA) for records published from January 2009 through December 2025. We synthesized authoritative guidance and peer-reviewed validation frameworks, including V3 and STaRT-RWE, and assessed landmark precedents (SV95C, ADAPTABLE, and RW-Response) selected a priori using pre-specified criteria for regulatory relevance, technical reporting, and first-of-kind pathway relevance. Results: The literature supports four recurring requirements for patient-centric endpoint development: early concept elicitation to establish meaningful aspects of health, explicit estimand specification to address intercurrent events, staged validation of digital measures under V3 principles, and formal validation of computable phenotypes for real-world evidence use. Across the reviewed sources, a recurring gap was the lack of an integrated framework linking these components across the evidence lifecycle. To address this, we organize existing guidance into an Integrated Lifecycle Roadmap that connects concept definition, measurement validation, causal inference, and real-world transportability. Conclusions: Patient-centric endpoints are most robust when they are developed as part of a continuous evidence lifecycle rather than as isolated study variables. The proposed roadmap does not introduce a new methodology, but it provides a practical structure for aligning existing regulatory and methodological frameworks to support scientifically rigorous and patient-relevant endpoint development.
    Keywords:  clinical outcome assessments; clinical trials; computable phenotypes; digital health technologies; estimands; patient-centric endpoints; real-world evidence
    DOI:  https://doi.org/10.3390/healthcare14101299
  30. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00018-X. [Epub ahead of print]207 53-74
    Analysis of murine CAR-T cell-mediated cytotoxicity in solid tumor models.
    Celia Martín-Otal, Álvaro Gómez-Morón, Noa Beatriz Martín-Cofreces, Teresa Lozano.
      Chimeric Antigen Receptor T-cell (CAR-T) based immunotherapy represents a ground-breaking advancement in the treatment of certain haematological malignancies, such as acute lymphoblastic leukemia (ALL) and multiple myeloma (MM), often leading to remarkable remission rates. Despite these successes, many patients relapse within the first-year post-treatment, highlighting a critical limitation of these therapies. Furthermore, translating the success of CAR-T therapies to solid tumors has been challenging, with limited clinical efficacy, highlighting the need for innovative designs and strategies to achieve durable responses. There is strong scientific interest in enhancing CAR-T antitumor efficacy in solid tumors. Current research efforts are focused primarily on two main strategies: first, the development of enhanced fourth- and fifth-generation CAR-T cells through genetic modification; and second, the optimization of the manufacturing protocols to improve cell quality and functionality. All these novel CAR-T cell designs must be rigorously characterized using standardized and robust protocols. In this review, we describe a protocol for generating murine CAR-T cells and, in detail, the methodology to assess their lytic capacity-both through a real-time impedance-based assay and a conventional endpoint cytotoxicity assay.
    Keywords:  CAR-T cells; Cell–mediated cytotoxicity; Flow cytometry; Impedance real time; Solid tumors
    DOI:  https://doi.org/10.1016/bs.mcb.2026.01.018
  31. Front Immunol. 2026 ;17 1818121
    Therapeutic cancer vaccines: navigating clinical translation and multimodal synergy.
    Tan-Huy Chu, Thuy Linh Huynh, Le-Tri Phuong.
      Over the past decades, the field of cancer treatment has been revolutionized by cancer immunotherapy. With therapeutic cancer vaccines (TCVs) are emerging as a promising strategy capable of eliciting potent and lasting T cell responses against cancer cells. While theoretically potent, the translation of TCVs into consistent clinical success remains an evolving challenge. Therefore, this review provides a comprehensive overview of TCVs, traversing from fundamental TCVs concepts, epitope spreading, antigen selection, and delivery platforms, to the current clinical landscape. We specifically examine the transition from monotherapy to innovative combination regimens and propose a translational concept of the strategic utility of TCVs in targeting minimal residual disease (MRD). Despite significant immunogenic potential, the clinical impact of TCVs is currently constrained by the manufacturing hurdles, immunosuppressive tumor microenvironment (TME), patient heterogeneity, and evaluation of outcomes. By addressing these barriers through rational therapeutic approaches and optimized patient selection, TCVs may offer a promising pathway for integration into future clinical paradigms to improve patient outcomes.
    Keywords:  cancer immunotherapy; epitope spreading; minimal residual disease; therapeutic cancer vaccines; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1818121
  32. J Mark Access Health Policy. 2026 Apr 28. pii: 25. [Epub ahead of print]14(2):
    Impact of Market Access Delays on Time to Patient Access: Multi-Country Comparative Analysis Assessing the First Commercial Launch Indications for Five Oncology Medicines Across Europe and Canada.
    Barry Crean, David Parry, Alison Horsfield, James Ryan, Nektarios Oraiopoulos.
      Background: The benefit of pharmaceutical innovation manifests when patients access treatment. Following regulatory approval in Europe and Canada, reimbursement decisions depend on health technology assessments (HTAs), which can be prolonged. To quantify the impact of delays on patients, we evaluated market access timelines for olaparib, osimertinib, durvalumab, acalabrutinib, and trastuzumab deruxtecan across six high-income countries with established HTA systems (Canada, England, France, Germany, Italy, Spain). Methods: Time to access was from regulatory approval to reimbursement. Survival benefit was median overall survival (OS) and progression-free survival (PFS) assessed versus the comparator at approval and the latest data cut-off. The number of eligible patients per year multiplied by the years to patient access and survival benefit reflects the lost survival benefit. Results: Efficacy benefits observed at approval continued to the latest data cut-offs. The mean time to patient access was 18 months. Although this varied by country and treatment, with England and Germany typically being the fastest and France and Spain the slowest, timelines often exceeded the 180-day EU target despite identical evidence used in HTA submissions. This resulted in an estimated mean of 2836 patients being unable to access treatment and 3391 OS-derived and 2739 PFS-derived life-years lost. Conclusions: Access processes must evolve to ensure the timely realization of new medicines' benefits.
    Keywords:  health technology assessment; life-years lost; market access process; oncology medicines; regulatory approval; reimbursement; survival benefit; time to patient access
    DOI:  https://doi.org/10.3390/jmahp14020025
  33. Mult Scler Relat Disord. 2026 May 23. pii: S2211-0348(26)00310-X. [Epub ahead of print]111 107274
    Building sustainable multiple sclerosis registries in Latin America: A practical framework for real-world evidence generation and healthcare access.
    Juan I Rojas, Liliana Patrucco, Edgardo Cristiano, Jefferson Becker, Diego H Giunta.
      Real-world evidence (RWE) plays an increasingly important role in multiple sclerosis (MS) and related disorders, complementing randomized clinical trials by capturing effectiveness, safety, treatment persistence, and access patterns in routine care. In Latin America (LATAM), fragmented healthcare systems and structural inequities in access to diagnosis, magnetic resonance imaging (MRI), biomarkers, and high-cost therapies underscore the need for regionally applicable real-world data.
    OBJECTIVES: To provide a practical methodological framework for the design, implementation, and sustainability of clinical registries in LATAM, drawing on regional experience in MS and neuromyelitis optica spectrum disorder (NMOSD).
    DESIGN/APPROACH: Narrative review integrating methodological principles for registry development with lessons learned from the implementation of multicenter MS registries in LATAM. Key domains analyzed include definition of objectives, core dataset selection, representativeness, bias mitigation, governance, data quality assurance, ethical considerations, and sustainability strategies.
    RESULTS: Clinical registries, when based on clearly defined objectives and essential minimum variables, enable standardized longitudinal data collection in routine practice. Regional experience highlights recurrent challenges, including selection bias toward high-complexity centers, missing data, operational burden, and governance conflicts. Pragmatic strategies-such as core datasets, progressive center inclusion, predefined authorship rules, and early dissemination of results-improve feasibility and long-term sustainability. Registries also provide actionable evidence on diagnostic timelines, treatment initiation, persistence, and access disparities, supporting clinical, regulatory, and health technology assessment decisions.
    CONCLUSIONS: Well-designed clinical registries represent a strategic platform for generating high-quality RWE in MS and related disorders in LATAM. By combining methodological rigor with operational pragmatism, registries can quantify healthcare gaps, enhance regional collaboration, and contribute to more equitable and evidence-informed decision-making.
    Keywords:  Clinical registry; Healthcare access; Latin America; Multiple sclerosis; Real-world evidence
    DOI:  https://doi.org/10.1016/j.msard.2026.107274
  34. J Mark Access Health Policy. 2026 May 07. pii: 30. [Epub ahead of print]14(2):
    Between Rigor and Relevance: Why the EU HTA Guidelines on Indirect Comparisons Miss the Mark.
    Samuel Aballéa, Mondher Toumi, Piotr Wojciechowski, Emilie Clay, Bruno Falissard, Steven Simoens, Pascal Auquier, Stefano Capri, Renato Bernardini, Joerg Ruof, Frank-Ulrich Fricke, Oriol Sola Morales, Laurent Boyer.
      Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group's (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies.
    Keywords:  European Union health technology assessment (EU HTA); indirect treatment comparison (ITC); joint clinical assessment (JCA); matching-adjusted indirect comparison (MAIC); network meta-analysis (NMA); population-adjusted indirect comparisons (PAICs); simulated treatment comparison (STC)
    DOI:  https://doi.org/10.3390/jmahp14020030
  35. Blockchain Healthc Today. 2026 ;9(1):
    Zero-Knowledge Process Verification: A Comprehensive Framework for a Distributed Healthcare System.
    Sathya Krishnasamy.
       Objective: This article introduces the ZK-PRET Business Process Prover framework that integrates Object Management Group (OMG) business process standards with zero-knowledge cryptographic verification to enable privacy-preserving healthcare process compliance across distributed systems.
    Methods: We developed a multilayer architecture combining formal business process modeling, zero-knowledge proof generation, and regulatory compliance verification. The framework extends established OMG standards with cryptographic verification capabilities to achieve verifiable compliance, privacy preservation, and regulatory accountability. Implementation testing were conducted in synthetic data environments designed to represent real-world healthcare scenarios.1 These environments enable comprehensive modeling and testing of multi-entity process orchestration patterns while maintaining privacy protections essential for healthcare research and development. All scenarios, clinical examples, and process expressions presented in this article utilize synthetic data to ensure no real patient data, clinical records, or identifiable health information were used.
    Results: The ZK-PRET Business Process Prover framework demonstrates practical applicability across many healthcare domains, including treatment planning, telemedicine coordination, healthcare administration, consumer health services, multientity clinical trials, and supply chain management. Implementation results demonstrate cryptographic verification capabilities that enable mathematical prevention of regulatory violations rather than post hoc detection. The results demonstrate configurable privacy preservation through zero-knowledge verification and consistent proof sizes suitable for modeling complex orchestrations, while leveraging already widely used Web 2 process models suitable for multiple runtime deployment topologies.
    Conclusions: Zero-knowledge healthcare process verification represents a foundational technology for regulatory compliance in distributed healthcare systems. While agentic AI systems present important opportunities for automation, the underlying requirement for verifiable process compliance through cryptographic means brings broader challenges. ZK-PRET Business Process Prover addresses these challenges in healthcare transformative flows, enabling safer deployment of autonomous systems while maintaining regulatory standards.
    Keywords:  AI agents; BPMN 2.0; distributed ledger technology; healthcare compliance; healthcare interoperability; privacy preservation; regulatory verification; zero-knowledge proofs
    DOI:  https://doi.org/10.30953/bhty.v9.430
  36. Cardiol Rev. 2026 May 25.
    Pre-emptive and Prophylactic Strategies to Prevent Cardiovascular and Neurotoxicity in Chimeric Antigen Receptor T-Cell Therapy: The Role of Tocilizumab, Anakinra, and Cytokine-Targeted Interventions.
    Jatin Thukral, Ninaad Sindhwani, Kuldeep Khan, Pyush Moudgil, Rohan Singla, Khushi Garg, Riya Kaushal Shah, Harbir Kaur, Nikhil Thukral, Siddharth Pravin Agrawal, William H Frishman, Wilbert S Aronow.
      Chimeric antigen receptor T-cell therapy has revolutionized the treatment of hematological malignancies but is associated with significant immune-mediated toxicities, particularly cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, driven by an exaggerated inflammatory response involving cytokines such as interleukin (IL)-6, IL-1, and tumor necrosis factor-alpha. These processes contribute to endothelial dysfunction and a spectrum of cardiovascular complications, including hypotension, arrhythmias, myocardial dysfunction, and heart failure. The underlying pathophysiology involves complex interactions between immune activation and vascular injury, often progressing rapidly and necessitating early recognition. Contemporary management is shifting from reactive treatment to proactive strategies, emphasizing early risk stratification using clinical parameters, biomarkers, and imaging, alongside timely intervention with cytokine-directed therapies such as IL-6 and IL-1 inhibitors. Integration of cardiology within multidisciplinary care teams is essential for optimizing outcomes through tailored monitoring and management of cardiovascular complications. As chimeric antigen receptor T-cell therapy expands to broader and higher-risk populations, including those with pre-existing cardiovascular disease, a structured cardio-oncology approach and further prospective research are critical to improving safety and long-term outcomes.
    Keywords:  CAR-T therapy; ICANS; anakinra; cardio-oncology; cardiotoxicity; cytokine modulation; cytokine release syndrome; endothelial dysfunction; risk stratification; tocilizumab
    DOI:  https://doi.org/10.1097/CRD.0000000000001327
  37. Med Sci (Basel). 2026 May 10. pii: 248. [Epub ahead of print]14(2):
    Artificial Intelligence Across the Drug Development Lifecycle.
    Grigory Demyashkin, Mikhail Parshenkov, Sergey Zyryanov, Alexander Yavorskiy, Petr Shegai, Andrey Kaprin.
      Artificial intelligence (AI) is becoming a central driver of change across the drug development lifecycle. However, its integration is evolving so rapidly that it remains essential to understand how these technologies are currently positioned within the field. Because reliable access to high-quality (effective and safe) drugs is essential to public health, the pharmaceutical product lifecycle (PPL) offers a coherent framework for evaluating how AI can enhance evidence and data creation across all stages. To understand where AI genuinely adds value, this review examines its contribution across the major stages of the PPL. Rather than treating drug discovery, nonclinical evaluation, clinical research, and post-marketing assessment as separate domains, we view them as a continuous chain of data, where digital technologies enhance different decision points in distinct ways. In early discovery, AI narrows the search space by integrating diverse datasets to prioritize candidates most likely to succeed. Nonclinical models increasingly rely on machine-learning systems designed to improve the human relevance of safety predictions. Within clinical trials, AI supports cohort formation, real-time monitoring, and new analytic strategies that supplement empirical evidence. Case studies from leading pharmaceutical companies illustrate that the most meaningful advances emerge when AI is embedded not as a standalone tool but as part of a broader data strategy that links information across stages. Taken together, current evidence suggests that AI is beginning to transform data generation and integration throughout the PPL. Given the accelerating pace of digital innovation, it is essential for the field to maintain continuous awareness of emerging methodologies and evolving regulatory frameworks to ensure that these technologies are implemented in a reliable, transparent, and scientifically grounded manner.
    Keywords:  artificial intelligence; clinical trials; drug development; drug discovery; machine learning; nonclinical trials; precision medicine
    DOI:  https://doi.org/10.3390/medsci14020248
  38. Epidemiologia (Basel). 2026 May 05. pii: 64. [Epub ahead of print]7(3):
    Evidence Synthesis via Indirect Treatment Comparisons in the European Framework of Joint Clinical Assessment.
    Alberto de la Cuadra-Grande, María Arruñada, Alejandro García-Solís, Ana Rossignoli-Montero, Miguel Ángel Casado.
      The application of the Health Technology Assessment Regulation (HTAR) gives way to joint European work, such as the Joint Clinical Assessment (JCA). This requires the definition of a PICO (Population-Intervention-Comparator-Outcome) question representative of all the member states of the European Union. The key to answering the PICO will be the synthesis of evidence through direct comparisons when there are randomized clinical trials (RCTs) including the same comparators, and via indirect treatment comparisons (ITCs) when comparators differ across RCTs. The aim of this report is to provide a synthesized and clear methodological framework to guide those stakeholders involved in JCAs when interpreting the results of ITCs, including descriptions on: (1) assumptions associated with ITCs; (2) how to select the method for ITC; (3) strengths and limitations associated with the methods; and (4) basics for understanding the method for ITC. This methodological framework could help those health care institutions, patient associations, consumer organizations, health-related nongovernmental organizations, health technology developers, and healthcare professionals involved in JCAs to better understand ITCs and incorporate this evidence into decision-making.
    Keywords:  PICO; health technology assessment; indirect treatment comparison; joint clinical assessment; matching-adjusted indirect comparison; network meta-analysis; simulated treatment comparison
    DOI:  https://doi.org/10.3390/epidemiologia7030064
  39. Pharmaceutics. 2026 Apr 30. pii: 551. [Epub ahead of print]18(5):
    Boosting the Activity of Melanoma-Targeting CAR-T Cells in the Presence of Citrate by the Application of Gluconate.
    Dennis Christoph Harrer, Sebastian Haferkamp, Wolfgang Herr, Maria Mycielska, Jan Dörrie, Niels Schaft, Hinrich Abken, Konstantin Drexler.
      Background: Chimeric antigen receptor (CAR) T cells achieve cure in the therapy of hematological malignancies. In solid tumors, however, CAR-T cells face an immunosuppressive tumor microenvironment (TME) which crucially impedes their cytotoxic capacities. Citrate accumulating in the TME is a crucial metabolite in mediating immune suppression and is consumed by cancer cells promoting growth of various tumors, including melanoma; blocking the citrate transporter pmCiC with gluconate abrogates citrate-mediated tumor growth. Methods: To bolster treatment of melanoma, we explored gluconate as adjuvant for CAR-T cell therapy. Results: First, gluconate did not impair CAR-T cell functional capacities with regard to cytotoxicity, cytokine secretion, and persistence in a "stress test" based on repetitive antigen stimulation with cognate cancer cells. The addition of gluconate antagonized the citrate-mediated enhanced proliferation of melanoma cells. As a consequence, the elimination of citrate-boosted melanoma cells by CSPG4-specific CAR-T cells was augmented in the presence of gluconate. Conclusions: Taken together, these data suggest that counteracting citrate-mediated enhanced tumor growth with gluconate may improve the cytotoxic activity of CAR-T cells against melanoma.
    Keywords:  CAR-T cell; adoptive T cell therapy; citrate; gluconate; melanoma; tumor microenvironment
    DOI:  https://doi.org/10.3390/pharmaceutics18050551
  40. Mol Ther Adv. 2026 Jun 11. 34(2): 201754
    External controls for rare disease drug development: Lessons for emerging and advanced therapeutic modalities.
    Samuel H Hughes, Lauren A Beretich, Matthew Fuller, Kimberly Goodspeed, Melissa Penn, Leonard A Valentino, Caitlin McCombs.
      External controls, particularly natural history studies, play an increasingly important role in rare disease therapeutic development where traditional randomized trials are often infeasible. This review examines regulatory acceptance patterns for gene and cell therapies approved between 2019 and 2025, analyzing successful cases like onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy and elivaldogene autotemcel (Skysona) for cerebral adrenoleukodystrophy alongside unsuccessful applications. Key success factors include systematic data collection, clinically meaningful endpoints, appropriate patient matching, and disease characteristics that preclude randomization. Recent FDA initiatives, including the Rare Disease Evidence Principles program, signal growing regulatory flexibility, although acceptance remains context-dependent and requires robust data quality standards.
    DOI:  https://doi.org/10.1016/j.omta.2026.201754
  41. Health Policy. 2026 Mar 24. pii: S0168-8510(26)00052-7. [Epub ahead of print]171 105615
    Coverage with evidence development programs: a scoping review on characteristics and patient access.
    Joost G E Verbeek, Rianne L Seefat, Erica A Wilthagen, Agnes Jager, Sabine C Linn, Valesca P Retèl, Wim H van Harten.
       BACKGROUND: Coverage with Evidence Development (CED) programs aim to balance early patient access to promising health technologies with robust evidence generation. However, whether these programs truly accelerate access and facilitate swift integration of health technologies into standard care remains unclear.
    OBJECTIVES: This study evaluates CED characteristics, timelines from application to coverage decisions, and key factors influencing patient access.
    METHODS: We conducted a scoping review. Study eligibility was assessed by one reviewer and verified on a random sample by a second reviewer. Data extraction was performed independently by two reviewers. From the existing literature on patient access in CED programs, we identified factors affecting timely access. Additionally, we conducted an in-depth analysis of the longest and shortest CED programs for each type of health technology.
    RESULTS: Our search identified 2,839 peer-reviewed articles and grey literature sources. We examined 347 sources in this review, revealing 136 finalized CED programs across eight countries (1995-2025). The average time from application to coverage decision was 73.7 months (range: 6-215 months, SD: 36.6). We identified 18 factors influencing patient access, with early identification of decision uncertainties, horizon scanning, and active stakeholder engagement helping to accelerate the evaluation process. However, slow patient accrual often delayed early access.
    CONCLUSIONS: CED programs vary widely in effectiveness, with delays in implementation affecting patient access. Systematic identification of decision uncertainties and streamlining evaluation processes are crucial for optimizing these programs. This study provides five key recommendations to enhance the efficiency of CED programs, ensuring that promising health technologies reach patients faster and more equitably.
    Keywords:  Biomedical / organization & administration; Cost-benefit analysis; Coverage with evidence development; Diffusion of innovation; Evidence-based medicine; Health policy; Health services accessibility / economics; Reimbursement mechanisms; Technology assessment
    DOI:  https://doi.org/10.1016/j.healthpol.2026.105615
  42. Mol Ther Adv. 2026 Jun 11. 34(2): 201749
    Efficient NK cell transduction with VSV-G-pseudotyped lentiviral vectors.
    Emmi Järvelä, Jan Koski, Farhana Jahan, Antti Tuhkala, Mira Saari, Manar Elmadani, Kari Salokas, Laurens Veltman, Lotta Andersson, Erja Kerkelä, Hekim Can, Marie Nyman, Seppo Ylä-Herttuala, Markku Varjosalo, Diana Schenkwein, Henrik Paavilainen, Kim Vettenranta, Matti Korhonen, Helka Göös.
      The need for safe, allogeneic cell therapies for cancer is driving a growing interest in CAR-NK-based therapies, which, unlike CAR-T cell therapies, offer the potential for off-the-shelf administration. Lentiviruses pseudotyped with vesicular stomatitis virus glycoprotein G (VSV-G) are commonly used for genetic modification of cell therapy products. Their use in NK cells, however, is limited by low transduction efficiency. This study explores the complexities of NK cell transduction using lentiviral vectors pseudotyped with VSV-G. We demonstrate that efficient transduction depends on multiple factors, such as NK cell activation, domain organization of CAR construct, lentivirus pseudotype selection, and the use of transduction enhancers. By optimizing these elements, we achieved effective transduction, facilitating the use of VSV-G-pseudotyped lentiviral vectors for therapeutic NK cell production. Our optimized workflow comprises NK cell activation with interleukins, followed by transduction with an NK-cell-specific CAR construct using VSV-G-pseudotyped LVs in the presence of BX795 and retronectin, resulting in excellent transduction efficiency (91% using GFP and 80% using CAR) without compromising NK cell phenotype, growth, or cytotoxicity. This allows for the use of a widely used gene transfer vector with an excellent safety record for producing therapeutic NK cell products.
    Keywords:  BX795; CAR-NK; VSV-G; chimeric antigen receptor; natural killer cell; retronectin; transduction; vesicular stomatitis virus glycoprotein
    DOI:  https://doi.org/10.1016/j.omta.2026.201749
  43. Front Immunol. 2026 ;17 1707783
    Data-driven computational modeling of CAR-T cell function.
    Viren Shah, Justin A Womack, Katie Palen, Bryon D Johnson, Peiman Hematti, Tyce J Kearl, Nirav N Shah, Scott S Terhune, Ranjan K Dash.
       Introduction: The complex dynamics of chimeric antigen receptor T-cell (CAR-T cell) cytotoxicity and proliferation are potential factors that influence the clinical response to CAR-T therapy. The patient-specific functionality of CAR-T products play a role in these dynamics. CAR-T products comprise phenotypically and functionally distinct populations of cells that impact therapy response in different ways. We hypothesized that product-specific parameters exist that predict individual patient responses to therapy and that these can be elucidated by simulating the interactions of CAR-T products and tumor cells using an in vitro assay-based model.
    Methods: We use an ordinary differential equation (ODE)-based pharmacokinetic (PK) and pharmacodynamic (PD) model to characterize key CAR-T cell functional parameters. Parameters for the model developed using our method are product-specific and derived from in vitro assays performed on individual patient CAR-T products from clinical trial NCT04186520.
    Results: Our results demonstrate that while considerable variability is present in in vitro cytotoxicity kinetics and subsequently estimated model parameters between each product, these differences do not predict early (28 days) or late responses (90 days) after treatment across the total cohort of patients investigated. However, we show that differences in an estimated model parameter for increased CAR-T cell responsiveness to tumor cytotoxicity are correlated with durable therapy responses (no relapse through 180 days). Additionally, in a cohort of diffuse large B-cell lymphoma (DLBCL) patients, we demonstrate that a model parameter estimating cooperativity between CAR-T cells is also correlated with durable therapy responses and that may be related to differences in CD4:CD8 ratios in the CAR-T cell product.
    Conclusions: Overall, our work demonstrates that while pre-treatment CAR-T cell functional parameters vary on a patient and product basis, these parameters do not predict initial therapeutic responses. We find that initial therapeutic responses are possible across a range of initial product kinetic parameters. However, we observed that their potentially exist unique kinetic properties associated with the initial product that is predictive of disease relapse.
    Keywords:  CAR-T cell cytotoxicity kinetics; CAR-T cells; CAR-T cellular differentiation; CAR-T therapy; chimeric antigen receptor; computational modeling; mathematical modeling
    DOI:  https://doi.org/10.3389/fimmu.2026.1707783
  44. J Natl Compr Canc Netw. 2026 May 26. 1-8
    Incorporating the Next Generation of Immunotherapies Into the Treatment of Multiple Myeloma.
    Kevin C Miller, Ross S Firestone, Malin Hultcrantz.
      Immunotherapies have recently changed the treatment landscape of multiple myeloma (MM). CAR T cells and T-cell-redirecting bispecific antibodies (BsAbs) yield impressive responses and extend survival in patients with relapsed/refractory MM. There are now 2 BCMA-directed CAR T-cell products and 4 BsAbs (3 targeting BCMA, 1 targeting GPRC5D) currently approved by the FDA for relapsed/refractory MM, in which they demonstrated considerable efficacy. These drugs are now being evaluated in early treatment settings, including as part of frontline regimens for newly diagnosed MM. Importantly, administration of CAR T-cell therapy and BsAbs necessitate careful attention to unique toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cytopenias, and heightened infection risk. This review summarizes the current landscape of immunotherapy in MM, including perspectives on sequencing CAR T-cell therapy and BsAbs. It also discusses ongoing clinical trials evaluating immunotherapy in new combinations and treatment contexts. Immunotherapies have become a key component of the MM therapeutic armamentarium and are poised to assume an even larger role in the coming years.
    DOI:  https://doi.org/10.6004/jnccn.2026.7004
  45. Life (Basel). 2026 Apr 28. pii: 736. [Epub ahead of print]16(5):
    A Focused Comparative Review of Innovative Therapeutics Across Autoimmune and Chronic Inflammatory Diseases.
    Harisa Hibić Kaknjašević, Emina Dervišević, Almir Fajkić, Azra Hodžić, Alexander Chupin, Emina Karahmet Sher.
      Chronic inflammatory diseases and autoimmune diseases are overlapping but distinct immune-mediated disorders that represent a growing worldwide health concern, characterised by persistent inflammation, tissue damage, and progressive organ dysfunction. In the United States alone, more than $180 billion is spent annually on managing these conditions, yet fewer than 10% of patients achieve long-term remission. These figures highlight the limitations of conventional therapies, which often control symptoms rather than adequately modify the underlying disease process. This review provides a focused and comparative overview of emerging therapeutic strategies across representative immune-mediated disorders, with particular emphasis on mesenchymal stem cells, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, chimeric antigen receptor T-cell therapies, therapeutic vaccines, microbiome-modulating interventions, and nanotechnology-based drug delivery systems. In parallel, artificial intelligence (AI) is increasingly contributing to biomarker discovery, drug repurposing, and treatment stratification, thereby supporting the development of predictive and personalised medicine. Overall, these advances support a shift toward mechanism-based, multimodal, and more durable treatment strategies, although further clinical validation remains necessary.
    Keywords:  JAK inhibitors; autoimmune diseases; biologics; chronic inflammatory diseases; immune-mediated disorders; nanotechnology-based drug delivery; precision medicine
    DOI:  https://doi.org/10.3390/life16050736
  46. J Am Acad Dermatol. 2026 May 28. pii: S0190-9622(26)02787-8. [Epub ahead of print]
    Secondary T-cell lymphomas after CAR T-cell therapy in dermatology.
    Jonathan J Park, Cuong V Nguyen, Sukul Mittal, Jennifer N Choi, Joan Guitart.
      
    Keywords:  CAR T-cell therapy; CTCL; T-cell lymphoma; T-cells; dermatology; immunology; lymphoma; oncodermatology; oncology
    DOI:  https://doi.org/10.1016/j.jaad.2026.05.089
  47. Inflamm Regen. 2026 May 30.
    Generation of therapeutic T cells from human induced pluripotent stem cells.
    Bo Wang, Shin Kaneko.
      T cell exhaustion remains a critical barrier in treating chronic infections and cancer. To overcome this, our laboratory has established a platform for generating "rejuvenated" T cells from induced pluripotent stem cells (iPSCs). This review outlines our research trajectory, transitioning from the foundational autologous "T-iPSC" concept to scalable, "off-the-shelf" allogeneic strategies. We detail the establishment of clinical-grade, xeno-free manufacturing protocols and the integration of advanced gene editing-including functional enhancement through intracellular signaling modulation, immune rejection-related gene editing to minimize immunogenicity, and optimization of synthetic receptor architectures to mitigate the risk of Graft-versus-Host Disease (GvHD) while enhancing targeting efficiency. Furthermore, we describe our activity on generating regulatory T cells from iPSC for managing autoimmune disorders and GvHD. Finally, we discuss the remaining challenges and the future roadmap for translating these therapeutic T cells into clinical practice.
    DOI:  https://doi.org/10.1186/s41232-026-00425-5
  48. Med Res Rev. 2026 May 25.
    Synthesis and Clinical Application of Small-Molecule Drugs Approved by FDA in 2025.
    Liang Chang, Min Wang, Huijie Zhang, Zhen Li, Zixuan Song, Lijie Zhao, Fengli Jiang, Jiao Wang, Yuan Quan.
      In 2025, the U.S. Food and Drug Administration (FDA) continued to advance therapeutic innovation by approving a diverse range of novel drugs. According to the FDA's 2025 Novel Drug Approvals list, 46 new drugs received approval, including both new chemical entities such as Ziftomenib, Sevabertinib, Zoliflodacin, and Gepotidacin, as well as new biologics. These approvals cover a wide range of therapeutic areas, including oncology, rare genetic diseases, infectious diseases, cardiovascular diseases, and immunomodulation. A significant proportion of the approved products navigated accelerated or priority review pathways, reflecting their potential impact on unmet medical needs. This review provides a comprehensive overview of the synthetic routes and clinical applications of FDA-approved small-molecule drugs in 2025, aiming to inspire future development in drug discovery.
    Keywords:  2025; FDA; clinical applications; synthesis
    DOI:  https://doi.org/10.1002/med.70064
  49. J Egypt Natl Canc Inst. 2026 May 28. pii: 30. [Epub ahead of print]38(1):
    Artificial intelligence in cancer immunotherapy: current trends in predicting response and personalizing treatment.
    Eloghosa Aisosa Nosa-Ihaza, Emmanuel Chidera Edeh, Wol Bol Geng, Ebenezer Okenwa.
      Artificial intelligence (AI) can transform cancer immunotherapy by enabling more accurate prediction of treatment responses, the discovery of specific biomarkers, and the development of personalised treatment plans. Traditional single-marker biomarkers (PD-L1, TMB, MSI) lack consistency across tumour types and cannot be used to assess tumour heterogeneity or the dynamic tumour microenvironment (TME). This review synthesises developments in multimodal AI models that combine genomics, transcriptomics, radiomics, digital pathology (pathomics), circulating biomarkers, and clinical evidence to create composite predictive signatures with significantly better discriminatory value. AUCs over 0.8 have been seen in a few retrospective studies with deep learning and ensemble models on whole-slide images, CT/MRI/PET radiomics, spatial and single-cell omics, and multi-omics fusion models, but prospective and multicentre validation is scarce, and external validation often shows deterioration in performance. AI is also used to enhance the translational pipelines of adoptive cell therapies (e.g., CAR-T) by improving patient selection, manufacturing (e.g., digital twins), and early toxicity prediction (e.g., CRS, ICANS). Nevertheless, clinical implementation remains hindered by data heterogeneity, bias, poor longitudinal validation, limited reproducibility, and a lack of transparency in most models, even though prospective, multicenter validation and explainable AI are crucial for clinician trust and regulatory acceptance. New systems such as federated learning, foundation models, spatial omics, digital twins, and wearable monitoring represent paths to generalizable, privacy-preserving, and actionable systems in clinical practice. To achieve the potential of AI, the generation of data will need to be standardized, reporting must be transparent, interdisciplinary, and regulatory frameworks must be strengthened focusing on the practical use of AI and patient safety. By taking these steps, AI could be shifted to prospective clinical decision support, which uses AI to meaningfully enhance personalization and outcomes in cancer immunotherapy based on a retrospective research tool.
    Keywords:  Artificial intelligence; Biomarker discovery; Cancer immunotherapy; Precision oncology; Treatment response prediction; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s43046-026-00371-w
  50. Am J Clin Oncol. 2026 May 25.
    The Landscape of Clinical Trials for TCR-T Cell Therapy.
    Xingcan Fan, Tao Yu, Qiuyu Liao, Yulin Song, Gang Liu.
      T cell receptor-engineered T cell (TCR-T) therapy represents an innovative tumor immunotherapy. Distinct from CAR-T, it recognizes MHC-restricted antigens to target tumor-specific antigens, exhibiting unique advantages for both solid and hematologic malignancies. To clarify the main trends, key targets, and therapeutic indications of TCR-T therapy, this study systematically summarizes the landscape of TCR-T-targeted clinical trials based on rigorous screening of the Trialtrove database, including 260 trials before April 1, 2026. Descriptive statistics were used to analyze the trials in terms of phase, status, distribution, disease indications, primary targets, and investigational drugs. Overall, TCR-T clinical research maintains sustained enthusiasm, dominated by early-phase trials (phase I and phase I/II, accounting for 88.85%), with active trials (open and planned) accounting for 51.92% and a considerable proportion of terminated trials (21.92%). Geographically, trials are concentrated in the United States and China, which serve as core collaboration nodes, with obvious geographical clustering characteristics in regional collaboration networks. In terms of disease indications, TCR-T therapy is more focused on solid tumors, with unspecified solid tumor, non-small cell lung cancer, and head/neck cancer as the top 3 indications. NY-ESO-1 is the most prominent target, followed by MAGE-A4, KRAS, PRAME, HPV16 E6/E7, and HBV surface antigen, with letetresgene autoleucel and LioCyx-M004 being the most investigated TCR-T products. Collectively, TCR-T therapy is a promising field in tumor immunotherapy with continuous research investment and advancing clinical progress.
    Keywords:  T cell receptor-engineered T cell; cancer; clinical trial
    DOI:  https://doi.org/10.1097/COC.0000000000001335
  51. J Ayurveda Integr Med. 2026 May 26. pii: S0975-9476(26)00027-6. [Epub ahead of print]17(3): 101343
    Navigating the regulatory landscape of herbal medicines: A global comparison of India, China, Europe, the United States and Japan.
    Anil Tukaram Pawar, S B Chandrasekar, M P Venkatesh.
      The use of herbal medicines is expanding rapidly worldwide, but regional regulatory systems vary greatly, leading to variations in quality, safety and efficacy. Varying legal frameworks, insufficient quality control and gaps in post-market surveillance create challenges in ensuring the reliability of herbal products. This study aims to analyze and compare the regulations that oversee herbal medicines in five major regions: India, China, Europe, the United States and Japan, highlighting key challenges and proposing recommendations for improving global regulatory alignment. Data were collected from official regulatory websites and scholarly articles. Additionally, the study tracked the progress of related regulations, advancements in scientific research, and the evolving infrastructure in the respective five geographical areas. The study examined regulatory components, including licensing requirements, pre-market validation, quality control and post-market surveillance across these five regions. Regulatory approaches vary significantly: Europe and Japan emphasize pre-market validation and scientific evidence, while the U.S. relies more on post-market monitoring. India and China integrate traditional practices with modern regulatory frameworks. These differences pose challenges for ensuring consistent safety and quality standards globally. Potential solutions involve adopting Good Manufacturing Practices (GMPs), harmonizing pharmacopoeial standards and leveraging emerging technologies such as artificial intelligence for quality assurance and supply chain transparency. Achieving global regulatory harmonization is crucial for ensuring the safety and efficacy of herbal medicines while preserving traditional knowledge. Strengthening international collaboration, enforcing standardized quality measures, and integrating scientific validation into traditional systems can enhance consumer confidence and facilitate international trade in herbal medicines.
    Keywords:  Herbal medicine; Regulatory authorities; Regulatory requirements
    DOI:  https://doi.org/10.1016/j.jaim.2026.101343
  52. Nature. 2026 May;653(8116): S66-S68
    Drugs that boost immunity are making lung cancer less deadly.
    Tammy Worth.
      
    Keywords:  Cancer; Diseases; Drug discovery; Medical research; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-026-01455-2
  53. Sci Transl Med. 2026 May 27. 18(851): eadx1799
    Efficacy and safety of durcabtagene autoleucel in a phase 1 trial for patients with relapsed/refractory multiple myeloma.
    Adam S Sperling, Benjamin A Derman, Sarah Nikiforow, Alejandro Alonso, Shuntaro Ikegawa, Nina Orwitz, David S Quinn, David Pearson, Dexiu Bu, Pedro Milanez-Almeida, Jennifer Mataraza, Omar Nadeem, Jessica Liegel, Anita D'Souza, Allison Charles, Marc Credi, Jerome Ritz, Andrzej J Jakubowiak, Serena De Vita, Nikhil C Munshi.
      Traditional manufacturing of B cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cell therapies is prolonged, leading to reduced patient access, T cell exhaustion, and consequently limiting therapeutic efficacy. To address this issue, we developed durcabtagene autoleucel, a BCMA-directed CAR T cell therapy manufactured using a rapid platform aimed at preserving T cell stemness. Here, we present the primary findings of part A of a phase 1 study (NCT04318327) of durcabtagene autoleucel in patients with relapsed/refractory multiple myeloma (r/r MM). The primary objective was safety; secondary objectives included response rates, cellular kinetics, immunogenicity, and manufacturing feasibility. Durcabtagene autoleucel was successfully manufactured for all 55 patients (median vein-to-vein time, 24 days) and given as a single infusion at one of four flat target doses (2.5 × 106 to 20 × 106 CAR T cells). Among all patients, the overall response rate was 98%, and the stringent complete response rate was 55%. Eighty percent of evaluable patients (35 of 44) achieved minimal residual disease negativity. There were no unexpected safety findings and no reports of delayed neurotoxicity. Immunophenotyping and transcriptomic analyses confirmed preservation of a stem-like phenotype in the manufactured final product. On the basis of the safety, efficacy, and cellular expansion results from the phase 1 trial, a phase 2 trial (NCT05172596) was initiated to further explore the efficacy and safety of durcabtagene autoleucel in heavily pretreated patients with aggressive r/r MM.
    DOI:  https://doi.org/10.1126/scitranslmed.adx1799
  54. J Int Med Res. 2026 May;54(5): 3000605261425080
    Virtual cell: Current perspectives and future prospects.
    Jinming Li, Hengheng Zhang, Weiwei Zhang, Na Li, Fuxing Zhao, Guoshuang Shen.
      Virtual cell is an emerging technology that integrates multiple disciplines, including biology, computer science, and artificial intelligence, to simulate cellular structures and functions. Compared with traditional methods, virtual cell technology offers a more holistic approach, enabling efficient simulation of cellular dynamics and prediction of biological phenomena. This technology holds significant potential in fields such as precision medicine, drug discovery, and synthetic biology. The development of virtual cells is driven by advancements in single-cell sequencing, subcellular imaging, and computational power, with platforms such as environment for cell simulation (E-Cell) and cell packing (CellPACK) enabling simulations across multiple biological scales. However, challenges remain, including data integration, model interpretability, and computational costs. Despite these challenges, virtual cell technology has made advances in drug development, disease research, and synthetic biology, offering a promising tool for personalized medicine and improving research accuracy. In the future, virtual cell technology is expected to find broader applications in cross-species simulations, quantum computing, and interdisciplinary collaborations.
    Keywords:  Virtual cell; artificial intelligence; computational modeling; drug discovery; precision medicine
    DOI:  https://doi.org/10.1177/03000605261425080
  55. Br J Pharmacol. 2026 May 24.
    Emerging therapeutic opportunities for psychedelic and related drugs.
    Susan Wonnacott, Gary J Stephens, Trevor Sharp.
      Increasing interest in psychedelic and related drugs as potential therapies for a wide spectrum of difficult-to-treat conditions, that extend beyond neuropsychiatric disorders, provided the impetus for this themed issue. This collection of reviews and original articles includes the mechanistic basis of how these drugs act, the current status of preclinical research and progress in clinical trials, and insight into the regulatory processes that determine clinical approval. In this editorial, we introduce these aspects and provide an overview of current controversies and challenges in the field, as well as highlighting the exciting potential that these drugs offer.
    DOI:  https://doi.org/10.1111/bph.70485
  56. J Integr Neurosci. 2026 May 19. 25(5): 50563
    Digital Twins in Neurology Care: Evidence, Limitations, and a Path Forward.
    Parisa Gazerani.
      Digital twins are increasingly promoted in neurology as an advancement beyond conventional artificial intelligence, yet the term is often applied without conceptual or methodological rigor. Strict definitions describe digital twins as dynamically updated, bidirectionally linked models that generate predictive, decision-relevant value, criteria rarely met by current neurological applications. This Opinion critically examines the state of digital twins across major neurological domains, including dementia, multiple sclerosis, Parkinson's disease, epilepsy, stroke, pain, and migraine. We argue that most existing systems are more accurately described as twin-inspired longitudinal decision-support or trial-analytics models rather than true clinical digital twins. While neurology is well-suited to digital twin approaches due to disease heterogeneity, multimodal data, and iterative care pathways, progress is limited by gaps in measurement validity, uncertainty handling, prospective evaluation, and governance. A pragmatic path forward is proposed, emphasizing question-specific, validated neurological digital twins over overgeneralized brain twin narratives, and suggesting that much of the current field is better understood as twin-inspired modeling rather than true clinical digital twin implementation.
    Keywords:  artificial intelligence; clinical decision support; digital twins; longitudinal modeling; neurology; personalized medicine
    DOI:  https://doi.org/10.31083/JIN50563
  57. Blockchain Healthc Today. 2026 ;9(1):
    Blockchain Technology to Enhance Clinical Data Management in Healthcare: A Systematic Literature Review.
    Khaoula Chafik, Mohamed Hanine, Abdellah Ouaguid, Sulieman Alshuhri.
      This systematic review examines how blockchain is applied in clinical data management (CDM) and what prevents its adoption in healthcare. A structured search in Scopus and Web of Science retrieved 554 records; after applying inclusion/exclusion criteria and quality assessment, 32 studies published between 2018 and 2024 were included. The analysis was guided by five research questions: (1) how blockchain supports clinical data workflows; (2) its role in data security and privacy; (3) key technical challenges and commonly used technologies; (4) integration with other healthcare technologies, and (5) how does blockchain technology integrate with and enhance other emerging healthcare technologies? Findings show that blockchain can support consent management, secure data sharing, traceability, and tamper-resistant audit trails using smart contracts and decentralized access control. It is also positioned as a trust layer for electronic health records, the Internet of Medical Things, artificial intelligence, and telemedicine by ensuring integrity and controlled access to sensitive clinical data. However, several barriers limit real-world deployment. Reported challenges include limited scalability and throughput, difficulty integrating with legacy electronic health record systems, heterogeneous regulatory requirements, and the complexity of encoding privacy, consent, and compliance into smart contracts. Ethereum and Hyperledger Fabric are the most frequently implemented platforms, often combined with off-chain storage and interoperability standards such as Fast Healthcare Interoperability Resources (FHIR)/Substitutable Medical Applications and Reusable Technologies on FHIR. Overall, blockchain shows strong potential to improve security, transparency, and cross-institution exchange in CDM, but its viability depends on addressing scalability, interoperability, and governance constraints. However, the evidence base remains heterogeneous, and only a minority of studies report quantitative benchmarks or real-world deployments, which limits cross-study comparability and generalizability.
    Keywords:  HL7 FHIR interoperability; audit trail; blockchain; clinical data management; consent management; healthcare; smart contracts
    DOI:  https://doi.org/10.30953/bhty.v9.471
  58. Folia Microbiol (Praha). 2026 May 27.
    Gut microbiota and cancer immunotherapy: from dysbiosis to personalized immune checkpoint blockade optimization.
    Fatima Akram, Salika Zainab, Ifrah Shabbir, Ikram Ul Haq.
      Cancer has become one of the most prominent causes of death worldwide due to its increasing mortality rate. Immune checkpoint blockade therapy is an effective regimen for tumor control. Still, it faces challenges, including primary resistance and interindividual variations, thereby directing the field towards a new era of immunotherapy adjuncts. Recent studies have shown that the microbiota of cancer patients influences the outcomes of ICB (immune checkpoint blockade) therapy through microbiome-immune system crosstalk. Homeostatic commensal microbial consortia aid in combating tumors by enhancing immunity, whereas dysbiotic microbes facilitate cancer development by mediating immunosuppression. Microbiota modulation via microbiome-targeted interventions, including fecal microbiota transplantation or washed microbiota transplantation from responders, biotic supplements, and dietary modifications, can convert primary resistance to durable responses and thus augment immunotherapy responsiveness in cancer treatment. This review discusses the dual nature of microbiota in mediating the development and treatment of cancer, its crucial role in shaping ICB therapy responsiveness, and the identification of microbial biomarkers into a refined Discovery-Validation-Clinical (DVC) pipeline linked to multi-omics profiling and personalized microbiome-modulation interventions for ICB therapy optimization. In addition, it presents the translational clinical decision framework that highlights patient stratification, intervention timing, and implementation barriers to support clinical translation. Ultimately, the gut microbiome emerges as a "force multiplier" of cancer ICB therapy, thereby enabling microbiome-guided precision oncology and strengthening a roadmap toward personalized cancer care.
    Keywords:  Cancer; Immunometabolism; Immunotherapy; Microbiota; Modulation; Personalization
    DOI:  https://doi.org/10.1007/s12223-026-01515-0
  59. Eur J Microbiol Immunol (Bp). 2026 May 27. pii: 1886.2026.00023. [Epub ahead of print]
    Therapeutic effects of Lentinan in gastrointestinal inflammation and carcinogenesis - A scoping review of evidence from preclinical and clinical studies.
    Jennifer S Scholz, Stefan Bereswill, Markus M Heimesaat.
      Lentinan, a β-(1,3)-glucan derived from the mushroom Lentinus edodes, is known for its health-beneficial including anti-oxidant, anti-inflammatory, and anti-tumor effects particularly in the gastrointestinal tract, and even regarded as adjuvant in cancer treatment in Asia. There is, however, a knowledge gap regarding lentinan's clinical application and the underlying mechanisms of its pleiotropic effects. This prompted us to perform a scoping review summarizing current knowledge of lentinan's health-promoting and disease-alleviating properties in the gastrointestinal tract and beyond. Preclinical and clinical studies revealed protective and therapeutic effects of the compound in distinct gastrointestinal pathologies, including colitis, chemotherapy- and immunosuppression-induced intestinal injury, infection models as well as in colorectal carcinogenesis by modulating intestinal epithelial barrier integrity, immune signaling, and microbiota composition. Lentinan was reported to exert its anti-tumor effects by interfering with apoptosis, autophagy, stemness, and angiogenesis. Notably, lentinan enhanced the effectiveness of chemotherapy and chimeric antigen receptor T-cell (CAR-T) therapy, reduced treatment-related adverse events, improved survival and quality of life. The observed effects were dependent on lentinan's molecular weight, dose, and route of administration. In conclusion, lentinan application constitutes a promising intervention strategy in gastrointestinal and extra-intestinal including systemic morbidities that should be further investigated in preclinical and clinical studies.
    Keywords:  Lentinan; Shiitake mushrooms; adjuvant anti-tumor therapy; anti-inflammatory properties; carcinogenesis; gastrointestinal cancer therapy; gut-liver axis; immunomodulatory effects
    DOI:  https://doi.org/10.1556/1886.2026.00023
  60. Cytotherapy. 2026 Feb 11. pii: S1465-3249(26)00064-2. [Epub ahead of print]28(7): 102102
    Yeast surface display meets immunotherapy: unlocking the potential of T cells.
    Jie Wang, Yukun Li, Jinglong Shi, Zhouchi Yao, Ping Yuan, Sizhe Li, Hong Wang, Guodong Chen, Weiguo He, Daichao Wu.
       BACKGROUND AIMS: While T-cell receptors (TCRs) hold immense therapeutic potential, their clinical translation is bottlenecked by the scarcity of high-affinity, specific clones and the instability of recombinant formats. Existing display technologies fall short: phage display often fails to produce properly folded TCRs, and mammalian display is low-throughput. This review is the first to comprehensively synthesize how yeast surface display (YSD) is uniquely positioned to overcome these hurdles and build a new pipeline for TCR based drug discovery.
    METHODS: We articulate how YSD's eukaryotic machinery enables the robust expression and engineering of complex TCRs and peptide-MHC (pMHC) libraries. We then critically catalog and evaluate pioneering strategies where YSD has been used to evolve TCRs with enhanced affinity and stability while minimizing cross-reactivity and discover novel antigenic targets through unbiased library-to-library screening.
    RESULTS: By mapping this largely pre-clinical landscape, our work establishes a foundational framework that bridges fundamental protein engineering with future therapeutic applications.
    CONCLUSIONS: We conclude by outlining a translational roadmap, arguing that YSD derived molecules are poised to become the cornerstone of safer, more effective, and personalized T-cell therapies.
    Keywords:  ScTCR; T cell; T cell receptor; TCR Cancer immunotherapy; Yeast surface display (YSD)
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102102
  61. Nat Rev Endocrinol. 2026 May 26.
    T cell activity is boosted after meals.
    Senegal Carty.
      
    DOI:  https://doi.org/10.1038/s41574-026-01263-8
  62. Pharmaceuticals (Basel). 2026 Apr 24. pii: 663. [Epub ahead of print]19(5):
    Delivery of mRNA Therapeutics Beyond Infectious Diseases: Design Innovations and Applications in Oncology, Cardiovascular, and Rare Genetic Diseases.
    Snehitha Akkineni, Mahek Gulani, Samir A Kouzi, Martin J D'Souza, Mohammad N Uddin.
      Empowered by nanotechnology, messenger RNA (mRNA) therapeutics have shown a rapid evolution post COVID-19 from a conceptual platform to a clinically validated modality, and they diversified into oncology, cardiovascular diseases, and rare disorders. As a template for in situ protein production, it offers several advantages over traditional proteins and DNA drugs. The intrinsic stability of mRNA and its sensitivity to innate immune sensing hinder its capacity for immediate cellular entry, necessitating its need for a delivery system to obtain optimal therapeutic potential. This review explores the innovations in nanocarrier engineering, design principles for lipid nanoparticles-mRNA (LNPs) platforms, and their clinical translation across the prominent indications. It also addresses their safety, immunogenicity, and scalability while addressing the key limitations and manufacturing scalability through comparative platform analysis. Although LNPs usually dominate their delivery through encapsulation and manufacturability, their limitations, like repeat dose reactogenicity and liver tropism, require next-generation designs like SORT lipids, stimuli-responsive hybrids for extrahepatic targeting. In oncology, LNP-mRNA drives the neoantigen vaccines, and rare diseases leverage the transient enzyme replacement. While the safety profiles highlight the innate immune tuning through nucleoside mods and lipid biodegradability, chronic administration risks are still persistent. While there are novel scalability options like microfluidic mixing to support the production gaps in organ selectivity and durability, their adoption is hindered. We outline the future directions to perceive mRNA's full potential as a broader therapeutic class.
    Keywords:  design principles; lipid nanoparticles; mRNA; mRNA therapeutics; nanocarrier engineering
    DOI:  https://doi.org/10.3390/ph19050663
  63. Biomedicines. 2026 May 16. pii: 1129. [Epub ahead of print]14(5):
    Toward Precision Health in Autoimmunity and Immune-Related Adverse Events: The Autoantibody Reactome, Spatial Omics, and Multimodal Data Integration.
    Allan Stensballe.
      The autoantibody reactome refers to the multidimensional repertoire of antibody reactivities against self-antigens across the human proteome or selected antigenic compartments. This offers a scalable systemic layer for precision immunology across spontaneous autoimmunity and treatment-induced immune toxicity. Autoimmune diseases and immune-related adverse events (irAEs) share major features of dysregulated immunity, yet clinically useful tools for risk stratification, early detection, endotyping, and treatment guidance remain limited and slow. A central challenge is that tissue pathology is highly informative but not uniformly accessible across diseases and organ systems, whereas routine serology captures only a narrow fraction of immune heterogeneity. In this perspective, I argue that a global autoantibody reactome can serve as a central unifying framework linking systemic immune history, tissue pathology, and clinical trajectories across autoimmune disorders and irAEs. Rheumatoid arthritis (RA) provides a strong prototype because its serological diversity, major role of post-translationally modified autoantigens, and marked synovial heterogeneity allow reactome features to be interpreted against tissue biology. Immune checkpoint inhibitor-associated inflammatory arthritis serves as an illustrative rheumatic irAE and a model of treatment-induced immune dysregulation with clear opportunities for longitudinal blood-based profiling. Spatial transcriptomics and proteomics are therefore positioned not as stand-alone solutions, but as mechanistic tools that can decode reactome-defined immune states within tissue microenvironments where tissue is accessible. Clinical translation will require integration of autoantibody reactomes with tissue, circulating proteomic, imaging, genetic, and clinical data through transparent multimodal models, as well as a shift from exploratory resources such as AAgAtlas toward analytically validated and clinically interpretable biomarker panels for risk prediction, endotyping, monitoring, and biomarker-guided intervention. This perspective outlines technical and strategic steps toward clinically actionable decision support, including risk stratification before ICI initiation and treatment guidance for patients who develop ICI-induced inflammatory arthritis, through integration of autoantibody reactome profiling, spatial omics and transparent multimodal AI.
    Keywords:  autoantibody reactome; autoimmunity; immune-checkpoint inhibitors; immune-related adverse events; rheumatoid arthritis
    DOI:  https://doi.org/10.3390/biomedicines14051129
  64. J Med Internet Res. 2026 May 25. 28 e82380
    Exploring Technological Solutions for Interoperability Between Patient Electronic Medical Records and Clinical Registries: Scoping Review.
    Erika Haynes, James Brannigan, Jessica Suna, Reid Malseed, Alana Delaforce, Rachel Mulvenney-Fenner, Katherine Alog-Daroya, Karin Plummer, Craig McBride, Roy Kimble, Bronwyn Griffin.
       Background: The use of electronic medical records (EMRs) and clinical registries has transformed health care delivery by improving data management, care coordination, and research capacity. However, the full potential of these technologies can only be realized through effective interoperability, thereby reducing the burden of manual data entry and enhancing the use of real-world clinical data.
    Objective: This review examines technologies that enable automated data extraction and transfer, which promote interoperability between EMRs and clinical registries.
    Methods: A search of PubMed, CINAHL, Embase, and Web of Science, including studies published between January 2013 and April 2025, was registered with Open Science Framework a priori and involved three key concepts: (1) "registry," (2) "electronic medical records," and (3) "interoperability." A 2-phase screen identified studies evaluating technologies that facilitate automated data extraction or interoperability. Automation was defined as fully automated, where data are extracted and transferred without human intervention, or semiautomated, where extraction or transfer is predominantly automated but may include manual validation. Only technologies supporting ongoing database integration were eligible for inclusion. Screening, data extraction, and synthesis were conducted by multiple independent reviewers. Technology experts provided extensive input and guidance throughout to ensure the accuracy and relevance of the extracted information.
    Results: Overall, 36 studies met the inclusion criteria, representing 12 countries across 5 continents and addressing a wide range of acute and chronic health conditions. Epic was the most frequently reported EMR system, while the most common registry platforms were REDCap (Research Electronic Data Capture; Vanderbilt University), structured query language (SQL) server database, and EMR-embedded solutions. Most approaches centered around extracting data from structured formats (n=18), or a combination of both structured and unstructured formats (n=10), emphasizing the central role of structured EMR data in current automated extraction approaches.
    Conclusions: This review advances understanding of interoperability between EMRs and clinical registries by uniquely examining automated and sustainable solutions for data exchange, extending beyond prior work that has largely focused on technologies designed for isolated systems or study-specific data extraction. A novel contribution of this review is the synthesis of context-specific considerations derived from reported implementations, providing a comprehensive overview of how technology selection and implementation are shaped by the context in which they are deployed. While these advancements have reduced reliance on inefficient, error-prone, and resource-intensive manual processes, ongoing challenges in data standardization, seamless integration, and long-term sustainability are compounded by poor and inconsistent reporting across studies. Future efforts should follow comprehensive reporting guidelines, adhere to robust governance principles, and incorporate implementation science frameworks, to not only enable meaningful comparison and synthesis in future research, but also to ensure that technologies can be effectively, feasibly, and sustainably integrated within health care contexts, while upholding the ethical and equitable use of health care data.
    Keywords:  data extraction; data transfer; electronic medical record; interoperability; registry
    DOI:  https://doi.org/10.2196/82380
  65. JAMIA Open. 2026 Jun;9(3): ooag074
    The governance of health data in the AI era: a scoping review and computational topic model of the global research landscape.
    L Raymond Guo, Shuimei Liu.
       Background: The integration of artificial intelligence (AI) into health care is critically dependent on vast quantities of patient data, igniting an urgent global debate on data ownership, privacy, and governance. While numerous perspectives exist, the empirical structure and evolution of this scholarly discourse remain uncharacterized. We aimed to systematically map the conceptual landscape of research on AI and health data governance to identify its core themes, temporal trends, and key focus areas.
    Methods: We conducted a scoping review according to PRISMA guidelines, searching PubMed, Scopus, and Web of Science for peer-reviewed articles published between January 1, 2018, and May 31, 2025. We performed a descriptive analysis of publication trends. Using Latent Dirichlet Allocation (LDA), we applied computational topic modelling to the abstracts, which serve as concise summaries of each article's core contributions, to identify latent thematic structures. Topic trends were analyzed using linear regression.
    Findings: Forty-three articles met the inclusion criteria. The volume of publications has increased substantially since 2018. Our LDA analysis identified five distinct research topics: (1) AI Applications & Ownership, (2) AI Models & Data Privacy, (3) Data Sharing Platforms & Technology, (4) Ethical & Legal Concerns, and (5) AI Development & Implementation. Over the study period, research on Ethical & Legal Concerns showed a statistically significant increasing trend in prevalence (slope = 0.023, P = .008), becoming the most dominant topic in recent years.
    Interpretation: The scholarly discourse on AI and health data has matured, shifting from foundational questions of technical implementation towards a dominant focus on complex ethical and legal challenges. This data-driven evidence signals an urgent need for clinical leaders and policymakers to move beyond theoretical discussions and implement robust, practical governance frameworks. Failure to address this governance gap risks impeding trustworthy AI innovation and eroding public trust, thereby limiting the potential of AI to improve patient outcomes equitably.
    Keywords:  artificial intelligence; data governance; data ownership; health information management; topic model
    DOI:  https://doi.org/10.1093/jamiaopen/ooag074
  66. Pharmaceutics. 2026 May 07. pii: 577. [Epub ahead of print]18(5):
    Engineered Plant-Derived Extracellular Vesicles: A Novel Strategy for Tumor-Targeted Therapy.
    Yuan Zuo, Jinying Zhang, Xinxin Wang, Bo Sun, Shuo Tian, Mingsan Miao.
      Cancer remains a leading cause of premature death worldwide, posing a significant burden due to its high incidence and mortality. Radiotherapy and chemotherapy remain the most well-established and effective modalities in the current oncological therapeutic arsenal. However, their efficacy is often limited by toxicities owing to their non-selective targeting of rapidly dividing cells and consequent damage to healthy tissues. In recent years, advances in nanomedicine and biotechnology have drawn increasing attention to plant-derived extracellular vesicles (PDEVs) as an emerging, promising strategy for cancer therapy. As novel therapeutic vehicles, PDEVs offer key advantages, including high biocompatibility and low immunogenicity. However, their clinical translation has been significantly hampered by inherent limitations, including insufficient targeting specificity, low and uncontrollable drug-loading efficiency, and challenges in large-scale production and standardization. Current research is actively focused on overcoming these drawbacks through engineering strategies, for instance, surface modification with targeting peptides or antibodies to enhance targeting, alongside optimization of production and drug-loading processes. These developments underscore the potential of PDEVs as a promising platform for next-generation targeted cancer therapeutics. This review provides a comprehensive overview of PDEVs, covering their isolation, biogenesis, physicochemical properties, and anticancer applications. While summarizing these fundamental aspects, this review focuses on engineering strategies to enhance their active targeting capacity, offering theoretical insights to support their future role in cancer treatment.
    Keywords:  artificial bionic; cancer; covalent and noncovalent modifications; drug delivery; engineered plant-derived exosome-like nanovesicles; nanocarriers; surface modification
    DOI:  https://doi.org/10.3390/pharmaceutics18050577
  67. Nature. 2026 May;653(8116): S65
    Science takes on the world's most lethal malignancy.
    Herb Brody.
      
    Keywords:  Cancer; Diseases; Drug discovery; Health care; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-01381-3
  68. Cureus. 2026 Apr;18(4): e107497
    AI-Enabled Inclusive Oral-Systemic Integrated Care (AI-IOC+): An Equitable, Learning Framework for Managing Polypharmacy, Multimorbidity, and Special Health Needs Throughout Life.
    Sumeet Agarwal, Laresh N Mistry, Ashwin M Jawdekar, Deepak Sharma, Harsh Mishra, Sayem A Mulla.
      Increased polypharmacy, ineffective resource use, and worse results for people with chronic illnesses, especially older folks and those with specific healthcare needs, are all consequences of the fragmentation of dental and medical services. Few frameworks integrate AI with oral-systemic integration and a life-course, equity-centered approach, despite the fact that AI offers scalable potential to integrate diverse health data, improve clinical decision-making, and promote proactive population health management. Predictive risk modeling for oral-systemic disease clustering, adaptive patient and caregiver interfaces for special populations, AI-assisted clinical decision support, including medication reconciliation and contraindication alerts, and a learning health-system feedback mechanism to optimize care pathways are all included in the proposed AI-Enabled Inclusive Oral-Systemic Integrated Care (AI-IOC+) framework. The AI-IOC+ model, which places a strong emphasis on sustainability, fairness-by-design, data interoperability, and governance, seeks to improve early detection and prevention of systemic complications associated with oral disease, improve access and continuity of care for vulnerable populations, lower adverse drug events through AI-supported deprescribing, and increase healthcare efficiency by reducing duplication. With future prospects including focused scoping reviews, stakeholder co-design pilots, and health economic assessments to enable widespread implementation, this approach offers policymakers, academics, and healthcare systems a useful road map.
    Keywords:  ai-ioc+; artificial intelligence; dentistry; health; health technology
    DOI:  https://doi.org/10.7759/cureus.107497
  69. Am J Health Syst Pharm. 2026 May 25. pii: zxag149. [Epub ahead of print]
    Emerging trends impact drug expenditure.
    Denise Scarpelli.
      
    Keywords:  GLP-1; biosimilars; cell therapy; drug expenditure; federal regulations; gene therapy
    DOI:  https://doi.org/10.1093/ajhp/zxag149
  70. Curr Oncol. 2026 May 20. pii: 298. [Epub ahead of print]33(5):
    Optimizing the Efficacy-Toxicity Paradigm in Pediatric Oncology: A Narrative Review of Immunotherapy and Survivorship Outcomes.
    Zaure Dushimova, Timur Saliev, Aigul Bazarbayeva, Kymbat Karimova, Abay Kussainov, Ildar Fakhradiyev.
       BACKGROUND: Childhood cancer survival now approaches 80% in high-income countries, yet most survivors face lifelong toxicity. This review examines the interplay between treatment efficacy, relapse prevention, and therapy-related complications.
    METHODS: Narrative synthesis of landmark pediatric oncology trials (2000-2026), including AALL1731 (blinatumomab), ELIANA/PLAT-02 (CAR T-cell), and GD2-CART01 (neuroblastoma), with comparative analysis of efficacy and toxicity.
    RESULTS: In AALL1731, adding blinatumomab to chemotherapy improved 3-year disease-free survival from 87.9% to 96.0% (HR = 0.39, 95% CI: 0.27-0.56, p < 0.001), but increased sepsis from 5.1% to 14.8%. Comparison between AALL1731 (front-line blinatumomab) and ELIANA (CAR T-cell in relapsed disease) reveals that earlier immunotherapy deployment yields better outcomes: 96% DFS vs. 48% 3-year EFS, respectively. In GD2-CART01, early use (after 1-2 prior lines) achieved 89% 5-year survival vs. 43% with delayed use (HR = 0.31). Approximately 95% of survivors experience ≥1 late effect, with 60-90% carrying chronic conditions into adulthood.
    CONCLUSIONS: Immunotherapy transforms outcomes, but timing is critical, as earlier deployment dramatically improves survival. Toxicity remains pervasive, requiring systematic mitigation strategies.
    Keywords:  blinatumomab; immunotherapy; leukemia; neuroblastoma; pediatric; relapse prevention
    DOI:  https://doi.org/10.3390/curroncol33050298
  71. Pharmaceuticals (Basel). 2026 Apr 28. pii: 696. [Epub ahead of print]19(5):
    From Algorithms to Assets: A Comprehensive Review of AI's Role in Preclinical Drug Discovery and the Hurdles to Clinical Translation.
    Mengqi Cai, Tiancai Liu.
      The integration of artificial intelligence (AI) and big data is poised to significantly augment drug research and development, offering the potential to address persistent challenges such as lengthy timelines and high failure rates. This review provides a critical overview of AI applications across the preclinical drug discovery pipeline (the 2020-2026 literature), covering drug-target interaction prediction, structure prediction, de novo design, virtual screening, drug repurposing, and ADMET forecasting. Beyond surveying technical developments, we critically discuss key translational hurdles, including data quality, model interpretability, patient heterogeneity, and regulatory adaptation, and provide structured summaries of representative models. We conclude by outlining future directions, such as multimodal AI, digital twins, and closed-loop automation, that aim to bridge the gap between computational prediction and clinical application. This review aims to inform researchers and accelerate the delivery of safe and effective therapies.
    Keywords:  AI; de novo drug design; deep learning; drug discovery; drug–target interaction; machine learning; virtual screening
    DOI:  https://doi.org/10.3390/ph19050696
  72. Front Immunol. 2026 ;17 1822773
    Broadly neutralizing antibody-secreting CAR-T cells elicit Fc-mediated effector functions in vitro and suppress HIV in humanized mice.
    Zoe Stylianidou, Sarah Gerlo, Magdalena Wejda, Elianne Burg, Evelien De Smet, Ytse Noppe, Maxime Verschoore, Jolien Van Cleemput, Linos Vandekerckhove, Wojciech Witkowski.
      Despite significant advances in antiretroviral therapy (ART), human immunodeficiency virus (HIV) persists in long-lived viral reservoirs, requiring lifelong treatment and highlighting the need for curative strategies. Viral persistence across anatomically distinct reservoirs, together with HIV-associated immune dysregulation, supports the development of combination immunotherapies capable of acting through multiple antiviral mechanisms. Here, we developed and evaluated a Hybrid chimeric antigen receptor (CAR) platform that combines the targeted cytotoxicity of CAR-T cells with the secretion of broadly neutralizing antibodies (bNAbs). We assessed the capacity of Hybrid CAR-T cells to eliminate HIV-infected cells, neutralize free virus, and recruit Fc-mediated effector mechanisms in vitro, and evaluated their antiviral activity in humanized mice. In vitro, Hybrid CAR-T cells eliminated HIV-infected CD4+ T cells, while secreted bNAbs neutralized HIV and mediated robust Fc-effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In humanized mice, Hybrid CAR-T treatment achieved more than a 9-fold reduction in plasma viremia, accompanied by a significant decrease in viral levels across tissues and detectable circulating bNAbs in plasma. Collectively, these findings demonstrate that Hybrid CAR-T cells can bridge cellular and humoral immunity by combining direct killing of HIV-infected cells with antibody-mediated antiviral activity. This dual-function platform represents a synergistic next-generation immunotherapy with translational potential as a strategy toward a functional HIV cure.
    Keywords:  ADCC; ADCP; CAR-T cells; HIV; broadly-neutralizing antibodies
    DOI:  https://doi.org/10.3389/fimmu.2026.1822773
  73. Biosensors (Basel). 2026 Apr 24. pii: 240. [Epub ahead of print]16(5):
    Machine Learning-Assisted Rapid Optical Imaging for Label-Free CAR T-Cell Detection in Whole Blood.
    Nanxi Yu, Ryan M Porter, Xinyu Zhou, Wenwen Jing, Fenni Zhang, Eider F Moreno Cortes, Paula A Lengerke Diaz, Jose V Forero Forero, Erica Forzani, Januario E Castro, Shaopeng Wang.
      Chimeric antigen receptor (CAR) T-cell therapy is an effective treatment for hematologic malignancies. However, it is limited by high costs, risk of severe toxicities such as cytokine release syndrome and neurotoxicity, and heterogeneous patient responses. The current therapy monitoring depends largely on subjective symptom assessment, routine laboratory tests, and basic vital signs, without real-time, quantitative evaluation of CAR T-cell expansion or activation in clinical practice. This lack of timely immune monitoring hampers individualized care and contributes to increased treatment costs. To address this need, we present a proof-of-concept, label-free rapid optical imaging (ROI) biosensor with automated machine learning analysis for direct quantification of CAR T-cells from whole blood. This microfluidic platform integrates red blood cell (RBC) removal, CAR T-cell capture, and imaging-based quantification on a single chip, eliminating the need for centrifugation, staining, and operator-dependent interpretation. For validation, 50 μL whole blood samples spiked with Jurkat cells expressing CD19 CARs underwent RBC depletion by agglutination and microfiltration. The remaining blood components were then incubated on a sensor chip functionalized with recombinant CD19 protein. Captured CAR T-cells were imaged by brightfield microscopy and automatically enumerated using a machine learning algorithm trained on fluorescence-validated cells. The CD-19 cells' capture performance was validated by flow cytometry and fluorescence imaging. The trained machine learning model validated at 88% sensitivity and 96% specificity. Buffer and whole blood calibration curves were established across clinically relevant concentrations (1-1000 cells/µL) with triple replicates. The results showed high correlation (0.975 and 0.990 R2) between the spiked concentration and the detected CAR T-cells, with a 95% certainty limit of detection (LOD) and quantification (LOQ) of 0.6 and 1.1 cells/µL for spiked buffer, and 14 and 67 cells/µL for spiked whole-blood, respectively.
    Keywords:  CAR T; agglutination; chimeric antigen receptor T-cells; digital counting; machine learning; microfluidic chip; object classification; optical imaging; whole blood
    DOI:  https://doi.org/10.3390/bios16050240
  74. Funct Integr Genomics. 2026 May 29. pii: 113. [Epub ahead of print]26(1):
    Multiscale predictive cellular modeling: integrating hypothesis grammars, digital twins, and multi-omics for In silico oncology and precision theranostics.
    S T Gopukumar, Dyumn Dwivedi, Mohamed Rahamathulla, Mohammed Muqtader Ahmed, Tanveen Kaur Soni, Praveen Ganesh Natarajan, S Ramkanth, Arpita Mitra, Uddalak Das.
      Predictive multiscale cellular modeling is emerging as a consequential direction in precision medicine, converging hypothesis grammars, digital twins, and integrative genomics to interrogate tumor-immune dynamics, therapeutic resistance, and cellular plasticity. This perspective synthesizes recent progress across these domains and critically maps their translational potential alongside their current limitations. Hypothesis grammars translate mechanistic theories into executable agent-based models (ABMs) and hybrid ODE-PDE systems, enabling rapid in silico hypothesis testing while lowering the authoring barrier for domain scientists. Patient-specific digital twins, driven by multi-omics data, employ stochastic ensemble methods to simulate clonal evolution and microenvironmental interactions, though prospective clinical validation of these capabilities remains at an early stage. Integrative genomics, leveraging algorithms such as SCODE and SimiC, infers causal gene regulatory networks (GRNs) using Bayesian variational autoencoders, embedding dynamic intracellular logic into tissue-scale simulations. Emerging applications include in silico oncology trials for optimizing checkpoint blockade and combination therapies. Large language models are being explored to enhance rule induction, while FAIR-compliant digital cell repositories aim to ensure reproducibility and reuse. Verification, validation, and uncertainty quantification (VVUQ) via Sobol sensitivity analysis and Kennedy-O'Hagan calibration are identified as essential components for addressing non-identifiability and supporting regulatory credibility. Federated learning is discussed as a means of mitigating privacy and bias concerns in multi-institutional settings. Together, these converging approaches outline a plausible pathway toward virtual clinical trials and adaptive theranostics, contingent on the prospective validation, data infrastructure, and governance frameworks that clinical deployment will require.
    Keywords:   In silico oncology; Cancer; Digital twins; Drug; Genetics; Hypothesis grammars; Integrative genomics; Multiscale modeling
    DOI:  https://doi.org/10.1007/s10142-026-01890-4
  75. Health Res Policy Syst. 2026 May 28. pii: 46. [Epub ahead of print]24(1):
    Advancing the systematic implementation of patient experience data in healthcare decision-making: multi-stakeholder insights on barriers, opportunities and policy ways forward.
    Alice Vanneste, Io Wens, Peter Sinnaeve, Tom Adriaenssens, Isabelle Huys.
       BACKGROUND: Patient experience data (PED), including patient-reported outcomes (PROs), patient-reported experiences (PREs), patient preferences (PPs), and patient input, are instrumental to better understand patients' perspectives and inform decision-making. Healthcare decision-makers increasingly recognize the value of PED, but challenges impede its implementation in practice. This qualitative study aims to identify stakeholders' insights on these barriers, as well as opportunities and concrete policy ways forward for systematically implementing PED in healthcare decision-making.
    METHODS: Semistructured interviews (n = 38) were conducted with stakeholders from healthcare industry, academia, non-profit organizations, regulatory authorities, pricing and reimbursement (P&R) agencies, and patient organizations across Europe. The interviews were transcribed ad verbatim and analysed qualitatively using thematic framework analysis.
    RESULTS: Stakeholders raised several barriers impeding the integration of PED in healthcare decision-making: (1) lack of clear European policy frameworks and guidance on standardized requirements and quality criteria for collecting and evaluating PED, particularly concerning the design and implementation of PP studies, (2) lack of validated methods and tools for collecting high-quality PED, such as validated PRO measures, and (3) limited knowledge and transparency on the assessment of PED in regulatory and P&R decision-making. Stakeholders emphasized the importance of providing training on effective patient involvement and more research on validated methods and fit-for-purpose tools. Stakeholders emphasized the importance of fostering collaboration and open dialogue among all stakeholders. Developing guidelines and a comprehensive policy strategy that clearly delineates expectations and responsibilities for each stakeholder group was seen as an important way forward.
    CONCLUSIONS: This policy- and practice-oriented qualitative study identified concrete ways to advance the systematic use of PED in healthcare decision-making. Suggested actions include developing validated and standardized methods and tools, co-created and flexible guidelines and a clear European policy framework delineating expectations and responsibilities. While there was broad alignment on the direction forward, views diverged on who should take the lead in initiating these efforts, underscoring the importance of continued coordination across stakeholder groups.
    Keywords:  Health technology assessment; Healthcare decision-making; Patient experience data; Policy ways forward; Qualitative study
    DOI:  https://doi.org/10.1186/s12961-025-01438-1
  76. Biomedicines. 2026 Apr 22. pii: 957. [Epub ahead of print]14(5):
    Functionalized Lipid Nanoparticles for Targeted RNA Delivery in Immune and Inflammatory Diseases.
    Yeongji Jang, Hyun Kyu Song, Man Kyu Shim, Yoosoo Yang.
      Lipid nanoparticles (LNPs) have become an important platform for the delivery of RNA therapeutics, including messenger RNA (mRNA) and small interfering RNA (siRNA). However, most clinically approved LNP formulations exhibit strong liver tropism following systemic administration, which limits efficient delivery to extrahepatic tissues. This inherent biodistribution profile has therefore been recognized as a key challenge for expanding the therapeutic applications of RNA nanomedicine. Recent efforts have focused on engineering functionalized LNP systems to improve delivery specificity beyond the liver. Surface modification with targeting ligands-such as antibodies, peptides, and nucleic acid aptamers-can promote receptor-mediated uptake by specific immune cell populations, including macrophages, dendritic cells and T lymphocytes. In parallel, advances in lipid design have improved intracellular RNA delivery by facilitating endosomal escape. These developments have broadened the potential use of RNA nanomedicine for inflammatory disorders, including autoimmune diseases, neuroinflammation, and cardiovascular inflammation. Functionalized LNPs are also being investigated for in vivo engineering of immune cells. This review summarizes current strategies for designing functionalized LNP systems, highlights their emerging applications in immune and inflammatory diseases, and discusses key challenges for clinical translation.
    Keywords:  RNA delivery; functionalized lipid nanoparticles; immune cell targeting; targeted nanomedicine
    DOI:  https://doi.org/10.3390/biomedicines14050957
  77. Radiographics. 2026 Jun;46(6): e250120
    Pediatric Rheumatic Disorders Revisited: Integrating Imaging and Pathophysiologic Insights across the Autoinflammatory-Autoimmune Continuum.
    Yuko Tsujioka, Atsuhiko Handa, Gen Nishimura, Masaru Takeshita, Yoshitake Yamada, Eugene Nishi, Tatsuo Kono, Masahiro Jinzaki.
      Recent advances in immunologic and molecular research on rheumatic diseases have significantly improved understanding of the diverse group of immune-mediated disorders. Rheumatic diseases were traditionally considered autoimmune diseases, caused by impaired adaptive immunity and often associated with pathogenic autoantibodies. However, in the late 20th century, certain genetic rheumatic diseases-such as tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF)-were found to result from antigen-independent activation of innate immune cells and the subsequent cytokine-mediated inflammation. This discovery introduced the new concept of autoinflammatory diseases, characterized by dysregulation of innate immunity. Although autoimmune and autoinflammatory diseases were initially regarded as distinct categories, substantial overlap has become evident. For instance, autoantibodies can be detected in disorders primarily affecting innate immunity, while recent cytokine-targeting therapies have proven effective for classic autoimmune diseases, such as systemic lupus erythematosus (SLE) and dermatomyositis. These insights led to the concept of an autoinflammatory-autoimmune continuum, highlighting that dysregulation of the interaction between innate and adaptive immune systems contributes to the clinical symptoms of rheumatic diseases. The authors explore clinical, imaging, pathophysiologic, and therapeutic aspects of pediatric rheumatic diseases through the lens of this continuum, providing a comprehensive overview of current diagnostic and treatment strategies. © RSNA, 2026 Supplemental material is available for this article.
    DOI:  https://doi.org/10.1148/rg.250120
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