bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–05–03
43 papers selected by
Luca Bolliger, lxBio
  1. CAR T cell engineering approaches to minimise toxicities.
  2. CAR-T cell therapy for pancreatic cancer: Translating emerging targets and dual-targeting strategies from solid tumors.
  3. In Vivo CAR-T Therapy for Cancer Treatment: Mechanisms, Technological Advances, and Clinical Translation.
  4. Organoid models: reshaping the paradigm for precision development and evaluation of CAR-T cell therapies.
  5. Advances in IL-15-Based Cancer Immunotherapy and Divergent Immunological Effects of IL-2 and IL-15 Signaling via the Shared IL-2Rβγ Receptor.
  6. From production to bedside: A tiered QC framework for regulatory alignment and analytical comparability in decentralized CGT.
  7. Advances in natural killer cell immunotherapy for hematologic malignancies.
  8. Breakthroughs and challenges of CAR-T cell therapy in treating hematologic malignancies of the central nervous system.
  9. Development of a flow cytometry method to measure antidrug antibodies against CAR T cells.
  10. Killer-cell Immunoglobulin-like Receptors define a potent effector program in human γδ T cells.
  11. On the road to in vivo CAR-T success: Comparing promising viral and non-viral vectors.
  12. In vivo CAR therapies: Turning the patient into their own CAR factory.
  13. The Impact of Health Technology Assessment on Pharmaceutical Prices: Evidence from Germany.
  14. Editorial: Advancements and challenges in CAR-T cell therapy for cancer treatment.
  15. Different Immune Cells Modified With Chimeric Antigen Receptors Are Being Applied to Ovarian Cancer: Which Is the Most Effective?
  16. Relational Utility in Genomic Health Technology Assessment.
  17. CAR T-Cell Therapy in Neurology: A Scoping Review of Neuro-Oncology, Autoimmune Diseases & Neurotoxicity.
  18. What the future holds: the growing role of real-world evidence in health technology assessment in Malaysia.
  19. Decoding the immune microenvironment: precision immunotherapy for medulloblastoma subtypes.
  20. Beyond HLA-Ia: A multidimensional framework for Neoantigen immunotherapy.
  21. Efficacy and Safety of Bendamustine Versus Fludarabine and Cyclophosphamide as Lymphodepleting Regimens for CAR-T Therapy in Hematological Malignancies: A Systematic Review and Meta-Analysis.
  22. CAR immune cell therapy strategies and advances for lung cancer.
  23. A parasite partner for regulatory affairs.
  24. Decoding Human T Cell Immunity with Artificial Intelligence and Single-Cell Genomics.
  25. Toward a Common Set of Interface Requirements for Genomic Data Management: Scoping Review.
  26. Programmable Chimeric Antigen Receptor T Cell Circuits With DNA Computing for Precision Tumor Therapy.
  27. The FDA's adoption of Bayesian methodology: transforming clinical trial justification from biosimilars to broader drug development.
  28. Treg cells as potential therapeutic targets for bullous pemphigoid: A review.
  29. Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety.
  30. Artificial intelligence-assisted neuropharmacology: reshaping drug discovery and translational strategies for neurological diseases.
  31. Pathways to embed digital health technologies and their governance mechanisms in Long-Term Care Insurance Systems: A comparative review of Japan, South Korea, and China.
  32. PSMA-directed CAR-T cell therapy for metastatic castration-resistant prostate cancer: a next-generation engineering perspective on stem cell-derived immune effectors.
  33. Ionizing radiation enhances CAR T-cell infiltration and efficacy in solid tumors.
  34. Detection of Diagnostic Antibodies in Immune-Mediated Diseases: A Focus on Antigens and Technologies.
  35. Regulatory challenges of personalized medicine in the real world: are the right patients being treated with CD19-targeting CAR T-cells?
  36. Clinical Knowledge Representation in Data Science.
  37. Geriatric Telemanagement of Health Conditions (GET HEALTH) in Nursing Home Residents Recently Discharged From the Hospital: Protocol for a Before-After Study.
  38. Evaluating the utility of amino acid similarity-aware kmers to represent TCR repertoires for classification.
  39. Natural Killer Cell-Based Immunotherapy in HCC.
  40. Role of Donor Unrestricted T Cells (DURTs) in TB Host Defense: Implications for Novel TB Vaccine Development.
  41. CAR-T cell therapy: "New black" for children with severe, refractory, B cell-mediated autoimmune disorders.
  42. Investigational approaches to multiple sclerosis therapy.
  43. Rethinking Trust in Synthetic Health Data: Lessons From 7 European Research Initiatives.
  1. Exp Biol Med (Maywood). 2026 ;251 11021
    CAR T cell engineering approaches to minimise toxicities.
    Elizabeth Hogben, Anna Schurich, Charlotte Graham.
      For the treatment of many forms of cancer, cell- and gene-based therapies are showing promise in both pre-clinical data and clinical trials. In particular, CAR T cell therapies, of which there are now 7 FDA-approved products, have shown ground-breaking results in haematological cancers such as multiple myeloma and B cell malignancies. Recent research is also attempting to develop effective CAR T cell therapies for solid tumours, with varying success. One of the key challenges faced by CAR T cell therapy is balancing strong cytotoxic activity for an effective treatment with preventing severe and potentially lethal toxicities, such as Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome. This mini review discusses some of the potential solutions that scientists have devised to overcome toxicities and improve existing CAR T cell therapies.
    Keywords:  CAR T cell; ICANS; cytokine release syndrome (CRS); non-ICANS neurotoxicity; safety; toxicity
    DOI:  https://doi.org/10.3389/ebm.2026.11021
  2. Front Immunol. 2026 ;17 1764452
    CAR-T cell therapy for pancreatic cancer: Translating emerging targets and dual-targeting strategies from solid tumors.
    Shijun Shen, Zhengcai Ruan, Beier Jiang, Wenjing Qiu, Feng Zhang, Runzhe Shu.
      Pancreatic ductal adenocarcinoma (PDAC) is regarded as one of the most lethal malignancies, characterized by a poor prognosis and significant resistance to conventional treatments. Although Chimeric Antigen Receptor (CAR)-T cell therapy has been considered to be a revolutionary treatment for B-cell malignancies, its efficacy against solid tumors, including PDAC, has been limited. Nevertheless, after numerous tests pre-clinically and clinically, the acceptance of the first New Drug Application (NDA) for a CAR-T therapy in a solid tumor has sparked considerable hope and interest, which could further accelerate the field. Unlocking the full potential of CAR-T in PDAC requires overcoming significant hurdles, primarily the lack of ideal tumor-specific antigens and the profoundly immunosuppressive tumor microenvironment (TME). Given the shared expression of tumor-associated antigens (TAAs) across diverse solid tumors, this review analyzes promising solid tumor targets to identify candidates with high translational viability for PDAC. We summarize the latest clinical progress of CAR-T cell therapy, highlight emerging therapeutic targets, and explore innovative engineering strategies for developing potent, multi-targeted CAR constructs that are advancing toward future clinical application.
    Keywords:  CAR-T; cancer targets; dual CAR-T cells; immunotherapy; pancreatic cancer; solid tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1764452
  3. Oncol Res. 2026 ;34(5): 10
    In Vivo CAR-T Therapy for Cancer Treatment: Mechanisms, Technological Advances, and Clinical Translation.
    Lu Hao, Jiao Lu, Jisu Xue.
      In vivo Chimeric Antigen Receptor (CAR)-T cell therapy reprograms a patient's own T cells directly inside the body, bypassing the complex and costly traditional manufacturing process. This is achieved by systemically delivering viral or non-viral vectors that genetically modify endogenous T lymphocytes to produce functional CAR-T cells de novo. By eliminating ex vivo cell processing, this strategy can simplify workflows, reduce costs, improve accessibility, and allow faster treatment. Key delivery platforms include engineered lentiviral and adeno-associated viral (AAV) vectors for lasting CAR expression and targeted lipid nanoparticles (LNPs) for transient mRNA delivery. Emerging technologies like biomaterial scaffolds and ultrasound stimulation further enable localized and spatiotemporally controlled T cell engineering. Clinically, early trials in relapsed/refractory multiple myeloma and B-cell malignancies have shown strong antitumor responses, even without preconditioning chemotherapy. Remaining challenges comprise achieving precise T cell targeting, overcoming the immunosuppressive tumor microenvironment, preventing antigen escape, and managing safety risks such as vector genotoxicity or LNP reactogenicity. Future translation will depend on combining synergistic regimens, refining vector design, and implementing tunable safety controls. The aim of the study is to highlight how in vivo CAR-T therapy is evolving from concept to clinical reality, poised to redefine adoptive cell therapy as a scalable and widely applicable pharmacologic intervention.
    Keywords:  Chimeric antigen receptor-T; cancer treatment; cell therapy; gene therapy; in vivo chimeric antigen receptor-T
    DOI:  https://doi.org/10.32604/or.2026.076420
  4. Front Bioeng Biotechnol. 2026 ;14 1797270
    Organoid models: reshaping the paradigm for precision development and evaluation of CAR-T cell therapies.
    Haipeng Li, Jiaqi Yan, Yuxi Liu, Xunqian Tao, Keying Guo, Jing Zhang.
      Chimeric antigen receptor T (CAR-T) cell therapy has achieved transformative success in hematological malignancies; however, its translation to solid tumors remains severely limited by tumor heterogeneity, immunosuppressive microenvironments, and safety concerns such as on-target/off-tumor toxicity. A major contributor to these challenges is the lack of preclinical models capable of faithfully recapitulating human tumor architecture and tumor-immune interactions. Conventional two-dimensional cell cultures and animal models frequently fail to predict CAR-T efficacy, resistance, and toxicity observed in patients. Organoid technology, particularly patient-derived organoids (PDOs) and immune-integrated organoid systems, has emerged as a next-generation platform that bridges this translational gap. By preserving patient-specific genetic, phenotypic, and spatial heterogeneity, organoids provide a physiologically relevant and scalable system for interrogating CAR-T cell behavior in human-like tumor contexts. Recent advances in tumor-immune co-culture, vascularized organoids, and microfluidic organoid-on-a-chip platforms have further expanded their utility for dynamic assessment of CAR-T infiltration, cytotoxicity, cytokine release, and adaptive resistance mechanisms. In this review, we comprehensively examine how organoid-based models are reshaping the CAR-T development pipeline, spanning target discovery and validation, functional efficacy assessment, safety profiling, and optimization of combination therapies. We further discuss emerging applications of organoids as patient-specific "avatars" for personalized CAR-T selection and response prediction. Finally, we highlight current technical limitations and future bioengineering directions required to enable clinical translation. Collectively, organoid platforms represent a transformative tool for accelerating precision development of next-generation CAR-T cell therapies and advancing human-relevant immuno-oncology research.
    Keywords:  chimeric antigen receptor T-cell therapy; organoid-on-a-chip; patient-derived tumor organoids; tumor-immune co-culture; tumor-immune microenvironment
    DOI:  https://doi.org/10.3389/fbioe.2026.1797270
  5. Front Immunol. 2026 ;17 1791059
    Advances in IL-15-Based Cancer Immunotherapy and Divergent Immunological Effects of IL-2 and IL-15 Signaling via the Shared IL-2Rβγ Receptor.
    Huiquan Gao, Tao Ma, Qinqin Jiang, Lanfang Gao, Jinfang Li, Shubo Wang, Ziyong Liu, Zhixin Zhang, Gang Wu, Wenxin He, Fuxin Zhou.
      Interleukin-15 (IL-15) has emerged as a central cytokine for next-generation cancer immunotherapy because of its unique ability to sustain the survival, proliferation, and cytotoxic function of memory CD8+ T cells and natural killer (NK) cells without promoting the expansion of regulatory T cells (Treg). These properties make IL-15 particularly attractive for achieving durable antitumor immunity, especially in solid tumors where immune persistence remains a major limitation. Although IL-15 shares the same signal-transducing receptor subunits (IL-2Rβ and the common γ chain) with interleukin-2 (IL-2), the two cytokines drive fundamentally different CD8+ T-cell fates, a distinction that underlies their markedly divergent therapeutic profiles in cancer immunotherapy. In recent years, multiple IL-15-based therapeutic strategies including recombinant IL-15, and IL-15 immunocytokines have entered clinical evaluation, demonstrating potent immune activation with manageable toxicity profiles. Recent clinical progress includes the FDA approval of Nogapendekin alfa inbakicept (N-803), the first IL-15-based immunotherapy approved for cancer treatment, alongside the advancement of other IL-15 superagonists into Phase II trials and growing evidence that IL-15 can enhance the efficacy of immune checkpoint blockade and engineered adoptive cell therapies such as CAR-T cells, CAR-NK cells, γδ T cells, and invariant NKT cells. Despite these advances, important challenges remain, including cytokine-associated toxicities, optimal delivery strategies, and the immunosuppressive tumor microenvironment. This review summarizes recent progress in IL-15-based cancer immunotherapy, integrates emerging insights into IL-2Rβγ-driven CD8+ T-cell fate decisions, and discusses key opportunities and challenges for translating IL-15-mediated immune enhancement into durable clinical benefit.
    Keywords:  CAR-NK cells; CAR-T cells; cancer immunotherapy; cytokine engineering; immune checkpoint inhibitor (ICI); immunocytokines; interleukin-15 (IL-15); interleukin-2 (IL-2)
    DOI:  https://doi.org/10.3389/fimmu.2026.1791059
  6. Regen Ther. 2026 Jun;32 101112
    From production to bedside: A tiered QC framework for regulatory alignment and analytical comparability in decentralized CGT.
    Sagi Nahum, Devanshi Doshi, Cris Kosnik, Emiko Jeffries, Kristine Nishida, Vered Caplan, Heiko von der Leyen.
      Decentralized and point-of-care (PoC) manufacturing is reshaping cell and gene therapy (CGT) by bringing production closer to patients. This model offers advantages, including reduced vein-to-vein times, streamlined logistics, and greater flexibility for patient-specific treatments, with the potential to improve affordability and broaden access. However, it introduces new quality control (QC) challenges that are central to ensuring product safety, potency, and consistency. Autologous CGTs, typically produced as single patient lots with limited shelf lives and compressed release timelines, require QC systems capable of delivering reliable results within hours for critical quality attributes (CQA) such as identity, potency, sterility, and safety. In both autologous and allogeneic settings, variability in starting material, shortages of trained personnel, and a lack of standardized assays across sites complicate consistency and hinder data pooling in multicenter trials. Hospital-based facilities also require enhanced infrastructure, harmonized procedures, and digital oversight to sustain network-wide comparability. Emerging solutions emphasize automation, validated rapid-testing platforms, and methods that minimize reliance on highly specialized expertise to accelerate batch release and improve reproducibility across distributed networks. Regulatory agencies are updating frameworks for modular and Point-of-Care (PoC) models, emphasizing flexibility while maintaining rigorous standards. Here, we outline a tiered QC model designed to maintain product comparability and enable timely release. QC has become the defining challenge of decentralized CGT manufacturing. However, implementing robust strategies, assay harmonization, and validated rapid-release methods can ensure uniform product quality across distributed sites, so that every patient, regardless of treatment site, receives safe, effective, and timely therapy.
    Keywords:  Automation-enabled modular manufacturing; Decentralized manufacturing; Network-wide QMS harmonization; QC decentralization strategy; Rapid-release analytics; Tiered QC model
    DOI:  https://doi.org/10.1016/j.reth.2026.101112
  7. Cancer Biol Ther. 2026 Dec 31. 27(1): 2658896
    Advances in natural killer cell immunotherapy for hematologic malignancies.
    Huijie Hu, Yan Xiong, Minxin Xia, Lixia Sheng.
      Natural killer (NK) cells are a unique subset of cytotoxic lymphocytes within the innate immune system. They play a pivotal role in antiviral and antitumor immunity. NK cell-based adoptive immunotherapy has advanced rapidly in recent years. Innovative approaches, such as autologous/haploidentical NK cell infusion, chimeric antigen receptor NK cells, and NK cell engagers, have emerged, demonstrating promising potential in the treatment of various diseases. Currently, enhancement strategies for NK cell therapy primarily focus on two key aspects: improving expansion efficiency and persistence, with a positive effect on the therapy's potency and cytotoxic efficacy. The present review systematically introduces the functional mechanisms of NK cells and their specialized functional subsets. This review discusses the progress and optimization methods of NK cell therapy and provides an outlook on future research directions.
    Keywords:  Cellular therapy; NK cell; cell transfer therapy; hematologic tumors; immunotherapy
    DOI:  https://doi.org/10.1080/15384047.2026.2658896
  8. Blood Sci. 2026 Jun;8(2): e00289
    Breakthroughs and challenges of CAR-T cell therapy in treating hematologic malignancies of the central nervous system.
    Xiaoning Li, Haili Da, Jie Zhao, Yan Yan, Jia Wei, Weiwei Tian.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed hematologic cancer treatment; however, its application in patients with central nervous system (CNS) involvement remains challenging because of exclusion from key trials. Recent data show that CAR-T cells can breach the blood-brain barrier (BBB) and achieve clinically significant responses in CNS lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). However, limited CNS trafficking, antigen escape, an immunosuppressive microenvironment, and treatment-related neurotoxicity constrain therapeutic efficacy. This review synthesizes recent clinical outcomes, elucidates mechanisms of CNS infiltration and neurotoxicity, and evaluates emerging strategies, including optimized CAR designs, BBB-modulating technologies, alternative delivery routes, and rational combination therapies, to enhance safety and efficacy. Disease-specific nuances, such as Parkinson-like symptoms in CNS myeloma and differential neurotoxicity profiles between primary and secondary CNS lymphomas, are highlighted. By identifying key knowledge gaps and proposing prioritized research directions, this study aims to guide the future translation of CAR-T therapy for CNS hematologic malignancies.
    Keywords:  Blood–brain barrier; Central nervous system; Chimeric antigen receptor T; Leukemia; Lymphoma; Multiple myeloma; Neurotoxicity
    DOI:  https://doi.org/10.1097/BS9.0000000000000289
  9. Immunohorizons. 2026 Apr 11. pii: vlag011. [Epub ahead of print]10(4):
    Development of a flow cytometry method to measure antidrug antibodies against CAR T cells.
    Georgia Day, Francisco Javier Sánchez-Martín, Lisa Seavers, Karen Cadwallader, Sara Morgado-García.
      Chimeric antigen receptor (CAR) T cell therapies are based on the genetic modification of the T cell receptor of a patient's own T cells. The resulting CAR T cells cytotoxic response is redirected against a specific tumor antigen. This innovative immunotherapy has been used successfully to treat blood malignancies, and it is also being developed as treatment for solid tumors. CAR T cells can lead to immune related adverse outcomes associated with an unwanted immune response in the host, ranging from acute events to those sustained with time, such as antidrug antibody (ADA) development, which can impact the efficacy and persistence of the CAR T cells once administered to the patient. The development of ADAs as response to a drug treatment is not exclusive to CAR T cells, and evidence of their production has been long acknowledged. While traditional types of analysis aim to measure the presence of ADAs by immunoassay methods, with the therapeutic agent being cells, the use of a flow cytometry approach has become the obvious choice for detection and quantification of ADAs against CAR T cells products, as well as any other cell therapies. Here, we present the results of the development of a flow cytometry method to measure ADAs using CAR T cells with an assay to detect the binding of an ADA-like molecule to the CAR T cells in a dose-dependent manner. This method allowed for quantification of ADAs and determination of the assay values needed for potential ADA measurement in clinical samples.
    Keywords:  ADA; CAR T cells; cut point; flow cytometry
    DOI:  https://doi.org/10.1093/immhor/vlag011
  10. JCI Insight. 2026 Apr 23. pii: e201160. [Epub ahead of print]
    Killer-cell Immunoglobulin-like Receptors define a potent effector program in human γδ T cells.
    Mahya Razmi, Yeganeh Almasi, Marilee Larrivée, Jonathan B Angel, Alexandre Blais, Zakia Djaoud.
      Human γδ T cells are a rare but functionally diverse lymphocyte subset critical for tumor surveillance and antimicrobial immunity. Although they express natural killer (NK) cell-associated receptors such as Killer-cell Immunoglobulin-like Receptors (KIRs), the relevance of KIR expression on γδ T cells remains largely unexplored. Using flow cytometry, ATAC-seq and RNA-seq, we identified KIR expression as a marker that distinguished two functionally and molecularly distinct γδ T cell subsets. KIR⁺ γδ T cells exhibited an advanced, memory-like differentiation state characterized by heightened cytotoxicity, stable epigenetic remodeling and a predominant IFNγ-producing profile. In contrast, KIR⁻ γδ T cells maintained a naïve-like phenotype and preferentially produced IL-17 upon polarization. Notably, KIR+ γδ T cells were consistently observed across individuals but were significantly enriched in cytomegalovirus (CMV)-seropositive donors, suggesting that chronic antigenic stimulation could promote the emergence of KIR⁺ effector γδ T cells. These findings reveal a functional dichotomy in human γδ T cells defined by KIR expression, linking IFNγ-driven cytotoxicity with KIR⁺ cells and IL-17 production with KIR⁻ cells. This insight advances our understanding of γδ T cell heterogeneity and has implications for viral immunity, immune memory and the development of γδ T cell-based immunotherapies.
    Keywords:  Hematology; Immunology; Innate immunity; NK cells
    DOI:  https://doi.org/10.1172/jci.insight.201160
  11. Biotechnol Adv. 2026 Apr 26. pii: S0734-9750(26)00113-8. [Epub ahead of print] 108907
    On the road to in vivo CAR-T success: Comparing promising viral and non-viral vectors.
    Sarah de la Mota, Leah Suchet, Mirthe van Wijk, Dale J Stibbs, Pedro Silva Couto, Qasim A Rafiq.
      Chimeric antigen receptor (CAR)-T-cell therapies have demonstrated substantial efficacy in haematological malignancies, with multiple products approved for clinical use. However, broader application remains limited by severe toxicities, reduced efficacy toward solid tumours, and the high cost and complexity of ex vivo manufacturing. The autologous nature of most current therapies contributes to variable product quality, lengthy vein-to-vein times, and restricted patient access. In vivo CAR-T therapy has emerged as a potential solution, aiming to generate functional CAR-T-cells within the patient, with several platforms progressing into early Phase I clinical trials. This approach eliminates reliance on patient-derived starting material, reduces manufacturing failure rates, and offers the prospect of off-the-shelf availability at lower cost. Central to in vivo CAR-T development is selecting an appropriate gene delivery platform. Viral vectors, including lentiviral, adenoviral, and adeno-associated viral systems, have an established role in ex vivo CAR-T manufacturing and in vivo gene therapies. Non-viral vectors, such as lipid nanoparticles (LNP) and polyplexes, have garnered increasing attention due to their high packaging capacity, potential for redosing, and validation in large-scale production, as exemplified by mRNA-LNP vaccines against COVID-19. Recently, the in vivo CAR-T engineering toolbox has expanded with DNA-based LNP platforms capable of stably integrating CAR transgenes via transposon systems, fourth-generation T-cell-targeted lentiviral systems that minimise CAR display on vector particles and aberrant splicing, and emerging genome-editing technologies. This review compares viral and non-viral vectors for in vivo CAR-T therapy, evaluating their relative advantages and limitations in terms of safety, efficacy, scalability, analytical methods, regulatory implementation and commercial feasibility.
    Keywords:  Efficient gene delivery; Gene therapy; In vivo CAR-T therapy; Non-viral vectors; Tissue-specificity; Viral vectors
    DOI:  https://doi.org/10.1016/j.biotechadv.2026.108907
  12. Hemasphere. 2026 May;10(5): e70328
    In vivo CAR therapies: Turning the patient into their own CAR factory.
    François Vilcot, Carole-Anne Brugère, Jaime Fuentealba, Roch Houot.
      Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)-T-cell therapies have reshaped the treatment of B-cell malignancies. Despite their remarkable clinical efficacy, their application remains limited by complex manufacturing processes, demanding logistics, long turnaround times, and substantial costs. In vivo CAR approaches are emerging as a potential solution to address these barriers by enabling direct induction of CAR expression in T cells and other immune cells through in-patient delivery of genetic constructs. This review provides an overview of the current landscape of in vivo CAR therapies. We describe the major delivery platforms under clinical development, with a focus on lentiviral vectors (LVVs) and lipid nanoparticles (LNPs), and discuss their distinct features in terms of manufacturing, mechanism of action, safety, therapeutic applications, and optimization strategies. We also summarize ongoing clinical trials exploring in vivo CAR approaches for hematologic malignancies, solid tumors, and autoimmune diseases. Finally, we highlight the key scientific and clinical challenges that remain, and examine strategies under investigation to overcome these limitations and advance in vivo CAR therapies toward broader clinical translation.
    DOI:  https://doi.org/10.1002/hem3.70328
  13. Eur J Health Econ. 2026 Apr 25.
    The Impact of Health Technology Assessment on Pharmaceutical Prices: Evidence from Germany.
    Giovanni Righetti.
      
    Keywords:  AMNOG; Health technology assessment; Pharmaceutical regulation; Triple differences
    DOI:  https://doi.org/10.1007/s10198-026-01924-5
  14. Front Pharmacol. 2026 ;17 1820259
    Editorial: Advancements and challenges in CAR-T cell therapy for cancer treatment.
    Alexander T Sougiannis, Angelica Meneses Acosta, Leonardo M R Ferreira.
      
    Keywords:  CAR (chimeric antigen receptor) T cells; T cell; cancer; cellular engineering; immunoengineering; personalized medicine; solid tumor; translational medicine
    DOI:  https://doi.org/10.3389/fphar.2026.1820259
  15. Cancer Med. 2026 May;15(5): e71897
    Different Immune Cells Modified With Chimeric Antigen Receptors Are Being Applied to Ovarian Cancer: Which Is the Most Effective?
    Liying Wang, Yisen Cao, Yuan Ren, Yuhang Zhang, Liang Wang.
      Ovarian Cancer (OC), the deadliest gynecological malignancy, poses a major therapeutic challenge in advanced stages owing to its high recurrence rate and metastatic potential. In this regard, it is noteworthy that immunotherapy has recently gained significant attention in OC treatment, a phenomenon attributable to notable advances in over-the-counter Chimeric Antigen Receptor (CAR)-based cell therapy. At the heart of CAR-T Cell (CAR-T) immunotherapy is genetically modified CAR molecules that enable immune cells to target and recognize tumor antigens. Based on such strategies, CAR-T therapies have developed rapidly in hematological oncology and are gradually being extended to solid tumors. Despite their potential in OC treatment, several factors, including off-target effects attributable to the lack of Tumor-Specific Antigens (TSAs), as well as severe side effects such as tumor immune barriers, Cytokine Release Syndrome (CRS), and neurotoxicity, have been established to limit the clinical use of CAR-T therapies. Moreover, compared to CAR-T, CAR-Natural Killer (NK) and CAR-Macrophage (M) therapies have distinct advantages. The killing mechanism of NK cells integrates both CAR-dependent and non-dependent pathways, avoiding severe CRS and neurotoxicity. Furthermore, besides directly phagocytosing tumors due to its strong ability to infiltrate tumors, CAR-M therapy could also effectively improve the Immunosuppressive Microenvironment (IME) via immunomodulatory factor secretion to remodel M2-type Tumor-Associated Macrophages (TAMs) into the M1 phenotype with anti-tumor function. In this review, we systematically describe the research progress in CAR-T therapy for OC and compare the similarities and differences of three types of cellular therapies (CAR-T, CAR-NK, and CAR-M) regarding their mechanisms of action, clinical advantages, and technological bottlenecks. We hope that our findings will provide a theoretical basis for optimizing immunotherapeutic strategies for OC. Trial Registration: ClinicalTrials.gov identifier: NCT03585764.
    Keywords:  CAR; CAR‐NK; CAR‐T; CAR‐macrophage; ovarian cancer
    DOI:  https://doi.org/10.1002/cam4.71897
  16. Am J Bioeth. 2026 May;26(5): 30-33
    Relational Utility in Genomic Health Technology Assessment.
    Joey Mackle.
      
    DOI:  https://doi.org/10.1080/15265161.2026.2645580
  17. Ann Clin Transl Neurol. 2026 Apr 27.
    CAR T-Cell Therapy in Neurology: A Scoping Review of Neuro-Oncology, Autoimmune Diseases & Neurotoxicity.
    Omar Alqaisi, Mohammed Dibas, Patricia Tai, Ala Dibas, Osama Souied, Suhair Al-Ghabeesh.
      Chimeric antigen receptor (CAR) T-cell therapy has been investigated in neurological diseases, encompassing both central nervous system malignancies and autoimmune disorders, thereby extending its application beyond hematological cancers. This scoping review evaluates CAR T-cell therapy applications in neurological conditions, assessing therapeutic efficacy, safety profiles, and neurotoxicity management strategies. A literature search across four databases (January 2020-December 2025) identified 33 studies meeting the inclusion criteria, encompassing original and secondary research from international centers. CAR T-cell therapy demonstrated promising efficacy across diverse neurological conditions. In glioblastoma trials, 44% of patients (n = 128) achieved partial or complete clinical/radiographic responses with favorable safety profiles. Moreover, compelling results emerged from neuromyelitis optica spectrum disorder studies, in which 92% of patients (11/12) achieved sustained relapse-free remission over a median follow-up of 5.5 months. Multiple sclerosis, myasthenia gravis, and stiff-person syndrome cases exhibited excellent treatment tolerance without significant immune effector cell-associated neurotoxicity syndrome (ICANS), which is a major concern affecting 27% of patients with hematological malignancies. Overall, CAR T-cell therapy emerges as a novel therapeutic strategy in neurology, encompassing both oncological and autoimmune conditions. Toxicity profiles in neurological CAR T-cell applications differ substantially from those observed in hematologic malignancies, underscoring the need for condition-specific risk assessment frameworks and customized management approaches. Future research should prioritize larger multicenter trials with extended follow-up to establish definitive efficacy and safety profiles in neurological indications.
    Keywords:  CAR T‐cell; ICANS; NMOSD; autoimmune neurological disorders; glioblastoma; multiple sclerosis; neurology; neurotoxicity
    DOI:  https://doi.org/10.1002/acn3.70415
  18. Int J Technol Assess Health Care. 2026 Apr 30. 42(1): e43
    What the future holds: the growing role of real-world evidence in health technology assessment in Malaysia.
    Jing Sheng Lim, Kenneth Kwing Chin Lee.
      Health technology assessment (HTA) has long been the cornerstone of evidence-informed policy for healthcare decision-making. While randomized controlled trials (RCTs) remain fundamental, they do not always reflect the realities of everyday clinical practice. Real-world evidence (RWE) is increasingly recognized as an important complement, capable of capturing variations in population, setting, and practice that influence health outcomes. In Malaysia and across ASEAN, the growing focus on RWE reflects both global momentum and regional aspirations to strengthen data-driven policymaking. This perspective reflects on Malaysia's experience in integrating RWE into HTA and considers how this evolution can inform regional efforts. It argues that the adoption of RWE signifies not only a methodological advance but a transformation in how evidence is conceptualized, governed, and applied. Developing robust data systems, analytical expertise, and cross-country collaboration will be essential to ensure that real-world data are translated into meaningful evidence for equitable and sustainable healthcare decisions.
    Keywords:  ASEAN; Malaysia real-world evidence; health technology assessment; healthcare decision-making
    DOI:  https://doi.org/10.1017/S0266462326103699
  19. Front Immunol. 2026 ;17 1714134
    Decoding the immune microenvironment: precision immunotherapy for medulloblastoma subtypes.
    Mengyuan Li, Jihong Peng, Chun Chen, Jinyang Hu.
      Medulloblastoma is a severe pediatric brain tumor with distinct molecular subtypes-WNT, SHH, Group 3, and Group 4-each having unique genetic drivers and immune microenvironments. This review highlights the immune characteristics of each subtype: SHH is rich in tumor-associated macrophages (TAMs), whose role in tumorigenesis is debated; Group 3 features cytotoxic T cells often neutralized by immune checkpoints like PD-L1, causing T cell exhaustion; and Group 4 is marked by natural killer (NK) cells and B cells. These immune landscapes, including tumor-associated astrocytes (TAAs) and abnormal vascular networks, influence tumor growth, spread, and treatment response. Precision immunotherapy must be tailored to specific subtypes. This article discusses CAR T-cell therapy targeting antigens like B7-H3 and GD2, prevalent in SHH subtypes, and examines immune checkpoint blockades targeting PD-1/PD-L1 and CD47-SIRPα. It also highlights innovative methods like oncolytic viruses to transform "cold" tumor microenvironments and combination therapies using CSF1R inhibitors and tumor-associated antigens to boost anti-tumor responses. Understanding the immune microenvironment's subtype-specific heterogeneity in medulloblastoma is crucial for advancing precision immunotherapy and improving patient outcomes.
    Keywords:  CAR-T cell therapy; immune checkpoint blockade; immunotherapy; medulloblastoma subtypes; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1714134
  20. Cell Immunol. 2026 Apr 27. pii: S0008-8749(26)00052-3. [Epub ahead of print]425 105112
    Beyond HLA-Ia: A multidimensional framework for Neoantigen immunotherapy.
    Liurui Ding, Chenjing Guo, Yehao Qin, Lichuan Wu, Pengcheng Wei.
      Glioblastoma (GBM) and other malignant gliomas are associated with aggressive progression, high recurrence rates, and poor long-term outcomes, while current standard therapies provide limited survival benefit. Neoantigen-based immunotherapy offers tumor specificity but is severely restricted in gliomas by HLA-Ia downregulation, pronounced intratumoral heterogeneity, an immunosuppressive tumor microenvironment, and the blood-brain barrier (BBB). In this review, we summarize recent advances and propose a multidimensional framework to address these barriers. Specifically, we discuss the potential use of HLA-E as an alternative antigen-presentation platform, γδ T cells as complementary effector populations capable of partially bypassing classical HLA-Ia dependence, artificial intelligence-assisted neoantigen prioritization and optimization, and emerging BBB-penetrating delivery technologies. Together, these strategies uncouple neoantigen targeting from individual HLA restrictions, establishing a "genotype-agnostic" foundation. Ultimately, this integrated framework aims to develop broadly applicable, off-the-shelf neoantigen immunotherapies, improving translational feasibility and providing new directions for overcoming immune escape in gliomas.
    Keywords:  Glioma immunotherapy; HLA-E; Immune escape; Non-classical HLA-Ib; γδ T cells
    DOI:  https://doi.org/10.1016/j.cellimm.2026.105112
  21. Eur J Haematol. 2026 May 01.
    Efficacy and Safety of Bendamustine Versus Fludarabine and Cyclophosphamide as Lymphodepleting Regimens for CAR-T Therapy in Hematological Malignancies: A Systematic Review and Meta-Analysis.
    Akihiro Miyashita, Magda Sofía Jiménez Castellanos, Thomas Rodgers.
       OBJECTIVES: Chimeric antigen receptor T-cell (CAR-T) therapy has become an established treatment for hematological malignancies. Lymphodepleting (LD) chemotherapy is a preparatory step that facilitates CAR-T cell expansion and persistence. While fludarabine and cyclophosphamide (Flu/Cy) are a standard LD regimen, bendamustine has emerged as a potential alternative.
    METHODS: We performed a systematic review and meta-analysis comparing the efficacy and safety of bendamustine versus Flu/Cy as LD regimens. We systematically searched PubMed, Scopus, and the Cochrane Central Register of Controlled Trials from inception to July 2025.
    RESULTS: Nine retrospective studies comprising 768 patients were included. The bendamustine cohort demonstrated a lower incidence of all-grade cytokine release syndrome (CRS) compared with Flu/Cy (60.2% vs. 71.7%; p = 0.011), whereas no difference was observed in grade ≥ 3 CRS. Overall infections were less frequent with bendamustine (18.3% vs. 53.7%; p < 0.001). There were no significant differences between groups in the incidence of immune effector cell-associated neurotoxicity syndrome, overall response rate, overall survival, and progression-free survival.
    CONCLUSION: Bendamustine LD therapy significantly reduced the incidence of all-grade CRS and overall infections without compromising CAR-T efficacy. These findings suggest that bendamustine may serve as a viable alternative LD regimen.
    Keywords:  CAR‐T; bendamustine; cytokine release syndrome; immune effector cell‐associated neurotoxicity syndrome; lymphodepleting therapy
    DOI:  https://doi.org/10.1111/ejh.70205
  22. Discov Oncol. 2026 Apr 25.
    CAR immune cell therapy strategies and advances for lung cancer.
    Song Zheng, Yingying Chen, Ruilin Li, Song Peng.
      
    Keywords:  Chimeric antigen receptor; Immunotherapy; Lung cancer; Macrophage; NK cell; T cell
    DOI:  https://doi.org/10.1007/s12672-026-04981-7
  23. Sci Immunol. 2026 May;11(119): eaei2411
    A parasite partner for regulatory affairs.
    Isabella O Conway, Christopher A Hunter.
      Targeting Treg cells to mitigate inflammation has been a challenge, but a parasite-derived cytokine may be key to engineering a Treg cell therapy.
    DOI:  https://doi.org/10.1126/sciimmunol.aei2411
  24. Annu Rev Immunol. 2026 Apr;44(1): 381-405
    Decoding Human T Cell Immunity with Artificial Intelligence and Single-Cell Genomics.
    Lisa M Dratva, Sarah A Teichmann, Lorenz Kretschmer.
      T cells are key mediators of adaptive immunity, yet their highly dynamic response states and immense T cell receptor (TCR) diversity pose challenges in deciphering their functional roles in human diseases. Recent advances in single-cell genomics and TCR sequencing provide unprecedented opportunities to resolve T cell heterogeneity, decode clonal response dynamics, and facilitate high-throughput antigen specificity mapping. In this review, we summarize major technological innovations that have transformed T cell research, from experimental tools for antigen-specific T cell profiling to machine learning frameworks for predicting interactions between the TCR and peptide-MHC (pMHC) and structural modeling powered by deep learning. We discuss current bottlenecks, including data limitations and model generalizability, and explore emerging strategies to guide the next generation of T cell discoveries. We argue that artificial intelligence and single-cell genomics will collectively pave the way for dissecting T cell heterogeneity, mapping TCR sequence to pMHC specificity, and interpreting these features in the context of clinical outcomes.
    Keywords:  T cell receptor; TCR repertoire analysis; adaptive immunity; antigen specificity prediction; artificial intelligence; human T cell responses; single-cell genomics
    DOI:  https://doi.org/10.1146/annurev-immunol-082724-011631
  25. J Med Internet Res. 2026 Apr 27. 28 e78405
    Toward a Common Set of Interface Requirements for Genomic Data Management: Scoping Review.
    Valeria Resendez, Funda Yıldırım, Eugenio Gaeta, Giuseppe Fico, Simone Borsci.
       BACKGROUND: Genomic data can advance precision medicine; however, to continue developing more targeted treatments, genomic datasets need to be integrated with health care data and become more disease-focused. This integration, in turn, amplifies existing challenges in health care data management, such as handling large data volumes, adhering to data standards, and protecting sensitive information. Addressing these challenges calls for unified digital ecosystems that combine data collection, standardization, analysis, and governance within a single platform, thereby reducing the technical burden for users. Currently, a clear set of indications about functional and nonfunctional requirements to help designers translate stakeholder needs into actionable design specifications is missing.
    OBJECTIVE: This scoping review aimed to identify the functional and nonfunctional requirements most frequently discussed in the literature from the perspective of end users (eg, clinicians and data analysts) to inform the design of a health and genomic data management platform that supports data sharing and analysis in clinical settings by conducting a PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Review) review.
    METHODS: We searched for peer-reviewed English studies that focused on platforms for managing genomic data from a user-centered perspective. We considered studies from 2014 to 2024 that were extracted from Scopus, PubMed, Web of Science, and Google Scholar for the scoping review. Insights were extrapolated for a thematic analysis to develop an initial set of requirements. We charted the functional and nonfunctional requirements according to their frequency of occurrence in the literature to provide a structured overview of the most commonly reported requirements.
    RESULTS: From 410 initial items, 210 items were preliminarily selected, and 53 items were included in the final analysis. Three primary groups of 26 interface functional requirements emerged: (1) general data management (acquisition, standardization, and sharing), (2) data processing and analysis (preprocessing and analysis pipelines), and (3) data visualization and reporting. Twenty nonfunctional requirements were identified and organized in 4 groups: (1) communication and support, (2) platform technical infrastructure, (3) user experience and user interface characteristics, and (4) security and compliance. We also investigated the issues that need to be resolved to develop an ideal platform.
    CONCLUSIONS: We identified and mapped the most frequently reported functional and nonfunctional requirements of clinical and data professionals when discussing a health and genomic data management platform. The 3 key functional requirements should be supported by nonfunctional requirements such as secure technical infrastructure and governance mechanisms that enable compliant data processing and sharing. Designers may use these insights and mapping to develop standardized data platforms that promote efficient data exchange between institutions and experts while ensuring regulatory compliance and secure access, as proposed by the European Health Data Space.
    Keywords:  data sharing; electronic health records; functional requirements; genomics; interfaces; nonfunctional requirements
    DOI:  https://doi.org/10.2196/78405
  26. Angew Chem Int Ed Engl. 2026 Apr 29. e9420497
    Programmable Chimeric Antigen Receptor T Cell Circuits With DNA Computing for Precision Tumor Therapy.
    Miao Zhang, Quan Zhang, Xin Yu, Yuhui Yan, Yueting Yu, Guangna Liu, Fenglin Wang, Xia Chu, Jian-Hui Jiang.
      Chimeric antigen receptor (CAR) T cells, a promising cancer therapeutics, still face challenges in safety and efficacy due to the incapability to precisely regulate T cell activation. Here we develop a DNA-logic CAR (DL-CAR) system that enables programmable targeting and precise ablation of tumors with specific antigen combination patterns. The DL-CAR system is engineered using HaloTag as an extracellular domain for DNA conjugation, which allows controlling the assembly of tumor-targeting aptamers for universal and combinatorial antigen recognition via DNA logic computation. DL-CAR-T cells are shown to be capable of targeting tumor cells with different antigens and controlling the CAR circuit through AND, OR, and INHIBIT Boolean logic for specific T-cell activation and cytolysis. The DL-CAR system demonstrated high efficacy for tumor eradication in mouse models, with the AND-, OR-, and INHIBIT-gated computation affording enhanced selectivity for tumors with specific antigen combinations. DL-CAR may provide a new paradigm to develop programmable CAR-T circuits for precision cancer therapy.
    Keywords:  CAR‐T; HaloTag; antitumor agents; aptamer; logic gate
    DOI:  https://doi.org/10.1002/anie.9420497
  27. Front Med (Lausanne). 2026 ;13 1790396
    The FDA's adoption of Bayesian methodology: transforming clinical trial justification from biosimilars to broader drug development.
    Sarfaraz K Niazi.
      The U.S. Food and Drug Administration released in January 2026 a draft guidance on the use of Bayesian methodology in clinical trials of drugs and biological products, representing a significant evolution in its regulatory approach to evaluating evidence supporting marketing authorization. The guidance reflects a growing consensus in regulatory science that traditional frequentist clinical efficacy trials, particularly equivalence and non-inferiority designs, are often poorly aligned with the scientific questions regulators must answer, mainly when substantial prior knowledge exists. This review examines the scientific literature questioning the value of routine clinical efficacy testing, with particular emphasis on biosimilars, and explains how Bayesian inference provides a coherent framework for integrating analytical, pharmacokinetic, clinical, and real-world evidence. The article analyzes the structure and reasoning of the FDA's new guidance, showing how it formalizes a justification-first approach to clinical testing and has potential implications beyond biosimilars, particularly where prior evidence is strong. The review addresses both the advantages and limitations of Bayesian regulatory applications, including potential failure modes and necessary safeguards. Finally, the broader implications of Bayesian regulatory decision-making for drug development efficiency, ethical standards, and global regulatory harmonization are discussed.
    Keywords:  Bayesian inference; FDA guidance; adaptive trials; biosimilars; clinical efficacy trials; drug development; equivalence testing; prior elicitation
    DOI:  https://doi.org/10.3389/fmed.2026.1790396
  28. J Dermatol Sci. 2026 Apr 16. pii: S0923-1811(26)00077-0. [Epub ahead of print]
    Treg cells as potential therapeutic targets for bullous pemphigoid: A review.
    Honghao He, Shiguang Peng, Xinyi Wei, Jinqing Zhang, Mei Cao, Fang Liu, Rina Su.
      Bullous pemphigoid (BP) is an autoimmune disease characterized by Bullous pemphigoid antigen 180(BP180) and Bullous pemphigoid antigen 230(BP230) autoantibodies production. Regulatory T cells (Tregs) are key cells for the maintenance of immune tolerance. Increasing evidence suggests that Treg dysfunction leads to autoantibody production and skin rashes in mice and humans, making immunomodulatory therapies targeting Tregs a potential therapeutic strategy for BP. Low-dose Interleukin-2 treatment and adoptive cell therapy are promising methods to modulate Tregs' numbers and function. Herein, we review the immunological mechanisms underlying BP pathogenesis, with an emphasis on the protective role of Treg cell-mediated immune tolerance in BP. Furthermore, we explore the potential therapeutic applications of Treg-based therapies for BP, providing novel insights into patient management.
    Keywords:  Adoptive cell therapy; Bullous pemphigoid; Low-dose IL-2; Regulatory T cells; Treg-based therapy
    DOI:  https://doi.org/10.1016/j.jdermsci.2026.04.003
  29. Drug Discov Today. 2026 Apr 24. pii: S1359-6446(26)00087-5. [Epub ahead of print] 104682
    Regulatory innovation for drug repurposing: Ten proposals to accelerate access and safety.
    Sara Pintado, Adelaide Fernandes, Esther A M Bührman, Joanna IntHout, Sofia Oliveira-Martins.
      Despite increasing efforts and incentives to address the critical lack of treatments for rare diseases, a substantial gap persists between patient needs and available therapies. Drug repurposing is a promising strategy in this field; nevertheless, it has not yet translated into a substantial increase in approved medicines. Although several EU regulatory pathways exist, none is tailored to drug repurposing, resulting in a complex landscape, particularly for nonprofit organisations. While there is no silver bullet, this article presents ten regulatory proposals to foster dialogue with decision-makers to tackle bottlenecks in areas of unmet medical need through a collaborative model with aligned incentives for all stakeholders. These proposals are based on published literature and the authors' experience in the SIMPATHIC project.
    Keywords:  European regulatory framework; drug approval; drug repurposing; orphan drugs; policy recommendations; rare diseases; real-world evidence
    DOI:  https://doi.org/10.1016/j.drudis.2026.104682
  30. Turk J Med Sci. 2026 ;56(2): 405-425
    Artificial intelligence-assisted neuropharmacology: reshaping drug discovery and translational strategies for neurological diseases.
    Priyanka Rathee, Sunidhi Lohan, Sarita Khatkar, Neelam Malik, Esra Küpeli Akkol, Renu Sehrawat, Pooja Rathee, Anurag Khatkar.
      The rapid expansion of data-driven technologies, particularly machine learning (ML) and artificial intelligence (AI), has substantially influenced biomedical research and drug discovery. In neuropharmacology, the availability of large-scale genomic, proteomic, chemical, and clinical datasets has stimulated the adoption of AI-based approaches to address persistent challenges in neurological drug development, including high attrition rates and the scarcity of disease-modifying therapies. Unlike prior reviews that broadly discuss AI applications in drug discovery or neurology, this narrative review focuses specifically on neuropharmacology, with an emphasis on translational relevance, disease-oriented examples, and real-world constraints. We critically examine the application of AI and ML across key stages of the neuropharmacological drug discovery pipeline, including target identification, drug-target interaction prediction, lead optimization, toxicity assessment, and early-stage clinical translation. Particular attention is given to concrete case studies in neurodegenerative and neurological disorders, illustrating where AI has meaningfully enhanced discovery efficiency and where its anticipated "revolutionary" impact has not yet been realized. In parallel, we analyze the biological, technical, and regulatory barriers that limit the clinical success of AI-driven strategies, including data bias, limited model interpretability, incomplete understanding of brain biology, and translational bottlenecks. By integrating case-based evidence with a critical analytical perspective, this review delineates both the opportunities and limitations of AI in neuropharmacology. We argue that AI is most effective when deployed as a complementary tool alongside mechanistic neuroscience and clinical expertise, rather than as a standalone solution. As AI methodologies continue to mature, their careful, transparent, and ethically governed integration into neuropharmacological research may advance precision medicine and help bridge persistent gaps in the treatment of neurological disorders.
    Keywords:  Neurological disorders; artificial intelligence; digital age; drug design; drug discovery; machine learning
    DOI:  https://doi.org/10.55730/1300-0144.6176
  31. Biosci Trends. 2026 Apr 26.
    Pathways to embed digital health technologies and their governance mechanisms in Long-Term Care Insurance Systems: A comparative review of Japan, South Korea, and China.
    Yuhan Cheng, Yue Han, Li Wang, Jiajia Ma, Kenji Karako, Yan Shi, Peipei Song.
      Rapid population aging is increasing demand for long-term care (LTC), prompting many countries to institutionalize financing and service provision through long-term care insurance (LTCI). Digital health technologies are increasingly embedded into LTCI, and yet the pathways in which they are embedded and their governance effects differ across institutional contexts. This comparative review synthesizes evidence from Japan, South Korea, and China across five operational domains-institutional foundations, eligibility determination, service management, fund oversight, and policy steering-and uses a sociotechnical systems lens to analyze how technology and institutions co-evolve. We propose a three-layer model of institutional embedding linking welfare-boundary constraints, governance mechanisms shaping data-driven operations, and path dependence in policy and implementation. In the three countries, digital health technologies have not fundamentally expanded the welfare boundary of LTCI, but they have reshaped how LTCI is administered, shifting i) needs assessment from experience-led judgment toward data-driven decision-making support, ii) service management from flexible discretion toward rules and platform-based coordination, and iii) oversight from ex post auditing toward process-oriented monitoring. Distinct national pathways have emerged: a supplementary-technology pathway in Japan, a state-led integration pathway in South Korea, and an exploratory co-evolutionary pathway in China. These benefits are accompanied by practical risks, including algorithmic bias, inconsistent data quality, privacy and security concerns, and potential erosion of institutional flexibility. The proposed model helps explain cross-national divergence and provides a governance-oriented basis for selecting embedding strategies and safeguards in different LTCI contexts.
    Keywords:  algorithmic bias; data infrastructure integration; fund oversight; model of institutional embedding; policy implementation; sociotechnical systems theory
    DOI:  https://doi.org/10.5582/bst.2026.01098
  32. Front Immunol. 2026 ;17 1819701
    PSMA-directed CAR-T cell therapy for metastatic castration-resistant prostate cancer: a next-generation engineering perspective on stem cell-derived immune effectors.
    Meng Zhang, Huimin Li, Kaisen Liao.
      The clinical translation of prostate-specific membrane antigen (PSMA)-directed chimeric antigen receptor (CAR) T-cell therapy for metastatic castration-resistant prostate cancer (mCRPC) has reached a critical impasse. Despite compelling preclinical rationale and early biological activity, durable clinical responses remain scarce, constrained by three core solid tumor challenges: a profoundly immunosuppressive/metabolically hostile tumor microenvironment (TME), pervasive antigen heterogeneity driving immune escape, and intrinsic limitations in T-cell fitness and in vivo persistence. This review synthesizes the current translational landscape (updated to February 2026), and posits a tripartite synergistic framework to systematically deconstruct these barriers: (1) advances in CAR synthetic biology; (2) active TME reprogramming via armored CAR-T cells, stromal-targeting agents, and rational combinations; (3) next-generation cellular product paradigms, with a focus on stem cell-derived immune effectors. Emerging platforms, including induced pluripotent stem cell (iPSC)-derived CAR-T, CAR-natural killer (NK) cells, and CAR-macrophages, offer unprecedented opportunities to overcome autologous product limitations via off-the-shelf availability, enhanced persistence, and intrinsic TME resistance. We further delineate a translational roadmap emphasizing biomarker-driven adaptive trials, predictive humanized preclinical models, and accessibility strategies. All core claims are graded using the 2011 Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence to ensure academic rigor. This work provides a strategic blueprint to advance PSMA-CAR-T therapy toward curative-intent mCRPC treatment, with insights broadly applicable to next-generation stem cell-derived immunotherapies.
    Keywords:  CAR-T cells; PSMA; induced pluripotent stem cells; metastatic castration-resistant prostate cancer; synthetic biology; translational medicine; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1819701
  33. Front Immunol. 2026 ;17 1704419
    Ionizing radiation enhances CAR T-cell infiltration and efficacy in solid tumors.
    Lisa Zhan, Meredith A Clark, Pauline Loos, Che-Min Lee, Laura E R Paulus, Rocky Shi, Prabhreet K Sekhon, James M Piret, Laura Evgin, Kevin L Bennewith.
      Chimeric antigen receptor (CAR) T cells represent an exciting therapeutic strategy with improved survival outcomes for patients with hematological malignancies. However, the efficacy of CAR T-cell therapy in the treatment of solid tumors remains suboptimal due to therapeutic barriers associated with the solid tumor microenvironment. We investigated whether ionizing radiation could improve vascular perfusion and CAR T-cell delivery in an EGFRvIII-expressing B16F10 melanoma model. Tumors received radiation doses of 2-12 Gy, and perfusion was evaluated at multiple time points using immunofluorescence detection of intravenously administered fluorescent dyes. We found that a single 8-Gy dose of ionizing radiation produced the most significant increase in B16F10 tumor perfusion 4 h after irradiation. Consistently, the irradiation of tumors 4 h prior to a systemic administration of EGFRvIII-targeting CAR T cells led to higher intratumoral CAR T-cell accumulation than in non-irradiated tumors. This approach also resulted in a significantly delayed tumor growth and improved survival relative to radiation or CAR T cells alone. Interestingly, the CD28ζ EGFRvIII-CAR T-cell levels substantially increased in irradiated tumors over time relative to 4-1BBζ EGFRvIII-CAR T cells and produced greater tumor growth delays and survival improvements in comparison to 4-1BBζ EGFRvIII-CAR T cells administered at a 10-fold higher concentration. Taken together, these data highlight the importance of co-stimulatory domains in CAR T-cell function in vivo and demonstrate that irradiating tumors prior to systemic CAR T-cell infusion can increase CAR T-cell infiltration and efficacy in solid tumors.
    Keywords:  CAR T cell therapy; ionizing radiation; melanoma; perfusion; solid tumors
    DOI:  https://doi.org/10.3389/fimmu.2026.1704419
  34. Chembiochem. 2026 May 14. 27(9): e70354
    Detection of Diagnostic Antibodies in Immune-Mediated Diseases: A Focus on Antigens and Technologies.
    Silvia Bracci, Feliciana Real-Fernandez, Federico Pratesi, Francesca Nuti, Paolo Rovero, Anna Maria Papini.
      Autoimmune diseases are conditions characterized by aberrant B-cell and T-cell reactivity against self-antigens. Autoantibodies are serological biomarkers of autoimmune diseases, as such, autoantibody testing is a key step for diagnosing and classifying many autoimmune diseases, as well as monitoring disease activity and devising a treatment strategy. Considering the rising number of people affected by autoimmune diseases worldwide, it is even more important to have efficient techniques that combine high sensitivity and specificity with reduced sample processing times and an automated high-throughput workflow. In this context, the identification and validation of new autoantigens and autoantibodies, together with the implementation of technological advancements, has led, in the last decades, to an improvement in patient diagnosis and stratification. Here, we review the major antigens of some of the most common autoimmune diseases, and the most widely used assays employed in diagnostic laboratories for the detection of their cognate antibody, confronting more traditional platforms with emerging ones in selected cases of study.
    Keywords:  autoantibodies; autoimmune diseases; immunoassays; peptide and protein antigens; serological biomarkers
    DOI:  https://doi.org/10.1002/cbic.70354
  35. EMBO Mol Med. 2026 Apr 27.
    Regulatory challenges of personalized medicine in the real world: are the right patients being treated with CD19-targeting CAR T-cells?
    Attila Sebe, Rafael Hernani, Jan Müller-Berghaus.
      Despite the clinical success of CD19-directed CAR T-cell therapies, less than 50% of patients achieve long-term remission. Emerging evidence indicates that loss or reduced expression of CD19-due to mutations, deletions, alternative splicing-is a significant, underrecognized mechanism of treatment failure. Notably, CD19-negative subpopulations can be detected even prior to therapy, and patients with low CD19 expression consistently show poorer outcomes. Although current clinical guidelines do not mandate routine CD19 testing before treatment, this situation reflects both scientific and technical challenges. Importantly, patients with partial/ low CD19 expression may still benefit from therapy, complicating the definition of "target positivity." From a regulatory perspective, targeted therapies should ideally be used only when target expression is confirmed. This principle is difficult to implement, considering the scarcity of data and the difficulties of current diagnostic tools, risking both undertreatment and overtreatment. EU regulators have addressed the issue by introducing harmonized warnings in product information, but more is needed. We highlight this regulatory-clinical gap and advocate for improved diagnostic standards, better data integration, and dialogue among clinicians, developers, and regulators.
    DOI:  https://doi.org/10.1038/s44321-026-00436-2
  36. Annu Rev Biomed Data Sci. 2026 Apr 28.
    Clinical Knowledge Representation in Data Science.
    Tram Anh Nguyen, Wendy Su, Ananya Rajagopalan, Nia Abdurezak, Oresta S I Hewryk, Joseph D Romano.
      The vast potential of observational healthcare data in biomedical discovery remains largely unrealized because clinical records are fragmented, unstructured, and generated for patient care rather than research. Clinical knowledge representation (KR) helps to bridge this gap by encoding information in standardized, computable formats that preserve meaning and context. This review examines KR across the clinical data life cycle, from the generation of data in healthcare settings to their transformation for secondary use and eventual application in data science. We highlight foundational components such as standardized terminologies, ontologies, and common data models that enable data harmonization and interoperability. We further discuss how these structured representations support multimodal data integration and the development of more accurate, interpretable artificial intelligence models. Adopting a semantics-first approach to KR is essential for transforming fragmented clinical data into reusable, trustworthy knowledge that advances data-driven discovery and improves patient care.
    DOI:  https://doi.org/10.1146/annurev-biodatasci-092724-050810
  37. JMIR Res Protoc. 2026 Apr 27. 15 e86001
    Geriatric Telemanagement of Health Conditions (GET HEALTH) in Nursing Home Residents Recently Discharged From the Hospital: Protocol for a Before-After Study.
    Giuseppina Dell'Aquila, Mirko Di Rosa, Irene Aguzzi, Francesca Suppa, Barbara Carrieri, Alessia Beccacece, Antonia Scrimieri, Lorena Rossi, Fabio Salvi, Massimiliano Fedecostante, Flavia Carle, Antonio Cherubini.
       Background: Nursing home (NH) residents have a high burden of multimorbidity and disability and are frequently hospitalized. Comprehensive geriatric assessment might reduce hospitalization. However, few geriatricians are working in NHs. Technology might be used to overcome this problem.
    Objective: This study aims to verify if a geriatric telemanagement model improves patient outcomes in NH residents recently discharged from the hospital.
    Methods: Clinical outcomes of NH residents recently discharged from the hospital are compared before and after the implementation of GTM, where a geriatrician evaluates each patient during televisits with NH staff and discusses the case with the general practitioner. NH residents aged ≥70 years readmitted to NHs after hospitalization in the 3 years prior to the COVID-19 pandemic (2017-2019) represent the control group enrolled in the retrospective preintervention phase. The primary outcome of the study is the hospital readmission rate during 6-month follow-up. Health technology assessment evaluates the cost-effectiveness of model implementation.
    Results: A total of 333 NH residents were included in the preintervention retrospective study. Data collection started in February 2022 and was completed in February 2023. A total of 104 NH residents were recruited in the intervention study, from March 2024 to March 2025. Data analysis is currently in progress.
    Conclusions: Currently, NHs in Italy are striving to manage the complexity of older patients who are often hospitalized. A geriatric telemanagement model might reduce hospitalizations, and therefore negative outcomes, as well as health care costs in this vulnerable population.
    Keywords:  comprehensive geriatric assessment; geriatrician; nursing home; telemedicine; televisit
    DOI:  https://doi.org/10.2196/86001
  38. PLoS Comput Biol. 2026 Apr;22(4): e1014211
    Evaluating the utility of amino acid similarity-aware kmers to represent TCR repertoires for classification.
    Hannah Kockelbergh, Shelley C Evans, Liam Brierley, Peter L Green, Andrea L Jorgensen, Elizabeth J Soilleux, Anna Fowler.
      Insights gained through interpretation of models trained on the T-cell receptor (TCR) repertoire contribute to advances in understanding of immune-mediated disease. This has the potential to improve diagnostic tests and treatments, particularly for autoimmune diseases. However, TCR repertoire datasets with samples from donors of known autoimmune disease status generally include orders of magnitude fewer samples than TCR sequences. Promising TCR repertoire classification approaches consider relationships between non-identical TCR sequences. In particular, kmer methods demonstrate strong and stable performance for small datasets. We propose a TCR repertoire representation that considers the relationships between amino acids within kmers flexibly and efficiently. XGBoost and logistic regression models are trained and tested on kmer representations of TCR repertoire datasets including samples from patients with coeliac disease as well as donors with previous cytomegalovirus infection. XGBoost models outperform logistic regression, indicating that interactions may be crucial for discriminative ability. We find that a reduced alphabet based on BLOSUM62 can lead to a model with slightly stronger XGBoost testing performance than other kmer features. Though it remains unclear whether there is an amino acid encoding that can substantially improve TCR repertoire classification with reduced alphabet kmers, evidence that this representation enables faster training of XGBoost models in comparison to kmer clusters suggests that our reduced alphabet approach permits wider exploration of amino acid similarity in practice. Finally, we detail motifs which are important in each top-performing XGBoost model and compare them to TCR sequences previously associated with each immune status. We highlight the challenge of interpreting non-linear TCR repertoire classification models trained on kmers which, if overcome, could lead to biomarker discovery for autoimmune diseases.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014211
  39. Immunology. 2026 Apr 28.
    Natural Killer Cell-Based Immunotherapy in HCC.
    Linlin Che, Xueting Xie, Xiaoyu Yang, Shiguo Zhu, Yufu Zhou.
      Hepatocellular carcinoma (HCC) poses a formidable therapeutic challenge due to its high heterogeneity, frequent late-stage diagnosis, and chemoresistance. Natural killer (NK) cells are essential for immune surveillance, yet their quantity and function become significantly compromised during HCC progression, thereby promoting tumour immune escape. This review systematically outlines current NK cell-based immunotherapeutic strategies for HCC, including adoptive NK cell transfer, genetic engineering of NK cells, NK cell inhibitory receptor-targeted therapies, reprogramming of the immunosuppressive HCC microenvironment, cytokine-mediated enhancement of NK cell function, and traditional Chinese medicine-augmented NK cell cytotoxicity. Representing a promising immunotherapeutic paradigm, NK cell-based therapy is rapidly advancing from conventional cell infusion toward more precise modalities, including CAR-NK cells and multifunctional antibody engagers. However, the efficacy of these approaches is frequently curtailed by the immunosuppressive tumour microenvironment and tumour heterogeneity. Given the multifactorial nature of NK cell dysfunction, we highlight that rationally designed combination strategies-integrating genetic engineering, TME reprogramming, and checkpoint blockade-represent the most viable path toward durable clinical responses in HCC.
    Keywords:  hepatocellular carcinoma; immunotherapy; natural killer cell; tumour escape
    DOI:  https://doi.org/10.1111/imm.70141
  40. Vaccines (Basel). 2026 Apr 21. pii: 365. [Epub ahead of print]14(4):
    Role of Donor Unrestricted T Cells (DURTs) in TB Host Defense: Implications for Novel TB Vaccine Development.
    Dylan Kain, David Michael Lewinsohn, Deborah Anne Lewinsohn.
      Tuberculosis (TB) is the leading cause of infectious disease-related death globally. Most TB vaccine strategies have focused on conventional CD4 T cell responses, but to date, these have failed to deliver durable sterilizing protection. Donor unrestricted T cells (DURTs), including CD1-restricted T cells, HLA-E-restricted T cells, MR1-restricted T cells and γδ T cells represent an attractive complementary target for future TB vaccine development. They recognize antigens through conserved, non-polymorphic restricting elements and are therefore broadly targetable across genetically diverse populations. They are also enriched at mucosal sites, have rapid effector and cytotoxic capacities and recognize conserved mycobacterial ligands. Emerging human and animal data support their participation in antimycobacterial immunity and suggest they can be shaped by BCG vaccination and other immunization strategies. Here, we review the evidence for DURT involvement in TB host defense, assess their strengths and current limitations as vaccine targets, and discuss how DURT-directed approaches may help to enable faster, broader, and more durable protection against Mycobacterium tuberculosis.
    Keywords:  Mycobacterium tuberculosis; donor unrestricted T cells (DURTs); tuberculosis
    DOI:  https://doi.org/10.3390/vaccines14040365
  41. Mol Ther. 2026 Apr 27. pii: S1525-0016(26)00288-1. [Epub ahead of print]
    CAR-T cell therapy: "New black" for children with severe, refractory, B cell-mediated autoimmune disorders.
    Franco Locatelli, Fabrizio De Benedetti, Georg Schett.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.023
  42. Curr Opin Neurol. 2026 Jun 01. 39(3): 273-280
    Investigational approaches to multiple sclerosis therapy.
    Joshua M Boeckers, Marc Pawlitzki, Hans-Peter Hartung, Tobias Ruck, Sven G Meuth.
       PURPOSE OF REVIEW: Multiple sclerosis (MS) research is entering a new therapeutic era. Beyond relapse rate reduction, the prevention of disability progression and, ideally, even the avoidance of disease development are now being formulated as new therapeutic goals. This review summarizes emerging treatment strategies spanning next-generation immunomodulation, Epstein-Barr virus (EBV) targeted interventions, remyelination agents, and cell-based therapies.
    RECENT FINDINGS: Central nervous system (CNS) penetrant Bruton's tyrosine kinase (BTK) inhibitors show early indications of slowing progression by targeting compartmentalized inflammation. Fc-silent CD40L blockade offers a non-depleting alternative and suppresses magnetic resonance imaging (MRI) activity in a phase 2 trial. EBV-directed strategies, including adoptive T-cell therapy and prophylactic or therapeutic vaccines, represent initial attempts to modify a likely causal driver of MS. Remyelination candidates including clemastine, selective M1 muscarinic receptor antagonists and other emerging agents, demonstrate biological activity but limited clinical benefit. Cell-based approaches, such as mesenchymal stem cell derived neural progenitors (MSC-NPs) and CD19 or B-cell maturation antigen (BCMA) targeted chimeric antigen receptor T-cell (CAR-T) constructs, remain early phase but show initial biological signals.
    SUMMARY: These advances mark a shift toward precision immunomodulation, causal targeting, and CNS repair, with BTK inhibitors and CD40L blockade advancing as promising candidates to address progression in MS.
    Keywords:  Bruton's tyrosine kinase inhibitors; CD40L blockade; Epstein–Barr virus-targeted therapies; multiple sclerosis; remyelination strategies
    DOI:  https://doi.org/10.1097/WCO.0000000000001494
  43. J Med Internet Res. 2026 Apr 29. 28 e83369
    Rethinking Trust in Synthetic Health Data: Lessons From 7 European Research Initiatives.
    Jens Declerck, Dipak Kalra, Antti Airola, Ahmed Youssef Ali Amer, Christos Chatzichristos, Maria Del Mar Mañu Pereira, Bruno M de Brito Robalo, Francesco Ghini, Alberto Gutierrez-Torre, Sem Hoogteijling, Susanne Hultsch, Jan Ramon, Sara Reidel, Francesco Regazzoni, Luís Silva, Inês Silveira, Tsekeridou Sofia, Christophe Maes.
      Synthetic data generation (SDG) structured health data is increasingly promoted as a solution to longstanding barriers in health data access. It is offering the promise of privacy-preserving data reuse for research, innovation, and policy. Despite rapid technical advances, the adoption of synthetic health data in real-world settings remains limited. Shaped by challenges around data quality, representativeness, infrastructure readiness, trust, and legal uncertainty, this viewpoint draws on experiences from 7 European research initiatives within the HealthData4EU cluster to reflect on how SDG is being operationalized in practice. It synthesizes cross-project insights to highlight recurring methodological and governance tensions and to examine their implications for trust and responsible use. The analysis argues that trustworthy SDG cannot be achieved through technical optimization alone but requires alignment between evaluation practices, upstream data stewardship, regulatory clarity, and sustained stakeholder engagement. Addressing these conditions is essential for moving synthetic data from experimental pilots toward a credible and sustainable component of European health research ecosystems.
    Keywords:  data quality dimensions; health data; health data quality; privacy; project; synthetic data generation
    DOI:  https://doi.org/10.2196/83369
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