bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–04–26
48 papers selected by
Luca Bolliger, lxBio
  1. Capacitance Technology Enables Automated Feeding, Improved Expansion, and Higher Throughput of CAR-T Cell Stirred-Tank Bioreactor Cultures.
  2. Cell immunotherapy in autoimmune rheumatic diseases: a paradigm shift in the therapy of autoimmune inflammatory rheumatic diseases.
  3. Harnessing Neoantigen-specific T Cells for Precision Immunotherapy in Hematologic Malignancies.
  4. CAR T cells for pediatric CNS tumors: Clinical experience and reverse translational opportunities.
  5. Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune disease.
  6. CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch.
  7. Mapping the Use of Real-World Evidence Across the EU Health Technology Assessment Regulation: Methodological Considerations, Challenges, and Opportunities for Harmonization.
  8. CAR-T Cells: Current Status, Challenges, and Future Prospects.
  9. Reprogramming Antitumor Immunity: NK Cell Strategies to Navigate the Immunosuppressive Tumor Microenvironment.
  10. CAR-NK cell therapy for hematological malignancies.
  11. HITE: HIV Inspired Lipid Nanoparticle Platform for CAR T Cell Engineering.
  12. CAR-NK cell-based therapies: translational and regulatory breakthroughs.
  13. Consideration of the limitations of cost-effectiveness analysis for severe-rare disease drugs and potential solutions: a structured literature review.
  14. Anti-CD19 CAR T Cells in Autoimmune Encephalitis: Inflammation Controlled, Neurodegeneration Unchecked?
  15. γδ T cells in colorectal and liver cancer.
  16. Modeling chimeric antigen receptor response at the single-cell level with conditional optimal transport.
  17. Bispecific T-cell engagers in autoimmune diseases: mechanisms of action, clinical evidence challenges, and therapeutic perspectives.
  18. Organoid: a promising solution to current challenges in cancer immunotherapy.
  19. Natural Killer Cell Therapy in Ovarian Cancer: From Preclinical Potentials to Clinical Applications and Combination Strategies.
  20. Cell therapy manufacturing at full clinical scale: enhancing the quality CAR-T cell therapy starting materials through massively parallel automated microfluidic cell sorting.
  21. Descartes-08: Unlocking the potential of mRNA CAR T-cell therapy in myasthenia gravis.
  22. Application of BCMA CAR-T in systemic lupus erythematosus.
  23. Thailand's Aging Society: Reconsidering Policy and Innovation Readiness for Elderly Care.
  24. In vivo CAR-cell therapy: current challenges and emerging therapeutic advances.
  25. Circular RNA therapeutics: a new class of long-acting RNA medicines for oncology, immunology, and rare diseases.
  26. Self-amplifying RNA (saRNA) and circular RNA (circRNA) vaccines: Progress, evidence gaps, and translational pathways for durable and scalable immunization.
  27. Building trust and privacy in cross-border health data sharing for European cancer research.
  28. BAR12: Bayesian Autoregressive Phase 1-2 Design for Cell Therapy Trials With Manufacturing Changes.
  29. Transferability of Patient Selection Model for Proton Radiation Therapy to Lower-Income European Countries.
  30. Exosomes as Emerging Nanocarriers for Targeted Cancer Therapy.
  31. A systematic review and meta-analysis of shRNA-IL-6-engineered CAR-T cells for B-cell Acute Lymphoblastic Leukemia: a stepping stone towards risk-free immunotherapy.
  32. Early technology review during prototype development and at proof of concept: the case for developing a sequential versus a single-stage approach to early evidence development for health technologies.
  33. Beyond Batch Release: Responsible Decision-Making, Professional Judgement, and Governance in Complex Pharmaceutical Manufacturing.
  34. The microbial metabolome: remodeling the therapeutic landscape in hematologic malignancies.
  35. Shared pathogenic mechanisms between systemic lupus erythematosus and autoimmune hepatitis: A unified view of autoimmune convergence.
  36. A Review of Medical Data Sharing Initiatives With a Focus on the Use of Blockchain Technologies: Qualitative Comparative Analysis.
  37. Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.
  38. Modern Clinical Trials: Seamless Designs and Master Protocols.
  39. Value frameworks for digital health technologies: a comparative analysis.
  40. Artificial Intelligence in Drug Discovery and Development: Transforming Pharmaceutical Innovation.
  41. Therapeutic Remodeling of the Gut Microbiome as a Strategy to Restore Immune Tolerance in Autoimmunity.
  42. Advancing AI for multi-omics and clinical data integration in basic and translational cancer research.
  43. EZH2 and intracellular Ca2+ signals interdependently coordinate alloreactive and CAR-T-cell responses.
  44. Standardization of clinical trials subject ID schematics: A portfolio-wide model to enhance data integrity and regulatory compliance.
  45. Local cues, local killers: human natural killer cells across tissues.
  46. DLK1 - a novel therapeutic target in cancer.
  47. Digital twin applications in radiology and radiotherapy: Applications, challenges, and future perspectives.
  48. Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
  1. Biotechnol J. 2026 Apr;21(4): e70226
    Capacitance Technology Enables Automated Feeding, Improved Expansion, and Higher Throughput of CAR-T Cell Stirred-Tank Bioreactor Cultures.
    Ivano Luigi Colao, Jacob Cunningham, Matthew Lee, Stephen Goldrick, Qasim Ali Rafiq.
      Chimeric antigen receptor (CAR) T cells present a novel and transformative approach to treat certain haematological malignancies. However, CAR-T cell expansion methods are still under development and often rely on manual, low-control culture methods. The transition to bioreactors would allow for greater process control and scalability and is a key focus of research in the field. Despite this, there are few methods to determine culture progression without the need for manual cell sampling which risks introducing errors and heightening contamination risks. In this article, we assessed whether capacitance technology could deliver reliable, on-line cell concentrations by comparing T cell, and CAR-T cell bioprocesses with Chinese hamster ovary (CHO) cultures-widely used in biotechnology and with established capacitance usage. Finding that capacitance technology could accurately measure CAR-T cell concentrations, we then demonstrated the automation of feeding using capacitance-derived triggers which improved bioprocess performance in terms of cell concentration and throughput. We anticipate that this study will expand avenues of investigation regarding capacitance as a suitable process analytical technology (PAT) to enable monitoring and control of CAR-T cell manufacture, and potentially other cell and gene therapy products. It may also enable remote monitoring of multiple batches, harvest control, and the generation of large collections of process data for modelling, which will further progress the field.
    Keywords:  Jurkat; bioprocess 4.0; cell and gene therapy; chimeric antigen receptor T cells; dielectric spectroscopy; process analytical technology
    DOI:  https://doi.org/10.1002/biot.70226
  2. Clin Rheumatol. 2026 Apr 18.
    Cell immunotherapy in autoimmune rheumatic diseases: a paradigm shift in the therapy of autoimmune inflammatory rheumatic diseases.
    Ian C Chikanza, Lazaros I Sakkas.
      Autoimmune inflammatory rheumatic diseases (AIRDs) remain a major cause of chronic morbidity worldwide despite substantial advances in biologic and targeted synthetic disease-modifying antirheumatic drugs. A considerable proportion of patients experience inadequate disease control, intolerance, or primary nonresponse, highlighting the need for fundamentally different therapeutic strategies. Cell-based immunotherapies represent a paradigm shift, aiming not merely to suppress inflammation but to re-establish immune tolerance and restore physiological immune homeostasis. Mesenchymal stem cell (MSC) therapy, regulatory T cell (Treg) immunotherapy, chimeric antigen receptor (CAR)-T cell therapy, and emerging exosome-based approaches are at the forefront of this transformation. MSCs exert broad immunomodulatory, anti-inflammatory, and reparative effects through coordinated actions on innate and adaptive immune cells, paracrine signalling, extracellular vesicles, and metabolic and epigenetic reprogramming. Early-phase clinical studies in refractory rheumatoid arthritis and systemic lupus erythematosus demonstrate clinically meaningful improvements with acceptable short-term safety, although heterogeneity in cell sources, manufacturing, and treatment protocols remains a key limitation. Treg-based therapies seek to correct defective immune tolerance by restoring regulatory cell number and function, offering the potential for durable disease control but currently constrained by cost, technical complexity, and safety considerations. CAR-T cell therapy, initially developed for haematological malignancies, has shown unprecedented efficacy in selected refractory autoimmune diseases by selectively depleting pathogenic immune cell populations, with reports of sustained, and in some cases drug-free, remission. Exosome-based therapies provide a promising cell-free alternative, potentially improving safety, scalability, and standardisation. Optimal patient selection, early intervention, and long-term safety will be critical determinants of success. Cell immunotherapy has the potential to redefine AIRD management, shifting from chronic immunosuppression toward sustained remission and possible cure.
    Keywords:  Autoimmune inflammatory rheumatic diseases; CAT T cells; Cell immunotherapy; Chimeric antigen receptor T cells; Exosomes; Immune tolerance; Mesenchymal stem cells; Precision immunotherapy; Regulatory T cells; Rheumatoid arthritis; SLE
    DOI:  https://doi.org/10.1007/s10067-026-08103-0
  3. Blood. 2026 Apr 20. pii: blood.2025030711. [Epub ahead of print]
    Harnessing Neoantigen-specific T Cells for Precision Immunotherapy in Hematologic Malignancies.
    Anmol Kandel, Soung-Chul Chul Cha, Larry W Kwak.
      Antigen-specific T-cell immunotherapies are transforming the treatment landscape of hematologic malignancies. Neoantigen-specific therapies that exploit the ability of endogenous T-cell receptors (TCRs) to recognize tumor-derived peptides in a human leukocyte antigen (HLA)-restricted context differ mechanistically from modalities employing chimeric antigen receptor (CAR) T cells, which target surface antigens in an HLA-independent manner. In contrast to approaches targeting tumor-associated antigens (TAAs), neoantigen-specific strategies offer more precise tumor selectivity and reduced off-target toxicity. Advances in immunogenomics, immunopeptidomics, and functional validation have accelerated the identification of both personalized and recurrent neoantigens, and high-resolution sequencing technologies have further facilitated the characterization of their cognate TCRs, which are currently being explored for developing TCR-engineered T cell therapies. Early-phase clinical trials in hematologic malignancies demonstrate that neoantigen-specific strategies are safe and feasible across multiple hematologic cancers, with ongoing studies actively assessing the immunogenicity, clinical efficacy, and durability of these approaches. This review synthesizes recent pre-clinical and clinical advances in the discovery, validation, and therapeutic exploitation of neoantigen-specific strategies in blood cancers, highlighting translational insights for prioritizing immunogenic neoantigens. Particular emphasis is placed on identifying biological and technological barriers that limit the therapeutic efficacy of neoantigen-specific immunotherapies, with the goal of distilling actionable insights to guide their development in hematologic malignancies.
    DOI:  https://doi.org/10.1182/blood.2025030711
  4. Mol Ther Oncol. 2026 Jun 18. 34(2): 201196
    CAR T cells for pediatric CNS tumors: Clinical experience and reverse translational opportunities.
    Kun-Wei Song, Aanchal Preet Kaur, Sneha Ramakrishna.
      Central nervous system (CNS) tumors are one of the leading causes of cancer-related mortality in children and young adults. Despite decades of research, effective treatments for these tumors are still lacking and new therapeutic options are urgently needed. While chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of hematologic malignancies, these cellular therapies are only beginning to show evidence of activity in CNS tumors. In this review, we will discuss current CAR T cell clinical trials with a focus on trials in the pediatric CNS tumor space. In addition, we will explore the power of reverse translation-defined by applying clinical research insights from bedside-to-bench to understand the mechanisms of CAR T cell success or failure in patients-for CNS tumor CAR T cells. Employing the full cycle of translational research, novel CAR T cell therapies are being tested in the clinic and reverse translational studies are being assessed at the bench. Combining these data, the CNS CAR T cell field is poised to iteratively improve CAR T cells for children and young adults with CNS tumors.
    Keywords:  CAR T cell therapy; CNS tumors; MT: Special Issue: advancements in pediatric cancer therapy; immunotherapy; pediatric cancer; reverse translation; translational research
    DOI:  https://doi.org/10.1016/j.omton.2026.201196
  5. Front Immunol. 2026 ;17 1806459
    Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune disease.
    Marc Scherlinger.
      CAR T-cell therapy has delivered durable remissions in several hematologic cancers, yet activity in solid tumors and extension to immune-mediated diseases remain constrained by recurring failure modes: imperfect antigen specificity, inadequate trafficking, progressive dysfunction under chronic stimulation, and toxic inflammatory syndromes. Early reports of CAR-based immune "resets" in refractory autoimmune disease amplify both promise and stakes, because acceptable risk is lower than in cancer and "on-target" effects may still be clinically unacceptable if they create long-term immunodeficiency. This review treats CAR T optimization as multi-layer reprogramming across genetic circuitry, epigenetic state, metabolism, and the tissue microenvironment. We argue that many celebrated single-layer upgrades (stronger signaling, checkpoint deletion, constitutive cytokine armoring) often trade one failure mode for another. Instead, the most credible path to simultaneously improving efficacy and safety is disciplined, failure-mode-driven design: (i) programmable antigen logic and titratable activation to reduce off-tissue damage; (ii) epigenetic programming that preserves renewable functional states without removing essential restraints; (iii) metabolic rewiring evaluated under physiologic stress conditions; and (iv) microenvironment-aware strategies that prioritize access and local control over brute-force potency.
    Keywords:  CAR T cells; CAR-Treg; autoimmunity; exhaustion; genome editing; immunometabolism; safety switches; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1806459
  6. Front Immunol. 2026 ;17 1692287
    CD19-negative relapse after CAR-T cell therapy: mechanisms of antigen escape and lineage switch.
    Jiawen Huang, Xiaobing Huang, Duonan Yu.
      CD19 chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of relapsed/refractory B-cell malignancies, achieving high remission rates. Nonetheless, 20%-40% of patients eventually relapse, classified as either CD19+ or CD19- relapse. Most relapses are CD19+, largely due to reduced potency and poor persistence of CAR-T cells after infusion. In contrast, a substantial fraction of patients develops CD19- relapse driven by selective pressure from CAR-T cell therapy. Post-CAR-T cell CD19- relapse primarily arises through three mechanisms. First, pre-existing CD19- subclones, particularly those with progenitor-like features, expand because of their survival advantages. Second, CD19 expression is downregulated through pre-existing or newly acquired genetic alterations (mutations and abnormal splicing), epigenetic silencing, and post-transcriptional dysregulation. Third, lineage switching to a myeloid phenotype increases notably after CAR-T cell treatment. This myeloid conversion is frequently associated with KMT2A rearrangements and is driven by epigenetic reprogramming, impaired expression of B-cell regulators, and the presence of bipotent progenitors within leukemia or lymphoma. CD19- relapse constitutes a major clinical barrier to the durable efficacy of CD19-CAR T-cell therapy. Understanding these diverse escape mechanisms is crucial for developing preventive strategies and effective salvage therapies to maintain long-term remission. To mitigate CD19- relapse, a coordinated dual strategy is needed. First, novel therapeutic approaches should be developed, including CAR products targeting alternative antigens, optimized salvage regimens, and CD19 re-induction strategies. Second, high-resolution molecular profiling should be used to identify high-risk patients and guide pre-emptive or combinatorial interventions based on the molecular underpinnings of CD19- relapse. Together, these approaches will deepen mechanistic insight into CD19- relapse and enable targeted prevention and management of this key limitation of CAR T-cell therapy.
    Keywords:  CAR-T cell therapy; CD19- relapse; leukemia; loss of antigen; lymphoma
    DOI:  https://doi.org/10.3389/fimmu.2026.1692287
  7. J Mark Access Health Policy. 2026 Apr 08. pii: 20. [Epub ahead of print]14(2):
    Mapping the Use of Real-World Evidence Across the EU Health Technology Assessment Regulation: Methodological Considerations, Challenges, and Opportunities for Harmonization.
    Grammati Sarri, Bengt Liljas, Keith R Abrams, Stephen J Duffield, Murtuza Bharmal.
      Methodological guidelines for real-world evidence (RWE) in European Union (EU) joint clinical assessments (JCA) are lacking. This manuscript explores RWE potential in EU health technology assessment (HTA) and offers recommendations for generating high-quality RWE. An environmental scan of peer-reviewed and gray literature was conducted to review RWE frameworks and documents in EU regulatory and HTA decision-making. Extraction elements were standardized across key RWE themes: data quality, methodological rigor, stakeholder engagement, and applications. In JCA, RWE has multiple uses, including informing PICO simulation exercises, understanding disease landscape, identifying prognostic factors and effect modifiers, and directly or indirectly informing comparative clinical assessments. Methodological guidance from the HTA Coordination Group is limited to cases in which evidence from non-randomized studies is used as direct inputs in comparative assessments. Individual HTA bodies provide more detailed guidance, missing an opportunity to leverage RWE within JCAs that can offer insight for local Member State submissions. Generating high-quality RWE that is credible, actionable, and acceptable for JCA submissions and local HTA bodies requires careful attention to methodological considerations and early planning. Broader RWE integration that reflects patient journeys is needed. Expanding the HTA Coordination Group guidance can unlock RWE's full potential in supporting EU JCA submissions.
    Keywords:  European Union; guidance; health technology assessment; joint clinical assessments; real-world data; real-world evidence
    DOI:  https://doi.org/10.3390/jmahp14020020
  8. MedComm (2020). 2026 May;7 e70606
    CAR-T Cells: Current Status, Challenges, and Future Prospects.
    Aya Sedky Adly, Guillaume Cartron, Afnan Sedky Adly, Jean-Christophe Egea, Pierre-Yves Collart Dutilleul, Mahmoud Sedky Adly, Martin Villalba.
      As chimeric antigen receptor (CAR)-T cell therapy has expanded rapidly to meet the growing global cancer burden; many challenges have emerged as a critical factor influencing its efficacy. However, due to the complicated mechanisms of CAR-T cells, human interference alone was insufficient to optimize the outcomes. In parallel, artificial intelligence (AI) has begun to intersect with CAR-T cells, offering novel computational interferences that can refine therapeutic mechanisms. The literature is still lacking a comprehensive investigation that merges CAR-T cell mechanistic biology and limitations with the advancing abilities of AI to meet these barriers. This review provides an overview of the mechanistic foundations of CAR-T cell. It also investigates the various challenges facing the current CAR-T therapies including toxicity, resistance, and accessibility issues. On this basis, we examined the way AI-based innovations are being utilized to optimize the CAR-T engineering and clinical management. Finally, we examined clinical studies and case studies incorporating AI elements, emphasizing both therapeutic mechanisms and outcomes of the study. By integrating mechanistic biology with computational innovation, this review provides a unified unique perspective that can guide the development of safer and more effective CAR-T therapies.
    Keywords:  algorithm; and machine learning; challenges; chimeric antigen receptor; mechanisms; trogocytosis
    DOI:  https://doi.org/10.1002/mco2.70606
  9. Adv Sci (Weinh). 2026 Apr 21. e75326
    Reprogramming Antitumor Immunity: NK Cell Strategies to Navigate the Immunosuppressive Tumor Microenvironment.
    Tereza Kochs, Pranay Nath, Alice Chen, Rizwan Romee, Andreia Maia.
      Tumor immune escape is a major barrier to durable cancer immunotherapy, as advanced malignancies create a tumor microenvironment (TME) that preferentially exhausts and disables T cell responses. While most approved cell therapies are T cell-based, this limitation motivates the exploration of an alternative effector cell platform. Natural killer (NK) cells, innate cytotoxic lymphocytes capable of antigen-independent recognition and killing, offer a compelling foundation for next-generation therapies with an improved safety profile. In this review, we first outline the cellular, molecular, and metabolic features of the immunosuppressive TME that restrict cytotoxic lymphocyte function, emphasizing mechanisms that limit immune cell-mediated responses. We then summarize key aspects of NK cell biology that can circumvent these barriers and critically evaluate current NK-based strategies, including engineered chimeric antigen receptor (CAR)-NK products and metabolic and trafficking interventions. Finally, we highlight emerging in vivo viral and mRNA/lipid nanoparticle platforms for CAR-NK generation and their potential to enhance scalability and therapeutic durability.
    Keywords:  CAR‐NK cells; cell therapy; immunotherapy; in vivo gene editing; natural killer cells; tumor immune escape
    DOI:  https://doi.org/10.1002/advs.75326
  10. Blood Adv. 2026 Apr 22. pii: bloodadvances.2024014082. [Epub ahead of print]
    CAR-NK cell therapy for hematological malignancies.
    Gohar Shahwar Manzar, Md Faqrul Hasan, Madison Moore, Silvia Tiberti, Rafet Basar, May Daher.
      Chimeric antigen receptor (CAR)-natural killer (NK) cells represent a novel cell therapy platform distinguished from CAR-T cells by their more favorable safety profile, easier off-the-shelf allogeneic manufacturing and consequent scalability, and their innate cytotoxicity without needing prior sensitization. CAR-NK cells derived from a variety of sources have been used against hematologic malignancies in several clinical trials, showing significant therapeutic responses and efficacy without severe adverse effects. Limitations that are being addressed in CAR-NK cell therapy include challenges regarding NK cell persistence in vivo, metabolic bottlenecks, and tumor-coopted immunosuppressive mechanisms that induce NK cell exhaustion. This review synthesizes current trends and innovations in CAR-NK cell engineering, examines the biological and technical challenges encountered in the clinical setting, outlines targeted preclinical approaches being implemented, and introduces recent early-phase clinical trials in the pipeline. Summatively, we highlight the rapidly advancing and transformative potential of CAR-NK cell therapy for treating hematological cancers.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014082
  11. Nano Lett. 2026 Apr 21.
    HITE: HIV Inspired Lipid Nanoparticle Platform for CAR T Cell Engineering.
    Dongyoon Kim, So-Jeong Moon, Emily L Han, Ellie Feng, Amanda M Murray, Jinjin Wang, Wei Liu, Gu Kong, Carl H June, Michael J Mitchell.
      Chimeric antigen receptor (CAR)-T therapy has led to remarkable advancements in the treatment of hematologic malignancies, encouraging extensive studies on its application to solid tumors and other diseases. However, the production of CAR-T cells is mostly achieved through viral transduction, which results in permanent CAR expression in T cells, potentially leading to unintended adverse effects. Here, we present a lipid nanoparticle (LNP) platform for mRNA delivery to human primary T cells, inspired by the human immunodeficiency virus (HIV) which naturally infects T cells. We perform multiple rounds of screening to sequentially optimize the structure and ratio of ionizable lipid in the base formulation, the ratios of HIV lipid components, and the type and ratio of PEG-lipid for CD3 antibody conjugation. Our HIV envelope-Inspired T cell transfection-Enhancing (HITE) LNP enables efficient generation of CAR-T cells with potent cytotoxic activity against cancer cells in vitro, demonstrating its potential for efficient CAR-T cell production.
    Keywords:  CAR T cells; cancer immunotherapy; human immunodeficiency virus; lipid nanoparticles; mRNA
    DOI:  https://doi.org/10.1021/acs.nanolett.5c06317
  12. Immunol Cell Biol. 2026 Apr 20.
    CAR-NK cell-based therapies: translational and regulatory breakthroughs.
    Alison Felipe Bordini Biggi, Fernando Souza-Fonseca-Guimaraes.
      In this article for the "Highlights of 2025" series, we discuss advances in chimeric antigen receptor (CAR)-engineered natural killer (NK) cell therapies. We highlight iPSC-derived manufacturing, expansion into autoimmune disease, discovery of intrinsic regulators, and rational antigen targeting, illustrating how discovery-driven biology and engineering are reshaping CAR-NK therapies toward broader clinical applicability. Figure made in ©BioRender-biorender.com.
    Keywords:  CAR‐NK cells; CRISPR screening; adoptive cell therapy; cancer immunotherapy; iPSC‐derived NK cells; regulatory checkpoints
    DOI:  https://doi.org/10.1111/imcb.70120
  13. Health Econ Rev. 2026 Apr 18.
    Consideration of the limitations of cost-effectiveness analysis for severe-rare disease drugs and potential solutions: a structured literature review.
    Jia Pan, Anastasios Skroumpelos, Anouska Jha, Urs Arnet, Rachel Kewley, Johannes Michel, Ashleys C Humphries, Rogier Klok.
       BACKGROUND: Rare diseases affect more than 400 million people globally with only a small number having currently approved treatments. Drugs for rare diseases (medications developed to treat conditions affecting small patient populations), which may include innovative drugs (medications with novel mechanisms/new active ingredients) can face access challenges as they are often found not to be cost-effective under conventional health technology assessment methods. In this review we provide a comprehensive and up-to-date understanding of challenges associated with the economic evaluation of innovative drugs for severe-rare diseases, and any proposed solutions and associated barriers to solution adoption.
    METHODS: This review included searches of electronic databases and select health technology assessment agency websites to identify relevant publications, guidelines or recommendations from 1st January 2014 to 29th July 2024. A pre-authorised protocol, including detailed eligibility criteria, was used to ensure robust methodology in the capture of materials. Relevant data extracted from included publications were synthesised thematically to support identification of the most prominent concepts within current literature.
    RESULTS: Of the 1,803 records identified, 31 publications and eight health technology assessment guidance were included. Main challenges were related to the utilitarian principle underlying cost-effectiveness analysis, the limited scope of the quality-adjusted life year and the value elements assessed. Associated solutions included the incorporation of a societal willingness-to-pay or inclusion of equity in healthcare decision making, reduced weighting of the economic evaluation in resource allocation, consideration of additional value elements, and introducing a quality-adjusted life year weighting or alternative measures of health outcomes. While some payers have implemented modifications to economic evaluation guidelines in an attempt to address the challenges, for example including the consideration of additional value elements, the solutions employed are not consistent across payers and often do not address the root issue. Economic evaluation as part of health technology assessment therefore remains challenging for manufacturers of drugs for rare diseases.
    CONCLUSION: Conventional methods of economic evaluation contribute to the access challenge for innovative drugs for rare diseases. Collaboration between payers, manufacturers, and healthcare decision makers to foster greater understanding of how to evolve and adopt these novel solutions will be key to ensuring timely patient access.
    Keywords:  Cost-effectiveness; Economic evaluation; Health technology assessments; Limitations
    DOI:  https://doi.org/10.1186/s13561-026-00771-7
  14. Ann Clin Transl Neurol. 2026 Apr 24.
    Anti-CD19 CAR T Cells in Autoimmune Encephalitis: Inflammation Controlled, Neurodegeneration Unchecked?
    Dimitrios Mougiakakos, Marwa Al-Dubai, Denise Walther, Dominic Borie, Jan D Lünemann, Marc Pawlitzki, Sven G Meuth, Solveig Henneicke, Stefan Vielhaber, Stefanie Schreiber.
      Just recently, successful chimeric antigen receptor (CAR) T cell therapy was reported in the first patient with refractory, anti-diacylglycerol lipase alpha (DAGLA) antibody-mediated autoimmune encephalitis, achieving partial clinical remission. We now provide extended follow-up demonstrating a stable, relapse-free clinical course and persistent suppression of autoantibodies. However, the patient exhibited progressive neurodegeneration despite sustained control of B cell-mediated inflammation. This dissociation between immune quiescence and structural decline highlights that CAR T cell therapy, while highly effective in extinguishing inflammation, may not be sufficient to prevent or reverse ongoing neuronal damage in disorders characterized by both inflammation and neurodegeneration.
    Keywords:  CAR T cells; autoimmune encephalitis; neurodegeneration
    DOI:  https://doi.org/10.1002/acn3.70414
  15. Nat Rev Gastroenterol Hepatol. 2026 Apr 22.
    γδ T cells in colorectal and liver cancer.
    Dieter Kabelitz, Sebastian Zeissig.
      Among tissue-resident immune cells, γδ T cells have a unique role in local immune surveillance. Under homeostatic conditions, they control tissue integrity and maintain the epithelial barrier. In contrast to conventional αβ T cells, γδ T cells sense stress-induced cellular alterations and, therefore, can recognize transformed cells independently of MHC (HLA in humans) molecules. In colorectal cancer and hepatocellular carcinoma, γδ T cells constitute an important part of the antitumour immune response. However, there is evidence that γδ T cells can also promote tumorigenesis. In this Review, we present basic features of γδ T cells and their distribution and function in the context of the local immune response. We discuss the ligands and antigens recognized by circulating and tissue-resident human γδ T cells, as well as the functional diversity of γδ T cell subsets within tumour-infiltrating T cells in colorectal and liver cancer. Given their potent cytotoxic activity and HLA-independent mode of action, there is increasing interest in harnessing γδ T cells for application in cancer immunotherapy. We therefore discuss the current status and future challenges of using γδ T cells as an innovative immunotherapeutic strategy for gastrointestinal and liver cancer.
    DOI:  https://doi.org/10.1038/s41575-026-01196-7
  16. Cell Syst. 2026 Apr 22. pii: S2405-4712(26)00073-6. [Epub ahead of print] 101591
    Modeling chimeric antigen receptor response at the single-cell level with conditional optimal transport.
    Alice Driessen, Jannis Born, Rocio Castellanos Rueda, Sai T Reddy, Marianna Rapsomaniki.
      Chimeric antigen receptor (CAR) T cell therapy is a promising cancer immunotherapy; however, several challenges hamper its clinical efficacy. Although new computational models are attempting to explore the vast combinatorial design space of CAR components and suggest novel designs, challenges remain in capturing cellular heterogeneity as well as generalizing to unseen CAR variants. Here, we introduce an optimal transport (OT)-based framework designed to predict responses to CAR expression at the single-cell level, including variants that have not been experimentally tested. Our model accurately captures gene expression changes across diverse CAR variants, outperforming the baseline for in-distribution CARs while reflecting biological characteristics. By embedding CARs using protein language models, we extend our framework to a conditional OT-based model that successfully generalizes our predictions to out-of-distribution CAR designs. Our findings highlight the utility of OT-based modeling in elucidating CAR design-function relationships, enabling the rational design of novel CARs with therapeutic potential. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  CAR T cell; cancer; chimeric antigen receptor; computational biology; immunotherapy; optimal transport; perturbation modeling; protein engineering; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.cels.2026.101591
  17. Autoimmun Rev. 2026 Apr 17. pii: S1568-9972(26)00074-1. [Epub ahead of print]25(6): 104060
    Bispecific T-cell engagers in autoimmune diseases: mechanisms of action, clinical evidence challenges, and therapeutic perspectives.
    Marion Larue, Samuel Bitoun, Julien Zuber, Marc Michel, Alexis Talbot.
      Bispecific T-cell engagers (TCEs) represent a new generation of immunotherapies designed to redirect cytotoxic T lymphocytes toward specific cellular targets, particularly B cells and their differentiated progeny. Initially developed in hematology for the treatment of malignant B-cell and plasma-cell disorders, TCEs are now gaining growing interest as potential therapies for severe or refractory autoimmune diseases. By simultaneously binding CD3 on T cells and antigens such as CD19, CD20, or BCMA (B-cell maturation antigen) on B-lineage cells, TCEs induce the targeted elimination of autoreactive B cells and plasma cells responsible for autoantibody production. This approach combines the depth of immune depletion achieved with cellular therapies and the controllability of monoclonal antibodies, offering the potential for rapid, profound, and durable immunomodulation. However, it also raises important questions regarding safety, feasibility, and cost. Compared with CAR-T cell therapies, TCEs offer a more accessible and immediately deployable strategy, while potentially achieving comparable levels of B-cell and plasma-cell depletion, though with shorter exposure and possibly reduced long-term persistence. This review provides an integrated overview of mechanistic, preclinical, and emerging clinical data on the use of TCEs in autoimmune diseases, and discusses their therapeutic potential, and limitations in this evolving field.
    Keywords:  Autoimmune diseases; BCMA; BiTE; Bispecific T-cell engager; CD19; CD20; Immunotherapy; T-cell redirection
    DOI:  https://doi.org/10.1016/j.autrev.2026.104060
  18. NPJ Biomed Innov. 2025 Dec 12. pii: 49. [Epub ahead of print]2(1):
    Organoid: a promising solution to current challenges in cancer immunotherapy.
    Xiaowo Kang, Sriya K Cheemalamarri, Qian Yin.
      Cancer immunotherapies, including immune checkpoint blockade and engineered T cell therapies, have revolutionized cancer treatment but face challenges from cancer-specific heterogeneity, tumor-immune interaction complexity, age-associated immune alteration and interspecies limitations. Advances in organoid technologies, using the patient-derived, self-organizing three-dimensional tissues, provide physiologically relevant platforms to model tumor-immune interactions and evaluate therapies in a cancer- and patient-specific manner. This platform has significantly enhanced the predictive power of preclinical research and facilitated more effective immunotherapy development.
    DOI:  https://doi.org/10.1038/s44385-025-00051-9
  19. Int J Biol Sci. 2026 ;22(7): 3509-3521
    Natural Killer Cell Therapy in Ovarian Cancer: From Preclinical Potentials to Clinical Applications and Combination Strategies.
    Tian Chen, Jiaqi Lu, Haiou Liu.
      Ovarian cancer represents a leading cause of mortality among gynecologic cancers, with limited therapeutic options for advanced and recurrent disease, highlighting an urgent need for innovative immunotherapies. Natural Killer (NK) cells, functioning as crucial effector cells of the innate immune system, have been identified as promising candidates for ovarian cancer treatment. This review systematically examines the evolving landscape of NK cell-based therapies for ovarian cancer, spanning their preclinical rationale, clinical translation, and innovative combination strategies. Nevertheless, the highly immunosuppressive tumor microenvironment (TME) of ovarian cancer and barriers to tumor infiltration pose significant challenges to their clinical efficacy. Here, we discuss various therapeutic strategies (such as cytokine-based agents, NK cell engagers and chimeric antigen receptor NK cells) designed to enhance NK cell activity, which leverage the unique characteristics of NK cells to complement standard treatments and potentiate combination immunotherapies. Ongoing preclinical and clinical investigations are paramount to converting these advances into efficacious therapies, ultimately revolutionizing the therapeutic paradigm for ovarian cancer.
    Keywords:  chimeric antigen receptor; clinical trials; immunotherapy; natural killer cells; ovarian cancer; tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.130260
  20. Lab Chip. 2026 Apr 22.
    Cell therapy manufacturing at full clinical scale: enhancing the quality CAR-T cell therapy starting materials through massively parallel automated microfluidic cell sorting.
    Alison M Skelley, Yasna Behmardi, Luke F Peterson, David W Inglis, Mabel Shehada, Laurissa Ouaguia, Khushroo Gandhi, Roberto Campos-González, Tony Ward.
      Autologous CAR-T cell therapy has demonstrated remarkable clinical efficacy in hematologic malignancies, yet its broader application remains limited by complex, labor-intensive cell therapy manufacturing and inconsistent product quality. We describe a novel microfluidic cell separation platform based on deterministic lateral displacement (DLD), integrated into a fully automated, closed-system instrument (Curate system). N = 150 leukopacks were processed at a flow rate of 400 mL h-1 with processed volumes up to 250 mL, white blood cell concentrations up to 168 M mL-1 and total white blood cell counts up to 24 billion white blood cells. Compared to Ficoll®-based density gradient centrifugation, microfluidic DLD processing yielded significantly higher leukocyte recovery (88% vs. 58%), superior platelet and red blood cell depletion, and reduced CD69+ T cell activation. Flow cytometric analysis revealed improved phenotypic preservation across key T cell subsets, including naïve and central memory populations. Cytokine profiling demonstrated enhanced washing efficiency, with markedly lower levels of biologic response modifiers. DLD-purified T cells exhibited enhanced expansion kinetics and greater yield, supporting improved manufacturing outcomes. These findings position microfluidic DLD-based processing as a clinically relevant, scalable alternative to conventional methods, with potential to improve consistency, potency, and accessibility of CAR-T therapies.
    DOI:  https://doi.org/10.1039/d6lc00072j
  21. Mol Ther. 2026 Apr 21. pii: S1525-0016(26)00273-X. [Epub ahead of print]
    Descartes-08: Unlocking the potential of mRNA CAR T-cell therapy in myasthenia gravis.
    James F Howard.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.008
  22. Clin Rheumatol. 2026 Apr 20.
    Application of BCMA CAR-T in systemic lupus erythematosus.
    Hailing Liu, Hui Zhang, Yan Xu, Jianli Wang, Wanggang Zhang, Bo Lei.
       BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by autoantibody production, complement activation, and a chronic relapsing-remitting course. Patients with refractory SLE often have limited treatment options.
    METHODS: Three female patients with SLE (median age: 29 years) and active disease refractory to immunosuppressive therapies were enrolled in a B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell program. Autologous T cells were transduced with a lentiviral anti-BCMA CAR vector, expanded, and reinfused at a dose of 40 M CAR T cells on day 0 and day 2.
    RESULTS: By day 13, clinical improvement and normalization of laboratory parameters were observed in all patients.
    CONCLUSIONS: These findings suggest that BCMA CAR-T cell therapy is feasible, tolerable, and exhibits significant efficacy in the short term for the treatment of systemic lupus erythematosus (SLE), supporting further investigation into this therapy. Key Points • BCMA CAR-T cell therapy was used on three patients with treatment-resistant systemic lupus erythematosus (SLE). • The treatment led to rapid improvement in all patients and was found to be feasible, tolerable, and effective.
    Keywords:  BCMA; CAR-T cells; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s10067-026-08121-y
  23. Inquiry. 2026 Jan-Dec;63:63 469580261427095
    Thailand's Aging Society: Reconsidering Policy and Innovation Readiness for Elderly Care.
    Sopak Supakul, Pichaya Toyoda.
      Thailand has entered an aging society ahead of its economic readiness, with demographic pressures outpacing the capacity of existing health and social systems. Although the universal coverage scheme and the national long-term care (LTC) initiative provide an important policy foundation, elderly care remains fragmented across ministries, unevenly implemented, and heavily reliant on unpaid or undertrained community caregivers. This commentary synthesizes current evidence through 2025 and identifies key system gaps, including low utilization of local-level funds, shortages of trained personnel, and weak inter-ministerial coordination across the health, welfare, and local government sectors. Recent developments, such as community-based LTC models, expanded telehealth services, and Thailand's emerging regulatory framework for advanced therapy medicinal products (ATMPs), illustrate the country's growing innovation readiness, though major challenges remain. Digital platforms for chronic disease monitoring and post-stroke rehabilitation show early promise, whereas ATMPs require careful evaluation through health technology assessment, ethical oversight, and long-term cost-effectiveness considerations. As Thailand moves toward becoming a super-aged society, strategic reforms in financing, workforce development, digital infrastructure, and ATMP regulatory preparedness are essential. Without coordinated efforts, the country faces the risk of "aging before prosperity" and increasing care disparities. However, with strengthened collaboration and the careful implementation of existing initiatives and emerging technologies, Thailand can build an elderly care system that truly supports healthy and dignified aging.
    Keywords:  ATMPs; Thailand; aging society; elderly care; long-term care; policy
    DOI:  https://doi.org/10.1177/00469580261427095
  24. Mol Biomed. 2026 Apr 20. pii: 54. [Epub ahead of print]7(1):
    In vivo CAR-cell therapy: current challenges and emerging therapeutic advances.
    Yi-Min Yang, Bo Bao, Yu-Hao Cao, Jin Yao, Yu-Fan Ding, Yi-Yang Hu, Fan Fan, Jun-Long Zhao.
      In vivo chimeric antigen receptor (CAR) cell therapy is undergoing a transformative shift from conventional ex vivo manufacturing toward in situ cellular editing, aiming to generate functional CAR-engineered immune cells directly within patients through targeted vector delivery, thereby significantly enhancing therapeutic accessibility and applicability. While rapid advances have been made in both viral (lentiviral and adeno-associated viral vectors) and non-viral (lipid nanoparticle) delivery platforms, along with the expansion of effector cell lineages including CAR-T, CAR-NK, and CAR-M, critical translational bottlenecks remain. These include insufficient delivery precision, limited cellular persistence, immunosuppressive tumor microenvironment (TME) resistance, and challenges in safety controllability. This review systematically examines the working mechanisms and limitations of current delivery platforms for in vivo gene transfer. It provides a comprehensive comparison of how CAR-T, CAR-NK, and CAR-M platforms employ distinct yet complementary strategies to address tumor heterogeneity, solid tumor physical and immune barriers, and the specificity constraints of in situ editing. Furthermore, we highlight emerging frontiers such as artificial intelligence-guided personalized therapy design, smart delivery systems (logic-gated CARs, circular RNA vectors), and the development of multicellular synergistic "synthetic immune systems." By integrating multidisciplinary perspectives, this review not only offers a comprehensive roadmap bridging fundamental mechanisms to clinical translation but also lays a theoretical and technical foundation for advancing the next generation of safe, precise, and efficacious in vivo CAR therapies.
    Keywords:  Artificial intelligence; Delivery system; Gene editing; In vivo CAR therapy; Synthetic biology
    DOI:  https://doi.org/10.1186/s43556-026-00447-y
  25. Front Immunol. 2026 ;17 1758902
    Circular RNA therapeutics: a new class of long-acting RNA medicines for oncology, immunology, and rare diseases.
    Okechukwu Paul-Chima Ugwu, Michael Ben Okon, Fabian Chukwudi Ogenyi, Jovita Nnenna Ugwu, Chinyere Nneoma Ugwu.
      Circular RNAs (circRNAs) have progressed from being viewed as splicing by-products to emerging therapeutic constructs with a distinct pharmacology. Their covalently closed topology can increase RNA stability, prolong intracellular persistence, and under some conditions sustain translation relative to matched linear RNAs. However, circRNA performance and immunogenicity depend strongly on the circularisation chemistry, impurity profiles (linear RNA and double-stranded RNA (dsRNA) by-products), sequence and structural features, and the delivery formulation. Consequently, broad claims such as 'circRNA is less immunogenic than mRNA' are unreliable without rigorous, standardised benchmarking. This narrative review provides a conceptually grounded, evidence-informed synthesis of recent advances in synthetic (exogenous) circRNA therapeutics across oncology, immunology (including vaccines), and rare/chronic diseases. We combine structured literature identification (2018-November 2025) with qualitative appraisal of preclinical and early translational studies, focusing on: (i) platform engineering (circularisation, purification, translation elements, and delivery); (ii) therapeutic modality (protein-coding versus regulatory circRNAs and programmable circuits); (iii) disease-domain use cases; and (iv) unresolved controversies and translational constraints. We introduce a decision-oriented three-axis framework to delineate settings in which circRNA plausibly offers added value (for example, single-dose local protein depots; durable antigen expression for selected vaccine strategies) versus contexts where evidence remains preliminary or advantages may diminish when compared against optimised mRNA/self-amplifying RNA (saRNA) comparators. We also highlight emerging computational models that may accelerate circRNA target and drug-sensitivity discovery. Finally, we propose priorities for the field: standardised purity and identity assays, head-to-head platform comparisons, mechanistic immunoprofiling, and indication-focused early clinical development.
    Keywords:  RNA therapeutics; cancer vaccines; circRNA; circular RNA; immunotherapy; lipid nanoparticles; rare diseases
    DOI:  https://doi.org/10.3389/fimmu.2026.1758902
  26. Hum Vaccin Immunother. 2026 Dec;22(1): 2661120
    Self-amplifying RNA (saRNA) and circular RNA (circRNA) vaccines: Progress, evidence gaps, and translational pathways for durable and scalable immunization.
    Ugwu Okechukwu Paul-Chima, Okon Michael Ben, Ogenyi Fabian C, Ugwu Jovita Nnenna, Ugwu Chinyere N.
      Self-amplifying RNA (saRNA) and circular RNA (circRNA) are emerging vaccine modalities that extend conventional, non-replicating mRNA platforms. Self-amplifying RNA encodes a replicase that amplifies intracellular RNA templates, enabling high antigen expression at substantially lower doses than non-replicating mRNA. Circular RNA has a covalently closed topology that confers resistance to exonucleases and supports sustained translation through cap-independent initiation. The evidence base remains asymmetric: saRNA has progressed through multiple human studies, including phase 3 evaluations of COVID-19 vaccines, and has received regulatory authorization in several jurisdictions, whereas circRNA vaccines remain largely preclinical, with limited publicly available human data. This review integrates clinical, animal, and mechanistic evidence, proposes a '3D' framework (durability, dose-sparing, and deployability) and identifies key barriers to robust cross-platform comparison, encompassing delivery systems, innate immune sensing, and chemistry, manufacturing and controls (CMC).
    Keywords:  Self-amplifying RNA; circular RNA; dose-sparing; durability; lipid nanoparticles; mRNA vaccines; replicon
    DOI:  https://doi.org/10.1080/21645515.2026.2661120
  27. Radiol Adv. 2026 Mar;3(2): umag018
    Building trust and privacy in cross-border health data sharing for European cancer research.
    Ricard Martínez Martínez, Ana de Marco, Ignacio Blanquer, Luis Martí-Bonmatí.
      Data-driven research using artificial intelligence (AI) is transforming biomedical science, yet its application in medical imaging remains limited by fragmented datasets, heterogeneous legislation, and ethical uncertainties. The European Cancer Imaging Initiative (EUCAIM) addresses these barriers by establishing a federated, secure and interoperable European imaging infrastructure, fostering a trusted ecosystem for AI-enabled research. EUCAIM brings privacy, ethics, and security within a single, coherent operational framework. The project implements a risk-based, compliance-by-default approach that embeds Data Protection Impact Assessments throughout system design, translating legal requirements into verifiable technical safeguards. Its "de facto" anonymization model, aligned with the General Data Protection Regulation and Court of Justice jurisprudence, combines multi-stage anonymization pipelines, cryptographic hashing, and automated re-identification-risk analyses to deliver a federated Secure Processing Environment (SPE) for researchers. This federated infrastructure is consistent with the European Health Data Space Regulation (EHDSR) and national security frameworks, and ensures data sovereignty, interoperability, and accountability. A comprehensive governance and contractual framework, including Data Sharing and Transfer Agreements, clearly delineates roles and responsibilities, while the Data Access Committee provides robust ethical oversight. EUCAIM thus offers a lawful, secure, and sustainable model of a federated secure environment for the reuse of imaging data, advancing a genuinely data-driven research ecosystem.
    Keywords:  European Health Data Space; GDPR; anonymization; cancer imaging; data governance; federated learning
    DOI:  https://doi.org/10.1093/radadv/umag018
  28. Stat Med. 2026 Apr;45(8-9): e70551
    BAR12: Bayesian Autoregressive Phase 1-2 Design for Cell Therapy Trials With Manufacturing Changes.
    Cheng-Han Yang, Peter F Thall, David Marin, Sheferaw Y Belay, Ruitao Lin.
      An early phase dose-finding trial of a new cell therapy may involve one or more manufacturing modifications made during the trial, known as "tweaks," to improve the cell product quality. For example, a tweak may change the cell culture duration, cytokine cocktail, or donor criteria. Ideally, a tweak can be done without changing the treatment so much that the trial must be restarted as if the treatment were entirely new. However, a statistical design still should account for changes in the dose-response distribution due to the tweak. For such settings, we propose a Bayesian AutoRegressive Phase 1-2 (BAR12) design that accounts for manufacturing tweaks during a phase 1-2 trial by using a first order autoregressive model with spike-and-slab priors having components corresponding to pre- and post-tweak distributions of toxicity and efficacy parameters. Simulations under a broad range of dose-response functions were conducted to compare BAR12 to conventional phase 1-2 designs that either assume the tweak had no effect and use all available data, or ignore the pre-tweak data. The simulations show that BAR12 has superior operating characteristics, including higher probabilities of correct dose selection, allocation of more patients to optimal doses, and more efficient monitoring for identifying unsafe or ineffective doses.
    DOI:  https://doi.org/10.1002/sim.70551
  29. Value Health Reg Issues. 2026 Apr 24. pii: S2212-1099(26)00043-9. [Epub ahead of print] 101628
    Transferability of Patient Selection Model for Proton Radiation Therapy to Lower-Income European Countries.
    HTx Study Group
       OBJECTIVES: Proton therapy is an alternative treatment to photon therapy in head and neck cancer. The Normal Tissue Complication Probability (NTCP) model assists in the patient selection process. This study explores how health technology assessment (HTA) recommendations in lower-income European countries (LIECs) in head and neck cancer can be supported by transferring the NTCP model.
    METHODS: Through 2 workshops in November 2022 and May 2023, the scope of transferability recommendations was established for the head and neck cancer case study of the HTx project. HTA experts from LIECs and HTx consortium representatives reviewed draft recommendations at a final transferability workshop in November 2023. Experts anonymously voted on the main challenges of transferring the NTCP model to LIECs and ranked these by importance. Finally, an open discussion took place about potential solutions for overcoming the main challenges.
    RESULTS: Main challenges of transferring the NTCP model to LIECs include lack of available local data, differences in patient pathways, and shortage of HTA experts. Workshop participants agreed that the NTCP model is an improvement to current standard HTA methods. Multiple key recommendations were formed, including that dissemination of real-world data and real-world evidence should be gold standard, coupled with a wide collaboration across stakeholders, and that consideration of transferability aspects could help LIECs when adapting novel methods.
    CONCLUSIONS: According to a multinational panel of experts, the NTCP model is an improvement over current HTA methods. To overcome challenges of its adoption in LIECs, 5 key recommendations were formulated.
    Keywords:  central and Eastern European countries; head and neck cancer; health technology assessment; normal tissue complication probability model; transferability
    DOI:  https://doi.org/10.1016/j.vhri.2026.101628
  30. Int J Nanomedicine. 2026 ;21 585042
    Exosomes as Emerging Nanocarriers for Targeted Cancer Therapy.
    Yao Du, Di Liu, Jiaxing Liu, Jinling Yu, Zhixiong Hao, Manru Zhang, Jianwen Li, Xueqiang Peng.
      Exosomes are nanoscale lipid bilayer vesicles secreted by eukaryotic cells into biological fluids. As an important subtype of extracellular vesicles, they can mediate intercellular material exchange and signal transmission by carrying bioactive substances such as proteins, nucleic acids, and lipids, and participate in the maintenance of physiological homeostasis and the regulation of pathophysiological processes in the body. These biological characteristics make exosomes less likely to be recognized and cleared by the immune system after entering the human body, nor do they cause obvious immune rejection reactions, laying the foundation for their use as delivery carriers. Through engineering techniques, they can be modified, and nucleic acids, small molecule drugs, and other substances can be precisely encapsulated inside exosomes through artificial intervention, forming "exosome-treatment payload" complexes. These complexes can take advantage of the properties of exosomes to significantly enhance their permeability in human tissues and cells, easily cross biological barriers, and promote the enrichment of treatment payloads in specific sites such as tumor tissues, thereby effectively optimizing treatment outcomes. However, the current application of exosomes is still limited by low separation and purification efficiency, high preparation costs, and easy damage to vesicle structure, and the clinical transformation process needs to be accelerated. This review focuses on the latest progress in the research of exosome-targeted delivery platforms, combines existing exosome drug loading technologies, and analyzes the clinical application potential and core challenges of this delivery system in cancer treatment, aiming to provide research directions for the development and clinical transformation of exosome-mediated anti-tumor targeted therapy strategies.
    Keywords:  cancer; cargo loading; drug delivery system; exosome
    DOI:  https://doi.org/10.2147/IJN.S585042
  31. Biosci Rep. 2026 Apr 21. pii: BSR20260143. [Epub ahead of print]
    A systematic review and meta-analysis of shRNA-IL-6-engineered CAR-T cells for B-cell Acute Lymphoblastic Leukemia: a stepping stone towards risk-free immunotherapy.
    Mohamed S Attia, Brett Dyer, Nigel McMillan, Matthew Zunk.
      Clinical application of chimeric antigen receptor (CAR)-T cells, especially those targeting CD19, stands as a breakthrough in treating relapsed or refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). Yet, preventing immune-related adverse events (IrAEs), like severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANs), remains a significant concern. This meta-analysis looked at the efficacy and safety of IL-6 knockdown CAR-T therapy. The study's primary outcomes included the incidence of CRS, ICANS, and patient number achieving an early complete response (CR) and overall response rate (ORR) at one-month post-infusion of anti-CD19 shRNA-engineered CAR-T cells. Random-effects model was used to estimate summary effects. Certainty of evidence was assessed using GRADE. Out of 275 studies screened, 7 studies were eligible (n=178 patients). The pooled ORR and CR rates were 88% (95% CI,81-92) and 84% (95% CI,78-89), respectively, with no heterogeneity detected. Among 147 patients, 116 (78%, 95% CI,68-85) developed CRS, whereas 46 (28%, CI,21-35%) out of 178 were affected by severe grades (≥3). While ICANS were detected in 13 out of 159 patients (13%, 95% CI,2-51%, I2=69.5%), three studies confirmed the absence of severe grade ICANs. According to GRADE assessment, current analysis presents low certainty of evidence supporting investigated outcomes, except for ICANS (any grade) that was deemed very low. More importantly, as all included studies were conducted in China, the findings may not be readily generalizable to other healthcare systems and ethnically diverse populations. Therefore, our confidence in the effect estimates is limited and it may vary from true estimates.
    Keywords:  CAR T therapy; CD19; Cytokine release syndrome; immune-related adverse effects
    DOI:  https://doi.org/10.1042/BSR20260143
  32. Int J Technol Assess Health Care. 2026 Apr 22. 42(1): e40
    Early technology review during prototype development and at proof of concept: the case for developing a sequential versus a single-stage approach to early evidence development for health technologies.
    Leslie Levin, Robert S McDonough, Martin Cheatle, Haytham Kaafarani, Serge Korjian, Richard E Kuntz.
      The effect of Early Technology Review (ETR) through early engagement with multiple stakeholders on strategic development for technologies at prototype development and proof of concept was examined through two generic case studies of relevant outcomes. In both examples, advice to companies could have significantly changed strategic direction to become more relevant to payers and clinical experts. In one instance, the advice was followed and resulted in an expedited first-in-human study and was considered for a second ETR to inform the proof-of-concept study. In the second example, it was reported that changes in strategic direction were being considered.These reports provide descriptive accounts of very early applications of the ETR process that now spans the entire preclinical trajectory. Had the second case study at proof of concept been able to benefit from this approach at the point of prototype development, it could have avoided the costs and research through earlier advice. This begs the question whether a sequential iterative approach to evidentiary multiple stakeholder advice across the technology life cycle may reduce risk and cost while benefitting from efficiencies of applying adaptive design.
    Keywords:  device approval; diffusion of innovation; evidence-based medicine; investigational therapies; technical assessments
    DOI:  https://doi.org/10.1017/S0266462326103596
  33. PDA J Pharm Sci Technol. 2026 Apr 18. pii: pdajpst.2026-000016.1. [Epub ahead of print]
    Beyond Batch Release: Responsible Decision-Making, Professional Judgement, and Governance in Complex Pharmaceutical Manufacturing.
    Mario Stassen.
      Responsible decision-making in pharmaceutical manufacturing increasingly occurs within complex, distributed, and rapidly evolving environments. While the European Qualified Person (QP) holds defined regulatory accountability, modern decision contexts extend beyond compliance verification and require integration of scientific understanding, lifecycle knowledge, and organisational governance. Building on recent discussions surrounding technological evolution and regulatory expectations, this review explores how professional judgement operates in environments characterised by uncertainty, accelerating timelines, and expanding organisational interfaces.Specification compliance alone often provides insufficient confidence for decision-making. Confidence increasingly emerges through process understanding, integration of multidisciplinary expertise, and development of coherent scientific narratives that connect data, process behaviour, and patient expectations. Accelerated environments also reveal how governance structures and organisational systems influence decision quality, highlighting the importance of clear accountability, trusted expertise, and independent judgement.This paper introduces the concept of patient-relevant decision quality and discusses how experienced professionals contribute to continuity of understanding across lifecycle stages. Seen through this lens, the QP represents one perspective within a broader system of responsible decision-making, where organisational maturity, principled leadership, and stewardship of judgement support scientifically grounded and ethically sound outcomes.
    Keywords:  Decision-making; GMP manufacturing; Lifecycle quality management; Organisational maturity; Pharmaceutical governance; Professional judgement; Quality risk management
    DOI:  https://doi.org/10.5731/pdajpst.2026-000016.1
  34. NPJ Biofilms Microbiomes. 2026 Apr 21.
    The microbial metabolome: remodeling the therapeutic landscape in hematologic malignancies.
    Liang Zhang, Hamed Soleimani Samarkhazan, Yaseer Almajidi, Rushen Gafarov.
      The gut microbiome's metabolome critically shapes drug efficacy and toxicity in hematologic malignancies. This review explores how microbial metabolites influence chemotherapy, immunotherapy, and transplant outcomes, and how they can be harnessed as biomarkers and therapeutic targets. Moving from association to intervention, we outline a pathway toward metabolome-informed precision oncology, transforming the "second genome" into a actionable ally for improved cancer therapy.
    DOI:  https://doi.org/10.1038/s41522-026-00972-2
  35. Biochim Biophys Acta Mol Basis Dis. 2026 Apr 22. pii: S0925-4439(26)00137-7. [Epub ahead of print] 168274
    Shared pathogenic mechanisms between systemic lupus erythematosus and autoimmune hepatitis: A unified view of autoimmune convergence.
    Wu Yechen, Fengjiao Wang, Lanlan Xiao, Yanfei Chen, Lanjuan Li.
       BACKGROUND: Systemic lupus erythematosus (SLE) and autoimmune hepatitis (AIH) are clinically distinct autoimmune disorders characterized by multisystem involvement and liver-restricted inflammation, respectively; nevertheless, they exhibit considerable overlap in their underlying immunopathogenic features.
    AIM: To provide a systematic synthesis of recent advances in genetics, immunology, and microbiome science, and to delineate the convergent pathogenic mechanisms that underpin both SLE and AIH.
    METHODS: A comprehensive literature review was conducted using PubMed and other databases up to 2025, focusing on shared genetic, cellular, and microbial determinants in SLE and AIH. Core topics included genetic susceptibility loci, breakdown of immune tolerance, T-cell dysregulation, innate immune activation, and alterations in gut microbiota composition and function.
    RESULTS: SLE and AIH share several genetic risk variants, including HLA-DRB1*03:01, PTPN22, STAT4, and TNFAIP3. Both diseases are characterized by defective central and peripheral immune tolerance, imbalances in Th17/Treg and Tfh/Tfr compartments, and aberrant B-cell activation. Innate immune pathways-encompassing Toll-like receptor and NLRP3 inflammasome signaling as well as complement dysregulation-further amplify inflammation. Moreover, gut dysbiosis and perturbations in microbial metabolites, such as short-chain fatty acids, bile acids, and tryptophan derivatives, function as key mediators linking intestinal homeostasis to both systemic and hepatic autoimmunity.
    CONCLUSION: SLE and AIH represent overlapping entities along a unified autoimmune spectrum, driven by shared genetic susceptibility, convergent immune dysregulation, and microbial influences. This review advances an integrated immunological framework that bridges systemic and organ-specific autoimmunity, underscores the pivotal role of innate immunity and gut-liver crosstalk, and provides a mechanistic rationale for cross-disease therapeutic strategies targeting these common pathways.
    Keywords:  Autoimmune hepatitis; Autoimmune overlap syndrome; Gut microbiota; Immune tolerance; Innate immunity; Shared pathogenesis; Systemic lupus erythematosus; Th17/Treg imbalance
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168274
  36. J Med Internet Res. 2026 Apr 22. 28 e63575
    A Review of Medical Data Sharing Initiatives With a Focus on the Use of Blockchain Technologies: Qualitative Comparative Analysis.
    James Cunningham, Nigel Davies, Sarah Devaney, Mike Harding, Søren Holm, Victoria Neumann, Clare Smith, John Ainsworth.
       Background: Medical data sharing initiatives are crucial for advancing research, improving patient outcomes, and fostering innovation in health care. With the advent of blockchain technology, there has been significant interest in exploring its potential to enhance the security, transparency, and efficiency of medical data sharing.
    Objective: This study aimed to examine a selected set of blockchain-based medical data sharing initiatives, focusing on their governance, incentive structures, ownership models, business approaches, transaction mechanisms, and sustainability strategies. The analysis explored patterns in operational status and longevity, providing insight into the factors shaping these initiatives. The objective was to identify common characteristics and contextual factors that may influence their development and persistence.
    Methods: The study used snowball sampling to identify a selection of primarily blockchain-based medical data sharing initiatives, drawing from academic literature, web searches, and expert consultations. To examine structural and operational patterns, initiatives were selected based on the availability of sufficient public documentation for systematic classification. Each initiative was categorized by governance, incentives, ownership, business models, transaction mechanisms, and sustainability strategies. A follow-up assessment examined operational status over time. The analysis applied qualitative comparative analysis to identify common structural features and relationships between governance, incentives, and sustainability.
    Results: The survey identified 42 initiatives, categorizing them based on ownership, governance, business, incentive, transaction, and sustainability models. These categories were systematically identified and assigned numerical values to facilitate fuzzy-set qualitative comparative analysis. The base model, run at an inclusion threshold of 0.65, identified multiple configurations associated with sustained initiative activity, highlighting the role of governance mechanisms and transaction structures in supporting long-term viability. The sensitivity analysis, conducted across multiple thresholds, demonstrated that while several configurations remained stable, higher thresholds led to more restrictive solutions. At 0.80, only two configurations remained, representing the most consistent pathways to sustained activity, reinforcing the importance of governance and transaction models in initiative sustainability.
    Conclusions: The analysis revealed a range of governance, ownership, business, and sustainability models, with no single structural configuration guaranteeing long-term viability. The findings suggest that governance and transaction mechanisms are particularly influential in sustaining initiatives, often compensating for the absence of strong business or sustainability models. The scope was limited to initiatives identified through available documentation and snowball sampling, and the results underscore the need for further research into the interplay between governance structures, financial models, and long-term sustainability in medical data sharing.
    Keywords:  blockchain; data governance; data provision; ethics; medical data sharing; privacy; security; sustainability models; transparency
    DOI:  https://doi.org/10.2196/63575
  37. Genes Dis. 2026 Jul;13(4): 101978
    Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.
    Binglan Zhang, Fuping Zhu, Song Wang, Yong Huang, Shishi Yu, Shaorong Tian, Minmin Li, Pan Li, Qian Xue, Bingqiang Zhang.
      Strategies that enhance the function of chimeric antigen receptor-modified T (CAR-T) cells for solid tumors are critical. Inhibitory immuno-checkpoints blockade could potentially enhance CAR-T cell function. TIM-3 is an important negative regulator of T cell activity, but whether TIM-3 blockade could affect CAR-T cell function remains unclear. In our study, we successfully constructed TIM-3-silenced CAR-T cells by dual-promoter lentivirus vectors that simultaneously express the TIM-3 targeting short hairpin RNA (shRNA) and a third-generation CAR recognizing HER2. We demonstrated that down-regulation of TIM-3 did not affect the phenotype of CAR-T cells. CAR-T cells with TIM-3 blockade exhibited higher lytic cytotoxicity to target cells in vitro. Additionally, TIM-3-silenced CAR-T cells displayed robust anti-tumor activity in a murine xenograft model, which is comparable to standard CAR-T cells. Our study demonstrates the effect of down-regulation of immune checkpoint TIM-3 on the anti-tumor function of CAR T cells, providing new ideas for improving the potency of CAR-T cell therapies in solid tumors.
    Keywords:  Cell therapy; Chimeric antigen receptor; Immunotherapy; Inhibitory checkpoint; TIM-3
    DOI:  https://doi.org/10.1016/j.gendis.2025.101978
  38. Cancer Med. 2026 May;15(5): e71858
    Modern Clinical Trials: Seamless Designs and Master Protocols.
    Abigail Burdon, Thomas Jaki, Xijin Chen, Pavel Mozgunov, Haiyan Zheng, Richard Baird.
       BACKGROUND: Drug development is often inefficient, costly and lengthy, yet it is essential for evaluating the safety and efficacy of new interventions. Compared with other disease areas, this is particularly true for Phase II/III cancer clinical trials where many drug candidates fail to advance and reduced regulatory approvals are being seen. In response to these challenges, seamless clinical trials and master protocols have emerged to streamline the drug development process.
    METHODS: Seamless clinical trials, characterised by their ability to transition seamlessly from one phase to another, can lead to accelerating the development of promising therapies while Master protocols provide a framework for investigating multiple treatment options and patient subgroups within a single trial.
    RESULTS: We discuss the advantages of these methods through real trial examples and the principles that lead to their success while also acknowledging the associated regulatory considerations and challenges.
    CONCLUSION: Seamless designs and master protocols have the potential to improve confirmatory clinical trials. In the disease area of cancer, this ultimately means that patients can receive life-saving treatments sooner.
    Keywords:  adaptive designs; efficient trials; interim analysis; master protocols; seamless phase II/III
    DOI:  https://doi.org/10.1002/cam4.71858
  39. J Med Econ. 2026 Dec;29(1): 1246-1257
    Value frameworks for digital health technologies: a comparative analysis.
    Briana M Choi, Jeannie K Lee, Brian Erstad, Christopher Edwards, Ali McBride, Ivo Abraham.
       AIMS: This study aimed to review and compare existing value frameworks for digital health technologies (DHTs) and identify common domains to guide their evaluation.
    MATERIALS AND METHODS: A comprehensive literature search was conducted across PubMed, Embase, and Google Scholar, along with citation and website searches, was conducted in August 2025. English-language publications that provided guidance on evaluating value of DHTs were included. A narrative review approach was employed to synthesize findings and identify key value domains and indicators.
    RESULTS: From an initial pool of 1,132 articles, four met the inclusion criteria and formed the basis of the review, supplemented by additional frameworks from relevant organizations. Six core value domains were identified: technical and security aspects, data rights and governance, clinical characteristics, economic characteristics, health inequalities, and user preferences. Five value frameworks from the United Kingdom (UK) National Health Service, Digital Therapeutic Alliance, World Bank, Institute for Clinical and Economic Review-Peterson Health Technology Institute, and UK National Institute for Health and Care Excellence were compared across these domains. A heat map analysis demonstrated variation in the inclusion of indicators, reflecting differing stakeholder priorities and perspectives.
    LIMITATIONS: Limitations include potential bias, subjectivity, and limited scope inherent in a narrative review, although elements of PRISMA were applied to reduce risks. Non-English frameworks and those specific to certain technologies were excluded. Additionally, frameworks for both DHTs and digital therapeutics were considered together.
    CONCLUSION: Six core value domains are consistently emphasized across value frameworks. However, variations across value frameworks highlights the influence of stakeholder needs and priorities. Further research is needed to refine these frameworks and support consistent and informed decision-making in DHTs adoption and implementation.
    Keywords:  Digital health; I10; I18; digital health technologies; digital therapeutics; economic evaluations; health technology assessment; value frameworks
    DOI:  https://doi.org/10.1080/13696998.2026.2652777
  40. Drug Dev Res. 2026 May;87(3): e70281
    Artificial Intelligence in Drug Discovery and Development: Transforming Pharmaceutical Innovation.
    Mohd Shoab Ali, Taha Alqahtani, Humood Al Shmrany, Garima Gupta, Khang Wen Goh, Amirhossein Sahebkar, Prashant Kesharwani.
      Drug discovery remains a lengthy, costly, and high-risk endeavor, often requiring over a decade from target identification to clinical translation. Artificial intelligence (AI) is reshaping this paradigm by enabling more efficient and accurate decision-making across the discovery and development pipeline. Advances in machine learning, deep learning, and natural language processing now support target identification, hit finding, lead optimization, and drug repurposing with unprecedented speed and precision. AI-driven insilico platforms further enhance early-stage predictability by forecasting toxicity, pharmacokinetics, and developability, thereby reducing late-stage attrition. This review critically examines the evolving role of AI in modern drug discovery and its expanding impact on pharmaceutical formulation development and personalized medicine. Collaborative models between AI developers and the pharmaceutical industries, essential for accelerating translational outcomes, are also highlighted. Finally, key challenges, including algorithmic transparency, data quality, interoperability, and regulatory acceptance, are discussed, along with future directions for harnessing AI's full potential in pharmaceutics.
    Keywords:  artificial intelligence; deep learning; drug discovery; in silico modeling; machine learning; pharmaceutical development
    DOI:  https://doi.org/10.1002/ddr.70281
  41. Microbiologyopen. 2026 Apr;15(2): e70294
    Therapeutic Remodeling of the Gut Microbiome as a Strategy to Restore Immune Tolerance in Autoimmunity.
    Behshad Boroumand, Amirhossein Jaberi, Ghazal Zamani, Ehsan Zandi, Farshad Zare, Milad Vahedinezhad, Elham Abdollahi, Sepideh KarkonShayan, Sasan GhazanfarAhari, Mustafa Sattar.
      Autoimmune diseases happen when the immune system, which is supposed to defend the body from infections and other harmful things, starts to attack the body's own cells by mistake. In the last few years, they seem to be getting more public, and the reasons are quite complicated. It is usually not just one factor, but a mix of genes and environmental influences, such as diet, infections, or even stress. The gut microbiome, the vast community of bacteria and other tiny organisms living in our intestines, plays an important role in shaping how the immune system behaves. When this gut microbiota becomes unstable (a state called dysbiosis), it can be associated with the onset or worsening of various autoimmune diseases. In this review, we discuss the close relationship between the gut microbiome and autoimmune disorders and focus on how the microbiome can affect immune activation, immune tolerance, and inflammation at the molecular level. The general idea is that, if we understand these interactions better, we might be able in the future to design new ways to manage autoimmune diseases earlier and maybe in a more personalized way. In the end, the review suggests that if we understand better how the microbiome is involved in autoimmune diseases, it might be possible in the future to design more personalized therapies that change gut bacteria in a smart way and hopefully improve patient outcomes.
    Keywords:  autoimmune diseases; dysbiosis; gut microbiome; immune modulation; probiotics
    DOI:  https://doi.org/10.1002/mbo3.70294
  42. Nat Rev Cancer. 2026 Apr 21.
    Advancing AI for multi-omics and clinical data integration in basic and translational cancer research.
    Fei Liu, Stephan Beck, Lei Yang, Huiyan Luo, Kang Zhang.
      The extensive heterogeneity of cancer across biological scales necessitates a holistic approach beyond single-analyte methods. Integrating multi-omics data - from genomics to proteomics - with multimodal information, such as clinical records and medical imaging, offers a comprehensive, systems-level view of tumorigenesis. Artificial intelligence (AI) has emerged as the essential technology to decipher these complex, high-dimensional datasets, powering substantial advances in early diagnosis, precise patient stratification, prediction of therapeutic response and the elucidation of mechanisms of drug resistance. To translate these powerful predictive models into practice, explainable AI is critical for building clinical trust and generating novel, testable biological hypotheses. While challenges in data accessibility and model generalizability persist, the field is advancing toward patient-specific digital twins, promising to simulate individual disease trajectories and optimize treatments, thereby heralding a new era of precision oncology.
    DOI:  https://doi.org/10.1038/s41568-026-00922-2
  43. Cell Mol Immunol. 2026 Apr 22.
    EZH2 and intracellular Ca2+ signals interdependently coordinate alloreactive and CAR-T-cell responses.
    Ying Wang, Qingrong Huang, Yan Zhou, Robert Hooper, Ruqayyah Sanders-Braggs, Mimi Chen, Yuanyuan Tian, Tatiana Kent, Richard Pomerantz, Gennaro Clando, Woonbok Chung, Jean-Pierre J Issa, Jonathan Soboloff, Yi Zhang.
      In graft-versus-host disease (GVHD), Ca2+ signals in alloreactive T cells are carefully controlled to determine whether cells survive or thrive, although how this is accomplished during GVHD remains poorly defined. We demonstrate that EZH2, a chromatin-modifying enzyme, promotes alloreactive T-cell survival in GVHD by acting as a Ca2+ signaling brake to limit excessive intracellular Ca2+ responses. Ezh2 loss led to the upregulation of gene programs that promote effector differentiation in activated T cells, coincident with enhanced intracellular Ca2+ responses that ultimately caused massive cell death. Conditional deletion of Stim1 (required for cytosolic Ca2+ entry) led to "synthetic rescue" of Ezh2-null T cells by protecting them from cell death without interfering with effector differentiation, resulting in severe GVHD. Interestingly, Stim1 expression was unaffected by EZH2, whereas the expression of the endoplasmic reticulum Ca2+ release channel inositol 1,4,5-trisphosphate receptor 2 (Itpr2) was suppressed by EZH2. Notably, EZH2 and Ca2+ signals served mutually opposing roles in controlling the expression of genes in chimeric antigen receptor (CAR) T cells. Inhibiting Ca²⁺ signaling restored EZH2 function in CAR-T cells, significantly improving their antitumor activity. Our findings reveal the interdependent roles of EZH2 and Ca2+ signals in coordinating antigen-activated T-cell responses that mediate alloimmunity and tumor immunity.
    Keywords:  Allogeneic HSCT; ER calcium; EZH2; Epigenetic regulation; GVHD; T cell
    DOI:  https://doi.org/10.1038/s41423-026-01413-y
  44. Contemp Clin Trials Commun. 2026 Jun;51 101641
    Standardization of clinical trials subject ID schematics: A portfolio-wide model to enhance data integrity and regulatory compliance.
    Ananya Jain, Steve Demas, Todd Bazin.
       Background: Subject identification is a cornerstone of data integrity and regulatory compliance in clinical trials. Legacy, study-specific subject ID conventions may cause risk of duplication, hinder traceability of rescreened participants, and complicate regulatory submissions-particularly in large global portfolios where multiple trials for similar disease areas from the same sponsor are handled by the same site and the same PI. Regulatory guidance from the U.S. Food and Drug Administration (FDA Technical Conformance Guide), the Clinical Data Interchange Standards Consortium (CDISC SDTM), and ICH E6(R2) mandates unique subject traceability throughout a study's lifecycle.
    Aim: This paper introduces, validates, and evaluates a standardized subject-identification schema designed to eliminate risk of duplication, ensure traceable rescreening, and harmonize subject IDs across an organization's clinical portfolio while aligning with global regulatory requirements.
    Methods: A cross-functional Biogen team spanning Global Clinical Operations, Data Systems, IT, Clinical Supply, with inputs from external partners (CROs and IXRT vendors) designed a new schema (SSSS-PYZ-XXXA). The structure encodes site (SSSS), program (P), phase (Y), study sequence (Z), subject number (XXX), and screening attempt (A). Validation comprised retrospective pressure testing with historical data, pilot implementation in active trials, and benchmarking against CDISC SDTM and FDA TCG standards.
    Results: The standardized schema eliminated subject-ID overlap across parallel studies, enabled seamless rescreen tracking without creating multiple USUBJIDs, and proved compatible with EDC, CTMS, IXRT, and LIMS systems. As of 2025, the schema had been adopted in at least 59 new trials across multiple therapeutic areas, improving SDTM mapping and regulatory preparedness.
    Conclusion: A portfolio-wide standardized subject-ID schema provides a sustainable, scalable framework that strengthens data integrity, streamlines operations, and enhances regulatory compliance across clinical development programs.
    Keywords:  CDISC SDTM; Clinical trials; Data integrity; FDA technical conformance guide; Portfolio standardization; Regulatory compliance; Subject identification
    DOI:  https://doi.org/10.1016/j.conctc.2026.101641
  45. Trends Immunol. 2026 Apr 18. pii: S1471-4906(26)00070-0. [Epub ahead of print]
    Local cues, local killers: human natural killer cells across tissues.
    Annika Niehrs, Kejsi Zeqiraj, Andrea Ponzetta, Niklas K Björkström.
      Natural killer (NK) cells are part of the innate immune system and reside in multiple tissues. During steady-state conditions, they contribute to tissue homeostasis, while in disease settings, tissue-resident (tr) NK cells are positioned at the frontline of immune surveillance. Due to their exposure to local microenvironments, NK cells residing outside the bloodstream exhibit phenotypic, transcriptional, functional, and metabolic features that distinguish them from their circulating counterparts. In this review, we outline the defining characteristics of tr NK cells, discuss their recirculation potential, and summarize their functional and metabolic specialization across human tissues. Finally, using cancer as an example, we highlight how tr NK cells are altered in disease and how local tissue environments shape their functional states.
    Keywords:  immunometabolism; tissue microenvironment; tissue-resident NK cells
    DOI:  https://doi.org/10.1016/j.it.2026.03.009
  46. Endocr Relat Cancer. 2026 Apr 22. pii: ERC-25-0513. [Epub ahead of print]
    DLK1 - a novel therapeutic target in cancer.
    James Frederick Henry Pittaway.
      Delta-like non-canonical Notch ligand 1 (DLK1) is a cleavable transmembrane protein with tightly regulated, developmentally restricted expression. It is highly expressed during embryogenesis, where it plays a key role in controlling cellular differentiation and proliferation, but is largely silenced in adult tissues, persisting mainly within stem and progenitor compartments of endocrine organs. Notably, DLK1 is consistently re-expressed across a broad range of malignancies, with the highest prevalence observed in endocrine and neuroendocrine tumours, including adrenocortical carcinoma, phaeochromocytoma/paraganglioma, medullary thyroid carcinoma, and neuroblastoma. DLK1 expression is associated with adverse clinical outcomes and is increasingly implicated in maintaining a de-differentiated, stem-like tumour phenotype that might contribute to tumour progression and therapeutic resistance. The restricted expression of DLK1 in normal adult tissues, combined with its cell-surface localisation and functional relevance in tumour biology, makes it an attractive therapeutic target, particularly in endocrine malignancies where targetable options remain limited. Multiple DLK1-directed strategies are now advancing through preclinical and early clinical development, including afucosylated monoclonal antibodies, antibody-drug conjugates, dendritic cell vaccines, chimeric antigen receptor T-cell therapies, and radioimmunotherapy. Early-phase studies demonstrate encouraging safety profiles and signals of efficacy, with emerging evidence suggesting that tumour-specific factors-such as steroidogenesis, immune microenvironment, and drug efflux mechanisms-may influence response in endocrine cancers. This review collates current evidence on DLK1 biology and therapeutic targeting, with a focus on endocrine and neuroendocrine malignancies. We highlight key novel mechanistic insights, translational challenges, and future opportunities to exploit DLK1 as a precision therapeutic target in these high-need cancer subtypes.
    Keywords:  DLK1; cancer; target; therapy; treatment
    DOI:  https://doi.org/10.1530/ERC-25-0513
  47. Eur J Radiol. 2026 Apr 12. pii: S0720-048X(26)00213-5. [Epub ahead of print]200 112865
    Digital twin applications in radiology and radiotherapy: Applications, challenges, and future perspectives.
    David B Olawade, Oluwatosin Akinro, Emmanuel O Oisakede, Oluwakemi Jumoke Bello, Claret Chinenyenwa Analikwu, Eghosasere Egbon.
      Digital twin technology has emerged as a transformative innovation in healthcare, offering virtual replicas of physical entities at patient-level, equipment-level, and departmental-level that enable real-time monitoring, prediction, and optimisation. This narrative review synthesizes current evidence on digital twin maturity and clinical translation in radiology and radiotherapy. A comprehensive literature search was conducted across PubMed, Scopus, IEEE Xplore, and Web of Science databases for peer-reviewed articles published from 2018 onwards. The review reveals that digital twin applications in radiology remain predominantly experimental, with equipment-focused implementations (predictive maintenance, workflow optimization) showing greater maturity than patient-level applications. In radiology, emerging applications include personalised imaging protocol optimisation, predictive equipment maintenance, dose management, and workflow enhancement. In contrast, radiotherapy demonstrates more advanced patient-level digital twin integration, facilitating individualised treatment planning, real-time dose adaptation, treatment response prediction, and quality assurance. DT-aligned adaptive radiotherapy report improved local/locoregional control in the low-teens to ∼18% relative range, alongside clinically meaningful toxicity-risk reductions in selected endpoints, while maintaining lower radiation dose to organs. Key benefits include improved patient outcomes, reduced radiation exposure, enhanced treatment precision, and optimised resource utilisation. However, critical gaps persist in standardized validation frameworks, interoperability standards, and regulatory guidance. Implementation faces challenges including data integration complexity, computational requirements, regulatory uncertainties, and domain-specific barriers differing between radiology and radiotherapy contexts. Successful clinical translation requires addressing technical infrastructure gaps, establishing evidence-based validation protocols, and developing reimbursement mechanisms that recognize digital twin value. Digital twin technology demonstrates substantial potential for advancing precision medicine in imaging and radiation oncology.
    Keywords:  Artificial intelligence; Digital twin; Personalised medicine; Radiology; Radiotherapy
    DOI:  https://doi.org/10.1016/j.ejrad.2026.112865
  48. Cent Eur J Immunol. 2025 ;50(4): 341-352
    Glutaminase-mediated glutamate metabolism is critical for maintaining Th17/Treg balance.
    Xiaohan Jin, Jinglong Tao.
      Autoimmune diseases are severe disorders that affect populations worldwide. Their occurrence is considered to be multifactorial: genetic, hormonal and immunological factors all contribute to the development of autoimmune diseases. CD4 T cells differentiate into different subtypes, among which Th17 and Treg cells are the two most important in regulation of immune response balance. The Th17/Treg equilibrium is crucial in the pathogenesis of autoimmune diseases. Glutamate, an excitatory neurotransmitter in the nervous system, induces multiple effects. It activates normal T cells, enhancing cell adhesion, migration, secretion and gene expression. However, the effect of glutamate on T cell fate remains unclear. Here, we found that glutamate promotes Treg differentiation but suppresses Th17 differentiation. Further results showed that the rate-limiting enzyme of glutamate metabolism, glutaminase (GLS), is the key regulator for Treg cell generation. These findings suggest that GLS-mediated glutamate metabolism is critical for Treg cell differentiation, and may represent a potential therapeutic target for autoimmune disease.
    Keywords:  Th17; Treg; autoimmune; glutaminase; glutamine
    DOI:  https://doi.org/10.5114/ceji.2025.155429
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