bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–03–08
forty-four papers selected by
Luca Bolliger, lxBio
  1. Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.
  2. Implementation of CAR-T cell therapy in outpatient settings: a critical review of current literature regarding health outcomes, benefits, challenges, and future directions.
  3. Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.
  4. Advancing Cell Therapies for Solid Tumors: A Pathway to Overcome Biological, Operational, and Regulatory Hurdles.
  5. CAR-NKT cell therapy for tumors: promise and progress.
  6. T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications.
  7. Beyond autologous ex vivo CAR-expressing cell therapies: Toward allogeneic and nucleated cell-free delivery systems of CAR.
  8. Synergizing Artificial Intelligence with In Vivo CAR-T Cell Generation: A New Paradigm for Democratized Immunotherapy.
  9. Mapping the evolution of cell and gene therapy product research: trends, collaborations, and emerging frontiers.
  10. CAR-T cell therapy for treatment-refractory rheumatic autoimmune diseases: a systematic review of clinical outcomes and safety profiles.
  11. CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond.
  12. Legal implications of joint clinical assessments under the EU HTA regulation.
  13. Glycoengineering CAR-T cells to overcome galectin-3-mediated immunosuppression.
  14. Toxicities associated with CAR-T therapy compared with standard treatments in hematologic malignancies: a systematic review and meta-analysis.
  15. Tiny warriors, big impact: Targeted immunotherapy in kidney diseases.
  16. Progress in the development of cytokine armoured CAR T cells.
  17. PATIENT INVOLVEMENT IN HEALTH TECHNOLOGY ASSESSMENT: A NEW PROCESS IN SINGAPORE.
  18. Bridging process diversity in cell therapies toward standardization of manufacturing workflows.
  19. Advancing access to CAR T-cell therapy: insights and real-world experience from a community oncology practice.
  20. Health technology assessment system in Switzerland: Current state, gaps, and prospects for improvement.
  21. Early and accelerated access programs for medical devices in the European Union: mapping regulatory derogations and national schemes.
  22. Umbilical cord blood-derived natural killer cells as a viable and potent source for adoptive cell therapy.
  23. Navigating the complexities of digital health technology implementation: a scoping review of barriers and facilitators.
  24. HLA-E as an Emerging Checkpoint and Biomarker in Personalized Cancer Immunotherapy.
  25. Defining core competencies for advanced therapy medicinal products translation.
  26. Systemic lupus erythematosus patients eligible for chimeric antigen receptor T-cell therapy according to the 2024 EBMT and International Society for Cell and Gene Therapy expert-based recommendations: a 1-year clinical practice study in France.
  27. The Italian Assessment System for Innovative Medicines: An 8-Year Retrospective Analysis of Outcomes, Criteria, Timelines and Funding Dynamics.
  28. Steroid-induced modulation of the tumor immune microenvironment: Implications for cancer progression and immunotherapy outcomes.
  29. How I Treat HLH-Like Toxicities Following Immune Effector Cell Therapy.
  30. Use of artificial intelligence to draft a mini-HTA report on a new medical device belonging to class IIb-III.
  31. Regulatory T cells thrive in ammonia-rich tumors.
  32. Dual-Targeting BCMA-CD19 CAR-T Cell Therapy in Systemic Lupus Erythematosus: Single-Cell and Immune Repertoire Analysis Reveals Mechanisms of Immune Reconstitution.
  33. MS360°: a conceptual digital-first, data-driven hybrid care framework for personalised multiple sclerosis management.
  34. Exosomes in precision dermatology: From biomarkers to targeted therapeutics in personalized care.
  35. Nanovaccines in Cancer Immunotherapy: Lymph Node-Targeted Strategies and Mechanistic Insights.
  36. From algorithmic innovation to clinical deployment: A systematic review of methodological gaps limiting federated learning in healthcare.
  37. 38-Marker Full-Spectrum Flow Cytometry Panel for the Comprehensive Profiling of γδ T Cells in Human Blood and Lymphoid Tissues.
  38. Human VH-antibody-based CAR T cells targeting folate receptor-alpha show enhanced persistence and reduced T-cell exhaustion against ovarian cancer.
  39. Financial barriers to immunotherapy: challenges and potential mitigation strategies: a review paper.
  40. Immune checkpoint inhibitors in pediatric central nervous system tumors: biology, clinical experience, and translational pathways to precision immunotherapy.
  41. Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.
  42. Applications and Challenges of Artificial Intelligence and Big Data in Drug Regulation.
  43. Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC).
  44. RNA interference for lipid disorders: is this the future?
  1. Mol Immunol. 2026 Mar 05. pii: S0161-5890(26)00041-6. [Epub ahead of print]192 45-56
    Navigating the frontier of CAR-T cell resistance: From underlying mechanisms to innovative therapeutic solutions.
    Fei Lan, Jin Song, Xinfeng Chen, Yi Zhang.
      Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable success in the treatment of relapsed or refractory hematological malignancies, particularly acute B-cell lymphoblastic leukemia (B-ALL), B-cell lymphoma (BCL), and multiple myeloma (MM). However, resistance in hematological malignancies and limited immune responses in solid tumors remain major challenges for CAR-T cell therapy. Tumor antigen loss or modulation, dysregulated apoptotic signaling, CAR-T cell-intrinsic dysfunction, and immunosuppressive components within the tumor microenvironment (TME) significantly compromise therapeutic outcomes. Therefore, understanding the mechanisms that mediate resistance to CAR-T cell therapy and exploring strategies to overcome therapeutic failure are crucial for optimizing clinical results. This review systematically elucidates the mechanisms underlying resistance to CAR-T cell therapy and discusses potential countermeasures, including dual-targeted approaches, innovative CAR engineering strategies, TME reprogramming, and combination immunotherapies.
    Keywords:  CAR-T cell; Immunotherapy; Resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molimm.2026.02.011
  2. Postgrad Med. 2026 Mar 03. 1-8
    Implementation of CAR-T cell therapy in outpatient settings: a critical review of current literature regarding health outcomes, benefits, challenges, and future directions.
    Meghana Reddy, Rahulkumar J Amrutiya, Kaung Htet Hla Win.
      Chimeric Antigen Receptor (CAR) T-cell therapy has transformed the treatment landscape for hematologic malignancies. Although CAR-T cell therapy was traditionally administered in inpatient settings due to concerns related to acute toxicities, there is a growing trend toward outpatient administration. This review looks at the critical aspects of CAR T-cell therapy in outpatient settings, focusing on benefits, feasibility, limitations, and prospects. Implementation of careful selection criteria for outpatient therapy is found to achieve comparable efficacy and safety as in inpatient settings, particularly when supported by robust monitoring and rapid response protocols. Two major potential side effects of CAR-T cell therapy, namely, Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which appear to be key concerns related to outpatient administration, are discussed. Outpatient administration significantly lowers healthcare system costs, improves resource allocation, and, more importantly, increases patient psychological well-being. Despite these compelling factors, the outpatient model is not without risks and limitations, particularly necessitating comprehensive support strategies to ensure equitable and timely access and a specialized team of staff and resources for monitoring and timely management of the toxicity of CAR T-cell therapy. Continued development in CAR-T product design and remote monitoring technologies is of crucial importance to further establish and implement outpatient CAR-T therapy as a standard of care, expanding its reach and impact.
    Keywords:  CAR-T cell therapy; cancer immunotherapy; cytokine release syndrome; healthcare delivery models; hematological malignancies; outpatient oncology care
    DOI:  https://doi.org/10.1080/00325481.2026.2639107
  3. Front Immunol. 2026 ;17 1762453
    Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.
    Karama Makni-Maalej, Shaykhah Mujahhiz Alotaibi, Queenie Fernandes, Syed Osman Ahmed, Sarra Mestiri, Salim Bougarn, Waad Amir, Syed Farhatullah, Mohamed Kharfan-Dabaja, Maysaloun Merhi, Riad El Fakih, Mahmoud Aljurf, Said Dermime.
      T cell fitness has emerged as a critical determinant of the efficacy and persistence of Chimeric Antigen Receptor (CAR)-T cell therapy. Defined by the capacity of T cells to proliferate, resist exhaustion, persist in vivo, and exert sustained effector functions, T cell fitness reflects the integration of a dynamic network of intrinsic and extrinsic regulatory mechanisms. In this review, we present a comprehensive synthesis of the molecular and cellular foundations underlying T cell fitness, emphasizing the influence of differentiation trajectories, signaling pathways, metabolic reprogramming, and epigenetic modifications. We further discuss the impact of patient-specific conditions such as age as well as disease biology, prior therapeutic exposures, and timing and quality of T cell collection, on the phenotypic and functional efficacy of CAR-T cell products. Beyond delineating these determinants, we highlight emerging strategies aimed at enhancing T cell fitness. Importantly, we propose T cell fitness as an integrated, multi-layered systems property emerging from the interaction between differentiation state, signaling architecture, metabolic-mitochondrial competence, epigenetic stability, and host-specific inflammatory and treatment-related pressures. We introduce a mechanistic framework that links these layers across the CAR-T therapeutic timeline from leukapheresis to post-infusion tumor engagement and outline how this framework can be operationalized into measurable parameters to guide patient stratification, manufacturing decisions, and rational therapeutic interventions.
    Keywords:  CAR-T cell therapy; T cell fitness; T cell subsets; hematological malignancies; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1762453
  4. Transplant Cell Ther. 2026 Feb 26. pii: S2666-6367(26)00157-0. [Epub ahead of print]
    Advancing Cell Therapies for Solid Tumors: A Pathway to Overcome Biological, Operational, and Regulatory Hurdles.
    Kedar Kirtane, Michael Kalos, Rocky Billups, Aude G Chapuis, Vicki Coutinho, Steven A Feldman, Brian Gastman, John Haanen, Patrick J Hanley, Priti Hegde, Emily L Hopewell, Bruce L Levine, Frederick L Locke, Marcela V Maus, Nancy V Nair, Michael Nathenson, Miguel-Angel Perales, Isabelle Rivière, Devanjan Sikder, Craig Tendler, Cassian Yee, Jason Luke, Roisin E O'Cearbhaill.
      Cellular therapies have revolutionized the treatment of hematologic malignancies and are now emerging as potentially promising interventions for solid tumors. While considerable learnings can be leveraged from hematologic applications to inform the development of cell therapies in solid tumors, a number of biological and operational challenges-such as target-antigen heterogeneity; off-tumor target-mediated toxicity; immunosuppressive microenvironment; limited trafficking and persistence; tissue accessibility; and significantly larger patient populations-necessitate innovative clinical, manufacturing, regulatory, and operational strategies to deliver effective cell therapies for solid tumors. This white paper, informed by the 2025 Summit on Advancing Cell Therapy for Solid Tumors-co-sponsored by American Society for Transplantation and Cellular Therapy (ASTCT) and Society for Immunotherapy of Cancer (SITC)-proposes a framework for cellular therapy development in solid tumors, with an emphasis on logistical, operational, and regulatory considerations unique to this setting. The paper lays out an innovative, collaborative operational model to leverage collective experience and knowledge; emphasize standardization; invest in both prospective and retrospective banking of materials; engage in regulatory data-driven recalibration; engage payers before therapy begins; and establish regional manufacturing hubs and tailored accreditation pathways to support scalability and quality assurance. Operational innovations that can streamline access include hub-and-spoke clinical networks-where a central specialized facility is connected to smaller, more accessible locations-as well as early patient referrals. To safely implement new therapies, it is essential for providers to undergo enhanced training to manage cellular therapy-specific and delayed toxicities. Regulatory recalibrations-including streamlined evaluation of long-term follow-up requirements and proactive payer engagement for comprehensive reimbursement-are equally vital. Finally, cell therapy experts must lead cross-disciplinary education to ensure equitable and safe access as indications for cellular therapy expand across solid-tumor types, autoimmune diseases, and other disease types. Collaborative efforts across clinical, operational, regulatory, and policy initiatives are vital in order to unlock the full potential of cellular therapy for diverse patient populations.
    Keywords:  cellular therapies; operational considerations; solid tumors
    DOI:  https://doi.org/10.1016/j.jtct.2026.02.054
  5. Pathobiology. 2026 Feb 28. 1-20
    CAR-NKT cell therapy for tumors: promise and progress.
    Ruo-Bing Wang, Xuan Wang, Kun-Kun Han, Guo-Dong Chen, Yi-Li Yang, Xin Xu, Tao Zhang.
      Therapy based on chimeric antigen receptor-engineered invariant natural killer T (iNKT) cells (CAR-NKT cells) is an innovative cellular immunotherapy strategy that offers advantages over conventional CAR-T cell therapy in the treatment of solid tumors. This article reviews the research progress and current application of CAR-NKT cells in solid tumors. Current studies have shown that CAR-NKT cells can efficiently recognize tumor-associated antigens, infiltrate the tumor microenvironment, and exert anti-tumor effects through direct killing and cytokine secretion. Compared with CAR-T therapy, CAR-NKT therapy exhibits stronger anti-tumor potency and a reduced incidence of graft-versus-host disease. Furthermore, CAR-NKT cells can enhance anti-tumor immunity by regulating dendritic cells, NK cells, and CD8⁺ T cells. Early clinical trials for neuroblastoma and preclinical trials for other solid tumors have shown good safety and preliminary efficacy, and therapies have great potential for clinical translation. However, this therapy still faces challenges such as optimizing antigen selection, insufficient in vivo expansion and persistence, tumor heterogeneity, and immune suppression barriers. Future directions include advancing cytokine engineering and combination therapies. Collectively, CAR-NKT cells provide new ideas and new means to break through the difficulties in treating solid tumors and hold the promise of becoming the next generation of cellular immunotherapy.
    DOI:  https://doi.org/10.1159/000551197
  6. Med. 2026 Feb 27. pii: S2666-6340(26)00034-6. [Epub ahead of print] 101031
    T cell exhaustion in bi- and trispecific T cell engager therapy in hematologic malignancies: Mechanisms and implications.
    Amelie Muth, Alessandra Holzem, Anne-Sophie Neumann, Veit L Buecklein, Marion Subklewe, Nora Philipp.
      T cell engagers (TCEs) have revolutionized the treatment of hematologic malignancies, with eight approved bispecific constructs and numerous bi- and trispecific TCEs currently in clinical trials. However, despite their clinical success, lack of response and high relapse rates remain major challenges. T cell exhaustion has emerged as an important mechanism of resistance to TCE therapy. Characterizing the T cell pool in patients prior to and during TCE therapy is warranted (1) to identify patients who will benefit most from TCE therapy and (2) to develop strategies to circumvent exhaustion during treatment to improve patient outcomes. We here review the current evidence of pre-existing and acquired T cell exhaustion during TCE therapy in patients with hematologic malignancies. We furthermore review state-of-the-art (pre)clinical strategies aimed at ameliorating exhaustion and reinvigorating T cell function.
    Keywords:  T cell exhaustion; T cell-based immunotherapy; bi- and trispecific T cell engagers; biomarkers; cereblon-modulating agents; checkpoint blockade; costimulation; epigenetic modulators; hematologic; malignancies; optimized administration schedules; tumor microenvironment; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1016/j.medj.2026.101031
  7. Mol Ther Oncol. 2026 Mar 19. 34(1): 201155
    Beyond autologous ex vivo CAR-expressing cell therapies: Toward allogeneic and nucleated cell-free delivery systems of CAR.
    Kathrine S Rallis, Laura M Dionisio, Mubin Tarannum, Rizwan Romee, José A Cancelas.
      The success of ex vivo chimeric antigen receptor (CAR)-T cell therapies has transformed the treatment of hematologic malignancies but remains limited by individualized manufacturing complexity and cost. Emerging in situ and in vivo CAR engineering platforms aim to overcome these barriers by programming patient immune cells directly within the body. Targeted lipid nanoparticles, synthetic DNA nanocarriers, and viral and non-viral delivery systems have demonstrated the ability to generate functional CAR-T cells without ex vivo manipulation, enabling scalable, on-demand immunotherapy. In parallel, advances in allogeneic "off-the-shelf" cellular therapies provide donor-derived products that can be manufactured at scale, cryopreserved, and delivered rapidly. Additional cell types are also being explored as vehicles for in vivo CAR delivery. Hybrid approaches that leverage allogeneic cells as carriers for CAR constructs may combine the scalability of off-the-shelf products with the speed and flexibility of in vivo engineering. Despite this promise, challenges remain, including cell-specific targeting, control of transgene persistence, immunogenicity, and regulatory considerations. Together, these innovations signal a paradigm shift in the generation and deployment of CAR-based cellular immunotherapies.
    Keywords:  CAR-T therapy; MT: Regular Issue; allogeneic cell therapy; cellular immunotherapy; enveloped delivery vehicles; gene transfer; in vivo gene delivery; lipid nanoparticles; mRNA therapeutics; synthetic DNA nanocarriers
    DOI:  https://doi.org/10.1016/j.omton.2026.201155
  8. Biosystems. 2026 Feb 26. pii: S0303-2647(26)00060-2. [Epub ahead of print] 105750
    Synergizing Artificial Intelligence with In Vivo CAR-T Cell Generation: A New Paradigm for Democratized Immunotherapy.
    Alberto Boretti.
      In vivo CAR-T cell generation represents a paradigm shift in immunotherapy by transitioning the production of chimeric antigen receptor (CAR) T cells from external laboratories to the patient's own body. This innovative approach addresses the key limitations of conventional ex vivo CAR-T therapy, including prolonged manufacturing timelines, high costs, and restricted accessibility. The successful realization of this internalized manufacturing process is critically enabled by two interdependent pillars: advanced delivery platforms (viral vectors and non-viral lipid nanoparticle [LNP]-mRNA systems) and artificial intelligence (AI). AI acts as a transformative catalyst, accelerating the rational design of CAR constructs, optimizing the precision of targeted delivery systems, and enabling predictive safety modeling. Early clinical trials in oncology and autoimmune diseases provide compelling proof-of-concept, underscoring the potential of in vivo CAR-T strategies to substantially improve access and streamline treatment delivery. This review examines the mechanisms, comparative benefits, clinical progress, and future challenges of in vivo CAR-T generation, with a dedicated focus on the synergistic role of AI in shaping the next generation of safe, scalable, and intelligent cell-based immunotherapies.
    Keywords:  CAR-T therapy; autoimmune disease; cancer immunotherapy; clinical translation; immunotherapy; in vivo generation; lipid nanoparticles; mRNA delivery; nanomedicine; viral vectors
    DOI:  https://doi.org/10.1016/j.biosystems.2026.105750
  9. Ther Innov Regul Sci. 2026 Mar 05.
    Mapping the evolution of cell and gene therapy product research: trends, collaborations, and emerging frontiers.
    Yanmei Rao, Li Dong, Zhe Huang.
      Advanced therapeutic medicinal products represent a broad spectrum of biopharmaceutical innovations that prominently feature cell and gene therapy formulations. These cutting-edge therapeutic modalities are specifically engineered to intervene in and prevent illnesses that historically necessitated continuous, long-term management. To visually portray the most recent trajectories in cell and gene therapy investigations and to map out prevailing global advancements, a bibliometric assessment was conducted. This analysis meticulously sourced its data from the Web of Science Core Collection database and was significantly enhanced by analytical platforms such as VOSviewer and CiteSpace. Cell and gene therapy products demonstrate considerable promise for both foundational scientific inquiry and diverse clinical interventions, with their utility now extending far beyond cancer treatment to encompass a wide array of other pathological conditions. This paper provides a comprehensive examination of the evolving trends, collaborative endeavors, and burgeoning frontiers within the dynamic landscape of cell and gene therapy products.
    Keywords:  Bibliometric visualization; Cancer therapy; Cell and gene therapy products; Diseases
    DOI:  https://doi.org/10.1007/s43441-025-00913-9
  10. RMD Open. 2026 Mar 04. pii: e006417. [Epub ahead of print]12(1):
    CAR-T cell therapy for treatment-refractory rheumatic autoimmune diseases: a systematic review of clinical outcomes and safety profiles.
    Anindita Santosa, Tze Chin Tan.
       OBJECTIVES: Current therapeutic paradigms for treatment-refractory rheumatic diseases rely on chronic immunosuppression with variable efficacy and potential for cumulative toxicity. We systematically synthesised evidence on the clinical efficacy, safety and durability of chimeric antigen receptor T-cell (CAR-T) therapy in autoimmune rheumatic diseases.
    METHODS: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO: CRD42025641602). Five databases were searched from inception to February 2025 for primary studies investigating CAR-T therapy in autoimmune rheumatic diseases. Two reviewers independently assessed studies using the Joanna Briggs Institute tools and the Risk of Bias in Non-Randomised Studies of Interventions tool.
    RESULTS: 12 studies encompassed 44 patients with severe treatment-refractory disease across six rheumatic conditions. Patients had extensive prior exposure (median 5 therapies), including conventional and biological agents. Cluster of Differentiation antigen 19 (CD19)-targeted constructs predominated (83% of studies), with emerging dual-target approaches (17%). Universal clinical responses were achieved (100% of studies; individual response rates 92%-100%), with complete responses occurring within 2-16 weeks. Sustained drug-free remissions extended 6-46 months, accompanied by profound autoantibody reductions (80%-99% across disease-specific markers). Safety profiles diverged markedly from oncological experience: cytokine release syndrome (CRS) remained exclusively confined to grades 1-2, while immune effector cell-associated neurotoxicity occurred in 25% of studies, with predominantly grade 1 severity.
    CONCLUSIONS: CAR-T therapy demonstrates substantial efficacy in treatment-refractory rheumatic diseases, achieving sustained remissions through comprehensive B-cell elimination. Importantly, safety profiles were favourable, with CRS limited to grades 1-2 severity, no grade ≥3 events and rare immune effector cell-associated neurotoxicity, representing markedly superior tolerability compared with oncological applications.
    PROSPERO REGISTRATION NUMBER: CRD42025641602.
    Keywords:  Autoimmune Diseases; Systemic Lupus Erythematosus; Systemic Sclerosis
    DOI:  https://doi.org/10.1136/rmdopen-2025-006417
  11. Cancer Metastasis Rev. 2026 Mar 02. pii: 10. [Epub ahead of print]45(1):
    CAR-T cell therapy for pediatric solid tumors: armored CAR-T cells and beyond.
    Jeremy Wells, Ajay Gupta.
      CAR-T cell therapy, which uses endogenous T cells engineered to target specific cancer antigens, is one of the most promising recent developments in the treatment of hematologic malignancies in both children and adults. CAR-T cells have shown tremendous success in treating B-cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma, and they are currently FDA-approved for the treatment of six hematologic malignancies. Its success in solid tumors has been more modest, which has been attributed to several factors including the hostile tumor microenvironment (TME), poor persistence of CAR-T cells, and difficulty directing CAR-T cells towards solid tumors. Armored CAR-T cells, which modify the TME via secreted cytokines, have shown early success in the treatment of solid pediatric malignancies. We review recent trials of CAR-T cells to treat common pediatric solid malignancies, including Ewing sarcoma, osteosarcoma, neuroblastoma, diffuse intrinsic pontine glioma, rhabdomyosarcoma, Wilms tumor, and retinoblastoma. We focused particularly on armored CAR-T cells where applicable. Armored CAR-T cells have been utilized to target a variety of tumor-associated antigens on pediatric solid tumors with early successes both in vivo and in vitro, and innovative approaches for addressing their limitations are rapidly being developed.
    Keywords:  CAR-T; Immunotherapy; Pediatric; Solid; Tumor
    DOI:  https://doi.org/10.1007/s10555-026-10317-2
  12. Health Econ Policy Law. 2026 Mar 02. 1-13
    Legal implications of joint clinical assessments under the EU HTA regulation.
    Nicolas S H Xander, Maureen P M H Rutten-van Mölken, Louis Bertin, Nenad Miljković, Carin A Uyl-de Groot.
      Joint clinical assessments (JCAs) under the European Union (EU) Regulation 2021/2282 on health technology assessment (HTA-R) and its implementing regulations have been linked to various implementation challenges. However, legal implications of practically relevant issues have mostly remained unexplored. This study investigated potential legal implications of disparities regarding patient population, intervention, comparator, and outcomes (PICOs) in JCAs from respective member states (MSs), and of managing conflicts of interest (CoIs) of experts involved in a JCA. Moreover, we discussed potential consequences for patient access. JCA reports are not legally binding for MS; PICO disparities can underpin the required justification for their non-consideration at national level. Legal action against negative reimbursement decisions due to unjustified non-consideration falls under national jurisdiction. Furthermore, too strict CoI management might leave perspectives of MSs with fewer experts and thus a higher chance of CoI occurrence unheard, requiring corresponding expert elicitation at national level. These implications might lead to an increased workload for health technology developers and national HTA bodies, potentially fostering marketing strategies and access delays. Thorough scoping processes and prioritising the need for a JCA's scientific excellence could facilitate more streamlined national HTA procedures and accelerated patient access.
    Keywords:  PICOs; conflicts of interest; legal assessment; patient access
    DOI:  https://doi.org/10.1017/S1744133126100413
  13. Front Immunol. 2026 ;17 1766555
    Glycoengineering CAR-T cells to overcome galectin-3-mediated immunosuppression.
    Lee Seng Lau, Maria Suarez, Brandon Fernandez, Joseph Souchak, Aristotelis Antonopoulos, Nan Hu, Maria M Abreu, Guenther Koehne, Anne Dell, Stuart M Haslam, Avery D Posey, Charles J Dimitroff.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed treatment for relapsed or refractory B-cell malignancies; however, limited in vivo persistence and treatment-limiting toxicities continue to constrain durable efficacy. Because T cell glycan signatures and related galectin-binding properties impact their effector function, we postulated that CAR-T cells similarly displayed signature glycan features that govern their vulnerability to immunosuppressive galectins. In this report, public data mining, galectin-binding and glycosyltransferase expression assessments and glycomics showed that galectin (Gal)-3 was elevated in lymphoma-associated microenvironments and that anti-CD19 CAR-T cells displayed abundant Gal-3-binding glycans, reduced expression of the Gal-3-inhibitory enzyme α2,6-sialyltransferase 1 (ST6GAL1), and heightened susceptibility to Gal-3-mediated immunoregulation. To further explore this association, we enforced ST6GAL1 expression in anti-CD19 CAR-T cells and found that Gal-3-binding was obstructed and Gal-3-mediated cell death and IL-5-induction were reversed. Enforcing ST6GAL1 in CAR-T cells did not weaken tumoricidal activity and significantly improved anti-tumor responses and in vivo persistence. Collectively, this study identifies Gal-3 as a key extrinsic suppressor of CAR-T cell function and establish targeted cell surface α2,6 sialylation as a strategy to enhance CAR-T cell resistance to galectin-rich immunosuppressive microenvironments.
    Keywords:  CAR-T cells; cancer glycobiology; cancer immunotherapy; galectins; sialylation modification
    DOI:  https://doi.org/10.3389/fimmu.2026.1766555
  14. BMC Cancer. 2026 Mar 02.
    Toxicities associated with CAR-T therapy compared with standard treatments in hematologic malignancies: a systematic review and meta-analysis.
    Alexandra Porras Ramírez, Alejandro Rico Mendoza, Liliana Encinales, Oscar Madiedo, Marianna Carrillo Encinales, Juan Pablo Duque Bolívar, Juan Fernando Ramón Cuellar, Jorge Andrés Urquijo Méndez, Alexandra Marín Morales, Zuly Moreno Perilla, Alejandra Hernández Osorio.
      
    Keywords:  CAR-T therapy; Cytokine release syndrome; Cytopenia; Hematologic malignancies; Immune effector cell toxicity; Infections; Meta-analysis; Neurotoxicity; Safety profile; Supportive care
    DOI:  https://doi.org/10.1186/s12885-026-15780-2
  15. Kidney Int. 2026 Feb 27. pii: S0085-2538(26)00145-6. [Epub ahead of print]
    Tiny warriors, big impact: Targeted immunotherapy in kidney diseases.
    Johanna T Kurzhagen, William Laqua, Georg Schett, Ricardo Grieshaber-Bouyer, Hamid Rabb, Sanjeev Noel, Mario Schiffer.
      Recent advances in immunotherapy targeting B cells have ushered in a new era for disease treatment. Effectiveness of targeted approaches such as T cell engagers or B cell directed CAR-T cell therapy in treating autoimmune diseases has been demonstrated so far only in uncontrolled, investigator-initiated trials. Several case series in therapy-resistant systemic lupus erythematosus (SLE) patients showed efficacy and safety of CD19+ CAR-T cells showing depletion of autoreactive B cells and full clinical remission. Autoreactive B cells not only mediate pathogenesis of SLE and lupus nephritis, but also many other inflammatory kidney diseases such as ANCA-associated vasculitis, membranous nephropathy and IgA-associated nephropathy. Moreover, many patients do not respond to currently used treatment options, resulting in a high rate of disease progression or recurrence. Thus, implementing novel B cell targeting immunotherapies in kidney diseases could lead to a more effective depletion of autoreactive B cells and sustained suppression of autoimmunity than conventional anti-CD20 antibody therapy. However, data on the application of these approaches in kidney diseases remain limited. Therefore, it is important to investigate their effects on clinically relevant renal endpoints, such as proteinuria reduction, stabilization of eGFR, histological improvements and rates of disease remission, particularly in the context of autoimmune kidney diseases. This review provides a summary of kidney-specific applications and side effects associated with novel immunotherapies, including allogeneic and autologous CAR-T cells and T cell engagers, and offers a perspective on emerging immunotherapeutic approaches.
    Keywords:  CAR-T cells; T cell engager; Targeted immunotherapy; acute kidney injury; renal autoimmune diseases
    DOI:  https://doi.org/10.1016/j.kint.2026.01.032
  16. Nat Rev Immunol. 2026 Mar 06.
    Progress in the development of cytokine armoured CAR T cells.
    Krishneel Prasad, Ryan S Cross, Misty R Jenkins.
      The engineering of chimeric antigen receptor (CAR) T cells has evolved from first-generation constructs to sophisticated armoured CAR T cells of the fourth generation. These advanced cellular constructs are engineered to co-express cytokines, chemokines or other immunomodulatory factors alongside CARs, aiming to enhance the efficacy, safety and persistence of CAR T cells within the tumour microenvironment. In particular, the potential for reversion of immunosuppression may allow for the treatment of solid tumours, which are in need of new therapeutic options. Here, we explore clinical and preclinical findings with cytokine-enhanced CAR T cells and discuss strategies for conditional cytokine secretion to mitigate systemic toxicity.
    DOI:  https://doi.org/10.1038/s41577-026-01280-8
  17. Int J Technol Assess Health Care. 2026 Mar 06. 1-22
    PATIENT INVOLVEMENT IN HEALTH TECHNOLOGY ASSESSMENT: A NEW PROCESS IN SINGAPORE.
    Ping-Tee Tan, Fiona Pearce, Kiah Shen Quek, Sok Huang Teo, Jen Hun Koh.
      
    DOI:  https://doi.org/10.1017/S0266462326103584
  18. Cytotherapy. 2026 Jan 03. pii: S1465-3249(25)00937-5. [Epub ahead of print]28(5): 102041
    Bridging process diversity in cell therapies toward standardization of manufacturing workflows.
    Marta H G Costa, Manuel J T Carrondo, Paula M Alves, Margarida Serra.
      Cell therapies offer transformative potential for a wide range of diseases. However, their manufacturing remains complex due to the inherent variability of living cells, sensitivity to culture conditions and diverse differentiation and genetic engineering requirements. Autologous and allogeneic modalities, along with the intended clinical application, impose distinct demands on production scale, workflow flexibility and quality control, while donor variability and available starting material further challenge process reproducibility. This review examines the unique requirements of multiple cell therapy modalities, including chimeric antigen receptor T cells, induced pluripotent stem cell-derived products, and mesenchymal stem/stromal cells, and compares their manufacturing processes to identify opportunities for standardization. We analyze both upstream and downstream processing steps, including cell isolation, expansion, purification, concentration, formulation and cryopreservation, highlighting technological solutions such as closed, automated platforms and integrated modular systems that enable flexible operation. The use of real-time monitoring via process analytical technology, combined with machine learning and artificial intelligence, is also discussed for identifying critical quality attributes and guiding process control. We discuss the relevance of harmonizing workflows across modalities to not only improve reproducibility, scalability and cost-effectiveness in cell therapy manufacturing, but also accelerate the development of new cell therapies by enabling broadly applicable process steps to be adapted across multiple cell therapy platforms.
    Keywords:  automation; cell therapy manufacturing; immune cells; process standardization; scalable bioprocessing; stem cells
    DOI:  https://doi.org/10.1016/j.jcyt.2025.102041
  19. Front Oncol. 2026 ;16 1712533
    Advancing access to CAR T-cell therapy: insights and real-world experience from a community oncology practice.
    Gary L Simmons, Scott Cross, Elias C Pittos.
       Introduction: Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, offering durable remissions for patients with otherwise refractory disease. However, access to these therapies remains limited and primarily restricted to academic medical centers, contributing to significant geographic and demographic disparities in care delivery.
    Methods: We conducted a retrospective review of a community practice-based outpatient CAR T-cell therapy program, independent of academic or hospital affiliation, treating patients with relapsed hematologic malignancies. The implementation process, completed over six months, followed a structured series of steps to ensure safe and effective outpatient administration.
    Results: Between April 19, 2022, and December 18, 2024, 41 adult patients received outpatient CAR T-cell therapy. Products administered included liso-cel (n=19), ide-cel (n=12), axi-cel (n=8), and brex-cel (n=2). CRS occurred in 68% of patients, and ICANS in 22%. Hospital admission was required for 49% of patients, with 15% needing ICU care. Clinical remission rates at day 100 and 1 year were consistent with published data for each product. Patients receiving 4-1BB co-stimulatory domain CAR T-cells were observed to have numerically lower hospitalization rates (32%) compared to those receiving CD28-based products (100%). No unexpected safety concerns were observed under home-based monitoring.
    Conclusion: This analysis demonstrates that outpatient CAR T-cell therapy can be safely delivered in a community oncology practice setting, offering a viable solution to expand access and reduce geographic barriers. Despite clinical success, payer reluctance remains a significant barrier, highlighting the urgent need for policy reform to enable community-based delivery of advanced therapies.
    Keywords:  CAR T-cell therapy; community oncology; outpatient; patient access; program implementation; real-world outcomes
    DOI:  https://doi.org/10.3389/fonc.2026.1712533
  20. PLOS Glob Public Health. 2026 ;6(3): e0005848
    Health technology assessment system in Switzerland: Current state, gaps, and prospects for improvement.
    Mohammed Alkhaldi, Rima Kachach, Line Enjalbert, Aisha Al Basuoni, Malak Alrubaie, Sara Ahmed.
      Switzerland maintains a distinct HTA system that often aligns with EU requirements and reflects its unique healthcare governance model, with structured processes led by the Federal Office of Public Health (FOPH), despite lacking a comprehensive national framework. These processes, though sometimes limited in scope, produce nationally binding decisions. This study aims to comprehensively analyze and understand the key pillars of the national HTA system, identify obstacles, and propose insights to strengthen the HTA system in Switzerland. This system analysis study was conducted between 2021 and 2023, targeting key Swiss HTA-associated organizations and experts from various health sectors. Mixed methods were used to gather data using electronic institutional surveys completed by nine organizations to assess HTA technical aspects and virtual in-depth interviews (IDIs) with eight experts to understand HTA from a policy perspective. The study examined HTA practices in the Swiss organizations, comprising 67% academic, 22% public, and 11% non-governmental sectors. Findings revealed that 67% of the organizations mentioned that structured processes were led by the FOPH as the central agency (67%). While 56% (n = 5) of organizations reported substantial funding, challenges included a lack of government funding. In Switzerland, HTAs most frequently addressed safety, clinical effectiveness, and economic aspects, while social acceptability and feasibility were less commonly considered. Strong interest in expanding HTA capacity was expressed. However, there is limited awareness and advocacy for HTA, insufficient political support, limited institutional capacity, and persistent gaps in funding. The study highlights the importance of HTA in healthcare decision-making and resource allocation in Switzerland, and the need for addressing the integration gap of HTA into decision-making. Enhancing awareness and institutional strengthening are key to advancing HTA. This study offers insights to guide future research and to establish a national HTA agency, to improve integration and coordination of HTA across all Swiss Cantons.
    DOI:  https://doi.org/10.1371/journal.pgph.0005848
  21. Front Med Technol. 2026 ;8 1729631
    Early and accelerated access programs for medical devices in the European Union: mapping regulatory derogations and national schemes.
    Baptiste Haon, Mira Hartmann, Sanae Akodad, Hilde Stevens, Lise Rochaix.
       Background: Early access programs (EAPs) can provide patients with medical devices before full market access in urgent or high unmet-need situations. Unlike pharmaceuticals, the European Union (EU) has no harmonised early-access framework for medical devices, resulting in fragmented national practices. We use EAP as an umbrella term for two overlapping categories with distinct objectives: (1) early access in the strict sense, authorising exceptional pre-market use under defined conditions; and (2) accelerated access, aiming to shorten time to routine access by streamlining regulatory, reimbursement, or evidence-generation pathways. We map and compare these mechanisms across the 27 EU Member States (MS).
    Methods: We conducted a qualitative document-based analysis of peer-reviewed literature, grey literature (policy papers, regulatory guidance), and legal sources (EU legislation, national laws) published up to June 2025. We searched PubMed and Google Scholar, consulted Eur-Lex, and reviewed national competent authority websites. Search terms (English and local languages, then translated) combined "medical device" with "early access," "accelerated access," "compassionate use," and "derogation," plus "EU" or MS names. Documents were included if they described mechanisms enabling early use of medical devices. We synthesised and compared key program characteristics.
    Results: We identified early and accelerated access pathways at EU level and within MS. EU law provides derogations from CE-marking requirements, notably Article 59 of the EU Medical Device Regulation (EU MDR), allowing national authorisation of non-CE-marked devices in exceptional circumstances. The EU MDR also enables the use of custom-made devices and certain in-house manufactured devices by health institutions without full CE marking. Nationally, at least half of MS operate compassionate or expanded access schemes for devices, and some implement reimbursement or evidence-development mechanisms (e.g., France's forfait innovation) to support early use while generating decision-relevant data.
    Conclusions: Early access to medical devices in Europe relies on EU regulatory derogations and heterogeneous national schemes. The landscape remains fragmented and unevenly documented. We recommend: (1) a more structured EU-level route for high-risk and combination products, (2) lifecycle-based national schemes integrating regulatory and payer access, (3) measures to reduce inequities and administrative barriers, particularly in Central and Eastern Europe, and (4) improved transparency and standardised data collection on implemented pathways.
    Keywords:  Article 59; Regulation (EU) 2017/745; accelerated access; compassionate use; coverage with evidence development; early access; equity; medical devices
    DOI:  https://doi.org/10.3389/fmedt.2026.1729631
  22. Cytotherapy. 2026 Feb 05. pii: S1465-3249(26)00041-1. [Epub ahead of print]28(5): 102079
    Umbilical cord blood-derived natural killer cells as a viable and potent source for adoptive cell therapy.
    Raquel de Melo Alves-Paiva, Larissa L Coa, Julia T Azevedo, Jamile Ramos da Silva, Juliana A P de Godoy, Micheli Severo Sielski, Larissa Cardoso Zanetti, Denise C Oliveira, Oswaldo Keith Okamoto, José Mauro Kutner, Nelson Hamerschlak, Lucila N Kerbauy.
       BACKGROUND AIMS: Natural killer (NK) cells represent a key component of the innate immune response, capable of targeting a wide range of tumor and virus-infected cells independently of major histocompatibility complex restriction. Umbilical cord blood (UCB) is a promising source of NK cells because of its availability, lower human leukocyte antigen requirements and reduced risk of graft-versus-host disease.
    METHODS: In this study, UCB-derived NK cells were expanded ex vivo for 14 days using CSTX002 under Good Manufacturing Practice conditions.
    RESULTS: The expanded NK cells exhibited high viability (94.8 ± 1.3%) cryopreservation, which remained stable after 180 days (87.7 ± 1.1%) and after 365 days (91 ± 8.1%; n = 4). The immunophenotype (CD56⁺CD3⁻) was preserved, with more than 90% of cells maintaining this profile after long-term cryopreservation. Cytotoxic activity, assessed using a calcein-AM assay against K562 and HL-60 leukemia cell lines, remained robust after cryopreservation. At day 14, NK cells killed 54.55 ± 10.92% of K562 cells at a 0.5:1 effector-to-target ratio and 98.60 ± 0.66% at a 40:1 ratio. Cryopreserved NK cells demonstrated comparable activity, killing 44.56 ± 11.98% and 97.64 ± 2.36% of target cells at the same respective ratios.
    CONCLUSIONS: These findings support the feasibility of producing cryopreserved, UCB-derived NK cells as a stable and effective "off-the-shelf" product for adoptive immunotherapy, particularly in the treatment of acute myeloid leukemia, with advantages in scalability, standardization, and rapid clinical deployment.
    Keywords:  NK cells; cord blood; cryopreservation
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102079
  23. Implement Sci Commun. 2026 Mar 04.
    Navigating the complexities of digital health technology implementation: a scoping review of barriers and facilitators.
    Laura Wittich, Hendrikje Rödiger, Tanja Rombey, Anna-Lena Brecher, Lena Kraft, Sophia Sgraja, Viktoria Stein, Cornelia Henschke.
       BACKGROUND: The implementation of digital health technologies (DHTs) is a strategic priority for many health systems, yet integrating them into routine clinical use remains challenging. While numerous studies explore DHT adoption, few provide a comprehensive perspective across technologies and stakeholder groups. This review synthesises the most prevalent barriers and facilitators to DHT implementation in high-income healthcare settings.
    METHODS: A scoping review was conducted following Joanna Briggs Institute and PRISMA-ScR guidelines. Publications from 2019 to 2024 reporting barriers or facilitators to DHT implementation in upper-middle and high-income countries were identified through systematic searches in PubMed and Scopus. An inductive approach guided iterative coding and thematic categorisation. Findings were synthesised based on frequency, overlap, and variation across technologies and stakeholder groups.
    RESULTS: From 15,327 unique records screened, 238 publications were included. In total, 2538 barriers and 1433 facilitators were identified, grouped into three overarching dimensions: human and social dynamics, organisational structure and management, and infrastructure and data security. Human and social factors such as resistance to change, scepticism, and limited digital literacy were the most frequently reported across the majority of technologies and stakeholder groups. Organisational barriers, including funding constraints, workflow misalignment, and limited leadership engagement, along with infrastructure-related challenges such as poor usability, data privacy concerns, and interoperability issues, were also substantial but were comparatively less frequent. Patterns varied by technology type (e.g., telehealth, mobile health apps, AI tools) and stakeholder group (e.g., healthcare professionals, health system managers, users of health services), highlighting the complex, context-dependent nature of DHT implementation.
    CONCLUSIONS: Successful DHT implementation demands more than technical readiness. It requires organisational leadership, robust infrastructure, and system-wide alignment. While human and social dynamics remain central, leadership, resource allocation, and robust infrastructures are equally critical. Current evidence often underemphasises structural barriers such as governance gaps, misaligned incentives, and technical limitations. Sustainable digital transformation requires a balanced approach combining top-down strategic guidance for regulatory clarity with bottom-up engagement to foster cultural change. Future research should operationalise governance strategies, leadership practices, and monitoring indicators that support long-term digital health integration.
    REGISTRATION: A prospective protocol was uploaded to the Open Science Framework: https://osf.io/vr7d9/ (https://doi.org/10.17605/OSF.IO/VR7D9).
    Keywords:  Adoption Strategies; Digital Health Technologies; Digital Literacy; Human and Social Dynamics; Implementation Barriers; Implementation Facilitators; Infrastructure and Data Security; Organisational Readiness
    DOI:  https://doi.org/10.1186/s43058-026-00892-4
  24. Curr Med Sci. 2026 Mar 06.
    HLA-E as an Emerging Checkpoint and Biomarker in Personalized Cancer Immunotherapy.
    Rajeswary Sanmugawil, Lhoshiny Parmeswaran, Nafisah Abdul Rahman, Norfarazieda Hassan.
      Human leukocyte antigen (HLA) molecules play a predominant role in cancer immunotherapy by harnessing the immune system's capacity to differentiate between healthy and malignant cells. Most human cell types express HLA class I molecules, which interact with T-cell receptors (TCRs) to activate T cells and initiate adaptive immunological responses. The efficacy of several immunotherapeutic strategies, including checkpoint inhibitors, CAR-T-cell therapy, and personalized cancer vaccines, is significantly influenced by HLA diversity and polymorphisms. Human leukocyte antigen E (HLA-E) is a non-classical major histocompatibility complex class I (MHC-I) protein that plays a crucial role in immune regulation. Unlike classical HLA molecules, HLA-E exhibits unique immunosuppressive properties that influence tumor immune evasion mechanisms. Recent studies have highlighted the importance of HLA-E expression in various hematological malignancies and solid tumors. HLA-E interacts with inhibitory receptors on natural killer (NK) cells and certain T-cell subsets, thereby modulating immune responses against tumor cells. The expression of HLA-E on tumor cells can lead to immune escape by inhibiting the cytotoxic activity of NK and CD8+ T cells, which are critical for effective anti-tumor immunity. This review summarizes how HLA-E presents antigens, discusses recent advances in identifying HLA-E-restricted peptides, and evaluates current HLA-E-dependent and HLA-E-independent adoptive immunotherapies. Understanding the role of HLA-E in tumor immune evasion provides valuable insights for developing novel personalized cancer immunotherapies. Targeting HLA-E has the potential to increase the effectiveness of current treatments and improve patient prognosis across diverse cancer types.
    Keywords:  Biomarkers; Cancer immunotherapy; HLA-E; Immunocheckpoint inhibitors; NKG2A; Personalized medicine; Tumor immune evasion
    DOI:  https://doi.org/10.1007/s11596-026-00171-2
  25. Front Digit Health. 2026 ;8 1707741
    Defining core competencies for advanced therapy medicinal products translation.
    Elena Guillen, Ana Hidalgo-Simon.
       Background: Translating Advanced Therapy Medicinal Products (ATMPs) from research to clinical application requires a specialized set of priority topic areas that is not yet systematically defined.
    Methods: We employed a multi-phase approach combining a targeted literature review with a structured expert consensus survey. Selected experts evaluated a set of 35 preselected competencies across seven thematic areas using an anonymous online questionnaire, categorizing them as Fundamental, Ancillary, or Less Important for ATMPs translation.
    Results: Concordance was high, with 16 competencies reaching the ≥75% consensus threshold as Fundamental. These covered regulatory strategy, manufacturing scalability, quality management, clinical translation, and cross-disciplinary collaboration.
    Conclusions: This study establishes a validated set of ATMP-specific competencies that can serve as the basis for targeted training programs. Embedding these into education and professional development will help build a workforce capable of navigating the complex and constantly evolving translational needs of ATMPs.
    Keywords:  advanced therapy medicinal products (ATMPs); competencies; gene and cell therapies; regulatory science; training; translation; workforce
    DOI:  https://doi.org/10.3389/fdgth.2026.1707741
  26. Cytotherapy. 2026 Jan 20. pii: S1465-3249(26)00013-7. [Epub ahead of print]28(5): 102057
    Systemic lupus erythematosus patients eligible for chimeric antigen receptor T-cell therapy according to the 2024 EBMT and International Society for Cell and Gene Therapy expert-based recommendations: a 1-year clinical practice study in France.
    Maladies Auto Immunes et Thérapie Cellulaire Group-Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
       BACKGROUND AIMS: Systemic lupus erythematosus (SLE) is a rare and highly heterogeneous autoimmune disease in which standard treatment is based on corticosteroids and conventional or biological immunosuppressive drugs. In severe SLE patients (resistant to first- and second-line therapies), the 10-year mortality rate remains around 10-15%. Autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has recently demonstrated sustained remission in this subset of SLE patients, but the number of treated patients remains low. The objective of this study was to assess the clinical practices (CPs) and various challenges in recruiting severe SLE patients eligible for CAR T-cell therapy.
    METHODS: A 1-year (February 2024 to February 2025) retrospective multicenter study was conducted across seven certified autoimmune disease reference centers. All adult SLE patients fulfilling the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology criteria were screened for disease activity and severity according to the 2024 EBMT-International Society for Cell & Gene Therapy expert consensus. Eligibility for CAR T-cell or other non-cell and gene therapy trials and reasons for non-inclusion were analyzed.
    RESULTS: Among 1844 SLE patients screened over this 1-year retrospective study: 54 (2.9%) demonstrated severe disease criteria and, three (0.16 %) were ultimately treated by CAR- T while 49 were not selected for CAR T-cell trials because of either disease remission, lack of specific autoantibody, participation in other trials, physician/patient refusal or exclusion criteria at time of enrollment.
    CONCLUSIONS: Retrospective analysis of CPs showed that very few severe SLE patients were enrolled in the CAR T-cell trial despite eligibility criteria. Streamlined referral pathways, multidisciplinary coordination and improved physician education are needed to enhance access to advanced cell and gene therapies.
    Keywords:  CAR T-cell; Cell and Gene Therapy (CGT); Clinical trial; Eligibility; Enrollment; Systemic Lupus Erythematosus (SLE)
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102057
  27. Appl Health Econ Health Policy. 2026 Mar 04.
    The Italian Assessment System for Innovative Medicines: An 8-Year Retrospective Analysis of Outcomes, Criteria, Timelines and Funding Dynamics.
    Lorenzo Martellone, Camilla Servidio, Marcello Vaccaro, Katiuscja Malandrini, Adriana Coluccia, Alessandra Oliva, Claudio Maria Mastroianni, Giacomo Polito.
       BACKGROUND: The Italian assessment system for innovative medicines represents a distinctive European regulatory approach. Integrated with the Italian Medicines Agency (AIFA), since 2017 it has provided a formal evaluation based on three predefined criteria, Therapeutic Need (TN), Added Therapeutic Value (ATV) and Quality of Evidence (QoE), granting access to dedicated funds and simplified procedures.
    OBJECTIVE: This study investigated the evolution of the Italian system from 2017 to the 2025 reform, focusing on outcomes, decision criteria, timelines, and financial implications.
    METHODS: Publicly available AIFA data on 266 assessments were analysed and stratified by outcome, therapeutic area, orphan status and Advanced Therapy Medicinal Product (ATMP) designation. Logistic regression models were used to assess the internal consistency of appraisal criteria and to explore whether regulatory attributes modified their association with innovativeness outcomes. Time to recognition (TIR) and Decision-to-Implementation Interval (DII) were calculated for "Full Innovative" medicines. Annual spending was compared to fund availability to assess the financial impact of innovative medicines.
    RESULTS: Among the 266 evaluations, approximately 29% were classified as "Full Innovative", 29% "Conditionally Innovative" and 42% "Not Innovative". Added Therapeutic Value and QoE showed the strongest associations with positive designations, while orphan and ATMP status showed no independent association. Access timelines were comparable across therapeutic areas, with slightly longer delays for ATMPs. Spending exceeded fund limits several times but fell below budget after fund unification in 2022.
    CONCLUSIONS: The Italian system has been applied consistently over time, with appraisal outcomes largely reflecting the formal decision criteria rather than regulatory status. The 2025 reform may represent a turning point, potentially changing designation patterns and their determinants. Ongoing monitoring is needed to ensure access does not compromise evidence standards or sustainability, offering lessons that may be relevant to other health systems considering similar mechanisms.
    DOI:  https://doi.org/10.1007/s40258-026-01032-8
  28. J Steroid Biochem Mol Biol. 2026 Mar 01. pii: S0960-0760(26)00044-0. [Epub ahead of print]259 106978
    Steroid-induced modulation of the tumor immune microenvironment: Implications for cancer progression and immunotherapy outcomes.
    Kanimozhi Kaliyamoorthi.
      Glucocorticoids (GCs) remain indispensable in oncology due to their strong anti-inflammatory, anti-oedema, and immunosuppressive effects, which are crucial for controlling cancer symptoms and treatment-related toxicities. However, the expanding use of immunotherapies, particularly immune checkpoint blockade and CAR-T cell approaches, has highlighted the paradoxical influence of steroids on anti-tumor immunity. GCs profoundly reshape the tumor immune microenvironment (TIME) by suppressing cytotoxic T-cell activity, enhancing regulatory T cells, polarizing macrophages toward tumor-promoting states, inhibiting NK and dendritic cell function, and expanding myeloid-derived suppressor cells. Together, these alterations weaken immune surveillance and may promote tumor progression, metastasis, and therapeutic resistance. Both systemic and tumor-derived GC signaling further interact with niches that sustain cancer stemness. Clinical data indicate that the timing, dose, and duration of steroid exposure are decisive, with early or high-dose administration frequently associated with poorer immunotherapy outcomes. Therefore, clarifying GC-driven immune modulation is critical to balance toxicity control while preserving anti-tumor efficacy in precision immunotherapy.
    Keywords:  Cancer progression; Glucocorticoids; Immunosuppression; Immunotherapy; Steroid signaling; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.106978
  29. Blood. 2026 Mar 04. pii: blood.2025032352. [Epub ahead of print]
    How I Treat HLH-Like Toxicities Following Immune Effector Cell Therapy.
    William T Johnson, Kevin O McNerney, Matthew J Frank, Nirali N Shah.
      Breakthroughs in cancer immunotherapy have redefined patient care, ushering in a new era of therapeutic modalities including checkpoint inhibitors, chimeric antigen receptor (CAR) T-cells, and bispecific T-cell engagers, amongst others. However, their distinct toxicity profiles have required clinicians across all specialties to rapidly adopt an immunologic perspective in management. Among them, therapy related hemophagocytic lymphohistiocytosis (HLH)-like toxicities are increasingly recognized as part of a broader category of hyperinflammatory syndromes. The recently defined Immune effector cell-associated HLH-like syndrome (IEC-HS), characterized by hallmark clinical and biochemical features of secondary HLH, is both clinically and temporally distinct from cytokine release syndrome (CRS), typically emerging as CRS subsides or after it has resolved. In contrast, in CRS with multiorgan dysfunction (CRS-MOD), HLH-like manifestations often appear with worsening CRS and progress through standard CRS-directed therapy. Importantly, CRS-MOD is to be differentiated from the acute hyperferritinemia and transient organ toxicities seen with CRS, which often responds to standard CRS management. Clinically differentiating these HLH-like syndromes remains challenging; however, their shared pathophysiology has contributed to an evolving landscape of therapeutic strategies. Given the association of HLH-like toxicities with poor outcomes, enhanced recognition, comprehensive diagnostic approaches and early intervention strategies may improve outcomes-preserving the potential benefit of the therapies patients are receiving. In this "How I Treat," we highlight our collective approach in managing two recognized CAR-associated HLH-like toxicity syndromes, CRS-MOD and IEC-HS, and provide an overview of the current treatment landscape.
    DOI:  https://doi.org/10.1182/blood.2025032352
  30. Glob Reg Health Technol Assess. 2026 Jan-Dec;13:13 55-57
    Use of artificial intelligence to draft a mini-HTA report on a new medical device belonging to class IIb-III.
    Andrea Messori, Sabrina Beltramini, Paola Crosasso, Claudia Fruttero, Melania Rivano, Marco Chiumente, Maria C Silvani.
      The rapid evolution of artificial intelligence (AI) in the pharmaceutical and medical device (MD) sectors has prompted interest in its potential role in supporting health technology assessment (HTA). This editorial presents an innovative project aimed at facilitating and expanding HTA activities for high-risk MDs (Class IIb-III) in Italy, where structured HTA processes for MDs are inconsistently implemented. The project centers on a freely accessible AI-based web tool designed to generate preliminary mini-HTA reports. The tool operates through two steps: users provide essential device information via an online form, and ChatGPT produces a structured draft report, including PICO statements, coverage of the nine EUnetHTA domains, and a preliminary summary of relevant PubMed evidence. Although these AI-generated reports are imperfect and require expert verification and refinement, they offer substantial practical advantages by reducing the initial workload and enabling rapid production of a first draft-within minutes rather than hours. The project includes detailed operational instructions and real application examples, such as an artificial iris device, presented in supplementary appendices. Future developments include the release of an English-language version to support broader international use. While AI cannot replace expert judgment, the editorial highlights its value as an accelerative tool that can streamline early HTA steps and promote more systematic evaluation of MDs across Italian regions. Continued iterative use is expected to improve system performance and enhance integration into HTA workflows.
    Keywords:  Artificial intelligence; ChatGPT; Medical devices; Rapid mini-HTA report
    DOI:  https://doi.org/10.33393/grhta.2026.3691
  31. Cell Metab. 2026 Mar 03. pii: S1550-4131(26)00046-X. [Epub ahead of print]38(3): 447-448
    Regulatory T cells thrive in ammonia-rich tumors.
    Chenxian Ye, Greg M Delgoffe.
      In a recent issue of Cell, Gu et al. find that regulatory T (Treg) cells metabolize tumor-derived ammonia via the urea cycle and spermine synthesis, promoting immunosuppression through PPARγ-dependent oxidative phosphorylation. Inhibition of tumor glutamine metabolism reduces ammonia levels and overcomes Treg cell-mediated resistance to anti-PD-1 therapy.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.003
  32. Arthritis Rheumatol. 2026 Mar 05.
    Dual-Targeting BCMA-CD19 CAR-T Cell Therapy in Systemic Lupus Erythematosus: Single-Cell and Immune Repertoire Analysis Reveals Mechanisms of Immune Reconstitution.
    Zhenghao He, Weijia Wang, Qianwen Li, Shihao Ding, Mingxia Wang, Ming Hong.
       OBJECTIVE: To investigate peripheral immune reconstitution following BCMA-CD19 dual-targeting CAR-T therapy in patients with Systemic lupus erythematosus (SLE).
    METHODS: Single-cell RNA sequencing (scRNA-seq) and parallel B and T cell receptor (BCR/TCR) sequencing were performed on peripheral blood mononuclear cells (PBMCs) from five SLE patients before infusion and after peripheral B-cell reconstitution (median 90 days post-infusion). These data were integrated with public datasets from seven SLE patients treated with CD19 single-targeting CAR-T and three healthy controls for comparative analysis (total N=15 subjects; 176,182 single cells analyzed).
    RESULTS: Dual-targeting CAR-T induced marked depletion of B-lineage populations, including plasma-lineage clusters that persisted after CD19 therapy. Specifically, Cluster 2 decreased from 10.70% to 2.67% and Cluster 3 from 9.55% to 3.12% in the dual-targeting cohort, whereas Cluster 3 increased (6.78% to 12.19%) in the single-targeting comparator. In B cells, dual targeting produced greater suppression of RIG-I/MDA5 and type I interferon transcriptional programs than single-targeting therapy. BCR repertoires shifted toward an IGHM-dominant (49.83% to 89.19%, P < 0.05), naïve-biased profile, with contraction of PRE-enriched class-switched clones and restoration of diversity toward healthy-like profiles. Clinical improvement was significant (mean SLEDAI decreased from 9.6 to 2.4, P < 0.05), paralleling these molecular changes.
    CONCLUSIONS: BCMA-CD19 dual CAR-T therapy was associated with deeper depletion of plasma-lineage compartments and a tendency toward more pronounced reversal of SLE-associated molecular signatures. This exploratory finding suggests a potential advantage of dual targeting in achieving a more comprehensive humoral reset in SLE, which warrants further direct comparative studies to determine clinical superiority.
    DOI:  https://doi.org/10.1002/art.70117
  33. NPJ Digit Med. 2026 Mar 06.
    MS360°: a conceptual digital-first, data-driven hybrid care framework for personalised multiple sclerosis management.
    Isabel Voigt, Lars Masanneck, Marc Pawlitzki, Hernan Inojosa, Sven G Meuth, Tjalf Ziemssen.
      This perspective introduces MS360°, a conceptual hybrid care model for the management of multiple sclerosis (MS). It integrates traditional on-site assessments with digital health technologies (DHT) to enable more continuous, personalised, and proactive disease management. Current MS care is often fragmented, limiting timely interventions and patient engagement. MS360° addresses these challenges by introducing a digital-first hybrid framework for continuous data collection through remote monitoring, wearable sensors, and telemedicine. This data can be used to dynamically steer structured patient pathways and trigger targeted on-site assessments and interventions such as neurological examinations, imaging, laboratory assessments, and standardised functional tests based on predefined thresholds and patient profiles. The interaction of multidisciplinary teams, structured care pathways and bidirectional data flow enables timely clinical decision-making, stratified patient management and early detection of disease progression. Digital tools can further enhance patient engagement and lifestyle management, promoting adherence and outcomes. New technologies, including artificial intelligence and digital twins, are being discussed as potential future extensions for precision care, workflow optimisation, and risk prediction. MS360° provides a quality-driven conceptual framework, offering a roadmap for integrating digital innovations into patient-centred MS care.
    DOI:  https://doi.org/10.1038/s41746-026-02461-4
  34. J Eur Acad Dermatol Venereol. 2026 Mar 03.
    Exosomes in precision dermatology: From biomarkers to targeted therapeutics in personalized care.
    Dorsa Moslehi, William J Nahm, Gerry Serwald, Zahna Bigham, Vinod E Nambudiri.
      Exosomes, nanoscale extracellular vesicles released by nearly all cell types, have attracted substantial interest as potential diagnostic and therapeutic tools in dermatology due to their ability to selectively transport proteins, nucleic acids and lipids between cells. Experimental studies have demonstrated exosome involvement in immune signalling, inflammation, pigmentation, wound repair, hair biology and tumour behaviour, supporting their broad but still largely experimental relevance across dermatologic disease processes. However, despite rapid scientific progress, clinical translation remains at an early stage. Most evidence supporting dermatologic applications is derived from in vitro or animal studies, and few well-designed, adequately powered human trials exist. As of September 2025, only a small number of exosome-based clinical studies in dermatology have been completed, and no exosome therapeutic has received FDA approval. Major challenges-including the lack of standardized isolation and manufacturing methods, batch-to-batch variability, limited mechanistic understanding, inconsistent regulatory frameworks and unresolved safety considerations-continue to impede clinical adoption. Current clinical trials, although promising, are heterogeneous and often underpowered, with insufficient long-term safety and efficacy data to support routine use. Collectively, exosomes represent a compelling but still developmental platform for precision dermatology. Their successful integration into clinical practice will require rigorous mechanistic studies, harmonized quality control standards and large, high-quality randomized controlled trials to confirm therapeutic benefit, ensure safety and enable regulatory approval.
    Keywords:  biomarkers; dermatology; exosomes; extracellular vesicles; regenerative medicine; skin diseases
    DOI:  https://doi.org/10.1111/jdv.70387
  35. Curr Pharm Des. 2026 Feb 25.
    Nanovaccines in Cancer Immunotherapy: Lymph Node-Targeted Strategies and Mechanistic Insights.
    Rajni, Ramajay Gupta, Kamal Shah, Hitesh Kumar Dewangan.
       BACKGROUND: Cancer immunotherapy has been a rapidly growing therapeutic approach, with nanovaccines offering new opportunities to improve antigen delivery and activate immune responses. Nevertheless, traditional cancer vaccines are generally under-immunogenic and ineffective in lymphoid targeting. This article reviews progress in nanotechnology-based vaccine platforms, with a special emphasis on lymph node-targeting nanovaccines for cancer management and therapy.
    METHODS: We systematically reviewed the recent literature on nanovaccine delivery systems, including liposomes, polymeric nanoparticles, and mRNA-based formulations. The emphasis was on immunological mechanisms, antigen presentation pathways, and lymphatic targeting strategies.
    RESULTS: Nanovaccines can deliver tumor antigens and adjuvants together to lymphoid tissues, enhancing antigen uptake, dendritic cell activation, and T-cell priming. Systems, such as lipid nanoparticles, artificial dendritic networks, and CpG- or STING-charged nanocarriers, have been shown to exhibit enhanced therapeutic performance in both preclinical and early clinical trials. mRNA-4157 and BNT111 are clinical candidates showing encouraging results in melanoma and other cancer trials.
    CONCLUSION: Nanovaccine platforms can potentially overcome some constraints of conventional vaccines by enhancing lymph node targeting, antigen stability, and immunogenicity. Further research in this field could further advance targeted cancer immunotherapy.
    Keywords:  Nanovaccines; antigen-presenting cells; cancer immunotherapy; lymph node targeting; nanocarriers.; nanoparticle delivery; tumor microenvironment
    DOI:  https://doi.org/10.2174/0113816128384257251211183939
  36. Int J Med Inform. 2026 Mar 01. pii: S1386-5056(26)00105-X. [Epub ahead of print]213 106365
    From algorithmic innovation to clinical deployment: A systematic review of methodological gaps limiting federated learning in healthcare.
    Sandhya Vijayasarathy.
       OBJECTIVE: Federated learning (FL) is a distributed machine learning paradigm designed to enable model training across decentralized data sources without requiring data centralization. This review critically examines FL as a methodological approach in biomedical informatics, summarizing its conceptual foundations, methodological variants, successes, and limitations, and identifying directions for future research.
    METHODS: We conducted a systematic methodological review following PRISMA 2020 guidelines. Searches were performed in PubMed, Web of Science, Scopus, IEEE Xplore, and Google Scholar for studies published between January 2017 and March 2025. Articles were included if they proposed, extended, or critically analyzed FL methods for biomedical or life science data. Methods were categorized by federation topology, optimization strategy, data heterogeneity handling, privacy mechanisms, evaluation design, and translational readiness.
    RESULTS: From 8,412 records, 97 articles met inclusion criteria. Rapid methodological innovation exists in optimization and privacy mechanisms, while support for design-time evaluation and governance remains limited.
    CONCLUSION: Federated learning represents a significant methodological advance in biomedical informatics but current implementations address only a subset of translational challenges. Future work must integrate study design, evaluation, interpretability, and governance into FL methods.
    Keywords:  Biomedical informatics; Clinical research informatics; Data heterogeneity; Federated learning; Privacy-preserving machine learning; Systematic review
    DOI:  https://doi.org/10.1016/j.ijmedinf.2026.106365
  37. Eur J Immunol. 2026 Mar;56(3): e70155
    38-Marker Full-Spectrum Flow Cytometry Panel for the Comprehensive Profiling of γδ T Cells in Human Blood and Lymphoid Tissues.
    Mohamed Hamed, Daniela Moreno-Vicencio, Daniel Arsovski, Mustafa Farhat, Rosie Sanders, Ellen Mann, Annabelle Bennett, Priyanka Chevour, Martin S Davey.
      This is an update to the Guidelines for the Use of Flow Cytometry and Cell Sorting in Immunological Studies (Third Edition), Chapter 12C, by Cossarizza et al. A 38-marker full-spectrum flow cytometry panel enabling high-resolution profiling of human γδ T cells across blood and lymphoid tissues, including robust identification of rare, tissue-adapted subsets.
    DOI:  https://doi.org/10.1002/eji.70155
  38. Biomed Pharmacother. 2026 Feb 27. pii: S0753-3322(26)00202-7. [Epub ahead of print]197 119169
    Human VH-antibody-based CAR T cells targeting folate receptor-alpha show enhanced persistence and reduced T-cell exhaustion against ovarian cancer.
    Nithidol Sakunrangsit, Kannika Khantasup, Natapol Pornputtipong, Koramit Suppipat, Nattiya Hirankarn, Supannikar Tawinwung.
       BACKGROUND: Folate receptor-alpha (FOLR1) is highly expressed in ovarian cancer and correlates with poor clinical outcomes, making it an attractive target for adoptive cell therapy. Single-domain antibodies (VH domains) have gained increasing interest as antigen-binding domains for CAR T-cell engineering.
    METHODS: We generated a second-generation FOLR1-specific CAR incorporating a fully human VH-only antibody and compared its in vitro functional activity with a MOv19-derived scFV CAR. CAR expression, memory phenotype, cytotoxicity, cytokine secretion, and exhaustion markers were evaluated following antigen stimulation. Antitumor efficacy was further assessed in 3D spheroids and repeated tumor-rechallenge assays.
    RESULTS: Both VH-based and scFV-based FOLR1 CAR T cells demonstrated potent and antigen-specific cytotoxicity against FOLR1-positive ovarian cancer cells. Intriguingly, FOLR1-VH CAR T cells showed lower activation and cytokine release upon initial stimulation, accompanied by reduced expression of exhaustion markers including PD-1 and LAG-3. FOLR1-VH CAR T cells preferentially preserved a central-memory phenotype and displayed superior persistence and tumor control during multiple rounds of antigen rechallenge. Both CAR formats achieved comparable cytotoxicity in 3D spheroid models.
    CONCLUSION: Human FOLR1-VH CAR T cells demonstrated potent antitumor activity with reduced exhaustion and enhanced persistence. These properties highlight the VH domain as a promising targeting module for next-generation CAR T-cell therapies in ovarian cancer.
    Keywords:  Chimeric antigen receptor; Folate receptor alpha; Ovarian cancer; V(H) domain antibody
    DOI:  https://doi.org/10.1016/j.biopha.2026.119169
  39. Immunotherapy. 2026 Mar 02. 1-9
    Financial barriers to immunotherapy: challenges and potential mitigation strategies: a review paper.
    Hasan Numan, Arafat Tfayli.
       INTRODUCTION: Since the ipilimumab's approval in 2011, immune checkpoint inhibitors (ICIs) have become an integral aspect of oncology practice, offering unparalleled survival benefits across various cancers. Financial toxicities associated with the high pricing of ICIs have put a major constraint on their incorporation into oncology practice. Financial barriers of ICIs are particularly more pronounced in low-middle-income countries (LMICs).
    AREAS COVERED: This review aimed to summarize financial barriers associated with the integration of immunotherapy into oncology practice, including dosing, pharmacoeconomic insufficiencies, flat-dosing overuse, out-of-pocket expenditures in LMICs, and structural barriers to access, such as limited reimbursement, and lack of biosimilars. We integrated evidence on dose optimization, de-escalation strategies, and health-care policies that can mitigate costs. Furthermore, we outlined the under-representation of LMICs in trials and the limited evidence on low-dose strategies from prospective data.
    LITERATURE SEARCH: We performed a comprehensive literature review on PubMed and Google Scholar for English-language studies published between 2014 and 2025 using terms related to "immunotherapy," "financial toxicity," "dose optimization," and 'low- and middle-income countries."
    COMMENTARY: Dose-optimization strategies can reduce costs without compromising clinical efficacy, especially where financial barriers threaten continuity of care. Priorities include, prospective trials validating reduced dosing and international partnerships to integrate LMICs into research.
    Keywords:  Immunotherapy; biosimilars; de-escalation; dose optimization; financial barriers; financial toxicity; health policy; low- and middle-income countries (LMICs)
    DOI:  https://doi.org/10.1080/1750743X.2026.2639275
  40. J Neurooncol. 2026 Mar 02. pii: 27. [Epub ahead of print]177(1):
    Immune checkpoint inhibitors in pediatric central nervous system tumors: biology, clinical experience, and translational pathways to precision immunotherapy.
    Irem Yenidogan, Uri Tabori, Anirban Das.
       PURPOSE: Immune checkpoint inhibitors (ICI) have transformed cancer therapy but remain of limited efficacy in pediatric central nervous system tumors, which are characterized by low tumor mutational burden, sparse antigen presentation, and profoundly immunosuppressive microenvironments.
    CONTENT: Across pediatric trials, ICI monotherapy targeting the PD-1/PD-L1 axis has largely failed to show substantive benefits, underscoring the need for biomarker-driven patient selection and the identification of synergistic vulnerabilities. Recent high-dimensional profiling reveals that pediatric central nervous system tumors are not uniformly "immune cold." Subsets such as DNA replication-repair-deficient high-grade gliomas exhibit robust neoantigen burden and durable responses to PD-1 blockade, whereas data from other tumor subsets including some gliomas, germ cell tumors and select medulloblastomas demonstrate potential latent immune reactivity. Translational strategies are being developed to overcome barriers impacting ICI efficacy by studying resistance mechanisms, some of which are unique to central nervous system tumors. Potentially useful strategies to improve ICI efficacy in childhood brain tumors may involve exploration of early or neoadjuvant use, targeting non-traditional checkpoints as combination treatments, metabolic and genomic targeting for immune reprogramming, advanced drug-delivery approaches, studying and modulating the gut microbiota, improve toxicity management by limiting systemic steroid use, and parallel innovations redefining immunotherapy response assessment using advanced imaging and liquid biopsies.
    CONCLUSION: We provide an overview of the current checkpoint inhibitor landscape for pediatric brain tumors, highlight barriers and summarize possible approaches that can be efficaciously explored in future clinical trials.
    Keywords:  Biomarker-guided precision immunotherapy; Immune checkpoint inhibition; Mismatch repair–deficient / replication repair–deficient glioma; Pediatric central nervous system tumors; Tumor immune microenvironment
    DOI:  https://doi.org/10.1007/s11060-026-05491-w
  41. Neural Regen Res. 2026 Feb 28.
    Mesenchymal stem cell therapies for neurodegenerative diseases: Advancements, challenges, and opportunities.
    Faizan Ali Shah Rizvi, Yusuf Jimoh, Mohammed Z Allouh, Dalia Rahmon, G Rasul Chaudhry.
       ABSTRACT: Neurodegenerative diseases, including multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, retinal degenerative diseases, Alzheimer's disease, and Parkinson's disease, continue to pose a significant clinical challenge due to the progressive loss of neural tissue structure and function. Stem cell-based therapies are gaining attention for the treatment of neurodegenerative diseases. Mesenchymal stem cells, particularly those derived from perinatal tissues, exhibit remarkable plasticity, along with immunomodulatory, neurotrophic, and regenerative capabilities. Mesenchymal stem cells primarily influence their environment through paracrine signaling and can also differentiate into neural lineages, aiding in neuronal repair. Tissue-specific progenitor cells, such as neural stem cells and retinal progenitor cells, offer greater therapeutic precision. This review examines advancements in mesenchymal stem cell-based therapies for neurodegenerative diseases, discusses relevant clinical trials, and highlights the challenges, while proposing that personalized regenerative treatments utilizing lineage-restricted progenitors may improve patient outcomes in these complex disorders.
    Keywords:  Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; cell therapy; mesenchymal stem cells; multiple sclerosis; neurodegenerative diseases; neuroregeneration
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01147
  42. Ther Innov Regul Sci. 2026 Mar 05.
    Applications and Challenges of Artificial Intelligence and Big Data in Drug Regulation.
    Zhao Liu, Yang Zheng, Jun Fang, Lin Yuan.
      Artificial intelligence (AI) and big data are increasingly applied in drug regulation and have demonstrated significant potential worldwide. The U.S. Food and Drug Administration (FDA) has developed a relatively comprehensive approach through strategic frameworks, regulatory guidelines, and pilot programs. The European Medicines Agency (EMA) has promoted AI adoption via the Big Data Task Force, DARWIN EU®, and a multi-annual work plan, while Japan, Canada, and other countries have also advanced relevant initiatives and strengthened international cooperation. In China, smart regulation has been incorporated into the "14th Five-Year Plan" and subsequent strategies, with progress in establishing national regulatory data platforms, pharmaceutical traceability systems, and pilot AI applications. Nevertheless, AI in drug regulation remains at an exploratory stage, facing challenges such as limited model reliability and interpretability, insufficient data standards and interoperability, regulatory gaps, and ethical as well as public trust concerns. Future progress will depend on strengthening regulatory standards, enhancing data governance, improving regulatory capacity, and deepening international collaboration to achieve more scientific, intelligent, and efficient drug regulation.
    Keywords:  Artificial intelligence; Big data; Data governance; Drug regulation; ethics
    DOI:  https://doi.org/10.1007/s43441-026-00946-8
  43. Clin Cancer Res. 2026 Mar 04.
    Phase 1 Trial of P-PSMA-101 CAR-T Cells in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC).
    Susan Slovin, Xin Gao, Xiao X Wei, David Y Oh, Rana R McKay, Gerald Falchook, Arif Hussain, Meredith McKean, Andreas Wibmer, Alan Ho, Jeff D Eskew, Rajesh Belani, Julia Coronella, Sabrina Haag, Christopher E Martin, Joanne McCaigue, June Mendoza, Ann Murphy, Hamid Namini, Matthew A Spear, Devon J Shedlock, Tanya B Dorff.
       PURPOSE: Chimeric antigen receptor (CAR)-T cell therapies have potential in solid tumors. A higher proportion of stem cell-like memory T cells (TSCM) in CAR-T products could enhance engraftment, persistence, and prolong immune activity. This phase 1 trial (NCT04249947) evaluated the safety and efficacy of P-PSMA-101, an autologous TSCM-rich bone tropic CAR-T therapy targeting prostate-specific membrane antigen (PSMA), in metastatic castrate-resistant prostate carcinoma (mCRPC) patients. Secondary endpoints included objective response rate, PSA response, radiographic progression-free survival (PFS).
    PATIENTS AND METHODS: P-PSMA-101 was produced from leukapheresis using the piggyBac® DNA transposon-based platform, which integrates a multi-cistronic transgene encoding an iCasp9 safety switch in addition to the CAR, generating TSCM-rich CAR-T cells.
    RESULTS: Among 33 treated patients, 18% (n=6) had dose-limiting toxicities (DLTs). Cytokine release syndrome (CRS) occurred in 61% (n=20), with Grade ≥ 3 CRS in 9% (n=3). Activation of the iCasp9-based safety switch was required in 24% (n=8) of cases including one fatal toxicity, and successful resolution in the other seven. P-PSMA-101 yielded ≥50% PSA decline in 21% (n=7) of patients. Among 13 RECIST evaluable patients, one partial response was observed. Stable disease occurred in 61% (n=20), with 21% (n=7) maintaining stability for ≥3 months. Two patients' remissions exceeded 12 months characterized by PSA declines > 90%, corroborated by pharmacokinetic, biomarker, and PSMA-PET imaging data.
    CONCLUSIONS: Robust expansion of P-PSMA-101 CAR T cells resulted in toxicity but also durable responses in patients with mCRPC. Future trials of CAR T may be informed by the results with this nonviral engineering, TSCM cell-enriched approach.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-3052
  44. Curr Opin Lipidol. 2026 Feb 10.
    RNA interference for lipid disorders: is this the future?
    Miguel Nassif, Renata Turrini Jacob Fazoli, Giuliano Generoso.
       PURPOSE OF REVIEW: Advances in the management of lipid disorders have expanded therapeutic options for hypercholesterolemia and beyond. We review the current advances in RNA interference (RNAi) therapies as small interfering RNA (siRNA) drugs, critically assess their clinical positioning, and explore their potential role in reshaping lipid management over the next years.
    RECENT FINDINGS: RNAi enables targeted, durable suppression of key lipid-regulating proteins at the mRNA level. Inclisiran, the first approved RNAi therapy for hypercholesterolemia, achieves about 50% sustained LDL-c reduction with long-interval maintenance dosing, offering an alternative to monoclonal antibodies. Beyond LDL-c lowering, multiple RNAi drugs are in advanced development targeting lipoprotein(a), apolipoprotein C-III, and angiopoietin-like protein 3, aiming to address residual cardiovascular risk. Early safety and adherence data are encouraging, yet pivotal outcome trials and cost-effectiveness analyses are still pending.
    SUMMARY: RNAi is a naturally occurring gene-silencing mechanism that can be harnessed therapeutically through siRNA molecules. In lipidology, siRNA-based therapies represent a disruptive technology with the potential to transform both prevention and treatment of atherosclerotic cardiovascular disease. If ongoing trials confirm cardiovascular benefit and safety, RNAi agents could become foundational in personalized lipid management, moving the field toward long-acting, target-specific, and potentially combination-based regimens. The coming years will determine whether RNAi fulfills its promise as the future standard of care in lipid disorders.
    Keywords:  RNAi; gene silencing; inclisiran; lepodisiran; olpasiran (AMG 890); plozasiran; small interfering RNA
    DOI:  https://doi.org/10.1097/MOL.0000000000001033
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