bims-carter 2026-03-29 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–03–29
37 papers selected by
Luca Bolliger, lxBio

Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering.
The TCR in CAR T cell therapy: use it or lose it?
Advances in Chimeric Antigen Receptor T Cell Therapy in Neuroimmune Diseases.
Smart control of CAR-T cells: emerging strategies for safer and more effective cancer immunotherapy.
In vivo CAR T cell engineering: design principles and open questions.
Integrating Mechanistic Modeling and Machine Learning to Study CD4+/CD8+ CAR-T Cell Dynamics with Tumor Antigen Regulation.
Modeling and Simulation in Development and Regulatory Approval of Chimeric Antigen Receptor T-Cell Therapies: An Analysis of European Medicines Agency Centralized Procedures From 2018 to 2024.
The prospects of CAR T-cell therapies in changing the therapeutic algorithm of neurologic autoimmunities.
Epigenetic insights and innovations for overcoming barriers in CAR-T cell therapy for cancer.
Establishing a Consumer Panel to Inform Health Technology Assessment Processes and Policy: impact and insights from Singapore's experience.
Optimized High-Titer Lentivirus Production and Efficient CAR-T Cell Generation.
Nobel prize-winning Treg cells in autoimmune kidney diseases and transplantation.
RWE Submission for European Regulators and Payers: Challenges, Uncertainties, and Opportunities.
Pathing the way from regulatory approval to market access for gene therapy products (GTPs): An integrative review in the US, EU5, Japan and China.
The 1000+ mouse project for large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies.
Addressing Unmet Medical Needs in Drug Development: Assessment and Implications for Regulatory and Clinical Development Strategies.
Neurological implications of chimeric antigen receptor-T cell therapy.
Fast Science, Slow Evaluation: What Makes Health Technology Assessment of Genetic and Genomic Technologies So Complicated? A Systematic Review of Methodological Challenges and Identified Suggestions.
Empowerment of CAR-T Cells by IL-7 and IL-15 Boosts Their Efficacy Against HER2-Positive Tumors with Enhanced Expansion and Persistence.
CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies.
Patient organizations involvement in healthcare: a rapid review and conceptual framework.
Central memory T cells: stem-like biology, pathogenic roles in autoimmunity, and therapeutic applications.
Real-world safety profile of T-cell engagers: evidence from multi-database analysis with CAR-T comparisons.
γδ T cells at the interface of innate and adaptive immunity in cancer.
Flow cytometry-based monitoring of chimeric antigen receptor (CAR) T cells: Reagent selection, assay design, and clinical utility.
Locoregional delivery of CAR T cells in high-grade gliomas: a systematic analysis of safety, efficacy, and emerging biomarkers of response.
From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma.
Artificial Intelligence and the Transformation of Cell and Gene Therapy Development.
Can We Trust PAICs in Rare Diseases? Methodological Challenges and Limitations.
Organizational culture and forensic science reliability: A lifecycle analysis of latent error pathways.
Exploring alternative funding mechanisms to improve patient access to innovative medicines.
Tunable CAR-NK-92 activity in the tumor microenvironment via a dual ATF4-responsive circuit.
Natural killer cells: gatekeepers of healthy aging in longevity medicine.
TCR recognition of peptide-HLA class II complexes in autoimmunity: Structural insights for therapeutic targeting.
Privacy and Security Throughout the Health Data Life Cycle: From Primary Care to Research Networks.
Silence Kills 2.0: How Communication Failures Stifle Innovation and Harm Patients.
Microbiota-driven Immunopathogenesis in Systemic Lupus Erythematosus: Cross-site Mechanisms and Intervention Strategies.

Cells. 2026 Mar 10. pii: 494. [Epub ahead of print]15(6):

Re-Tooling of γδ T Cells for Cancer Immunotherapy Using Advanced Manufacturing and Genetic Engineering.

Benjamin J L Lim, John Maher.

  Adoptive immunotherapy using ex-vivo-amplified autologous αβ T cells has achieved notable success in the treatment of diverse cancer types. Pre-eminent among these developments has been the advent of chimeric antigen receptor (CAR) T cell therapy, which has revolutionised the treatment of selected haematological malignancies. However, autologous CAR T cell immunotherapy is poorly scalable and has demonstrated limited efficacy against solid tumours. Accordingly, there has been significant interest in alternative strategies that may bridge these gaps. The use of γδ T cells is an attractive alternative since they possess intrinsic anti-tumour activity and do not elicit graft versus host disease (GvHD) when employed as an allogeneic drug product. In this review, we evaluate the potential use of γδ T cells for cancer immunotherapy and how manufacturing and genetic engineering refinements can be used to potentiate this activity. We also summarise current clinical experience with CAR γδ T cell therapies and discuss the implications of these findings for the next generation of cellular immunotherapies.

Keywords:  chimeric antigen receptor; immunotherapy; malignancy; γδ T cell

DOI:  https://doi.org/10.3390/cells15060494
Cancer Gene Ther. 2026 Mar 24.

The TCR in CAR T cell therapy: use it or lose it?

Olivia Liseth, Richard Vile.

Chimeric antigen receptor (CAR) T cell therapy has become an indispensable immunotherapy for the treatment of some hematologic cancers, but still faces numerous challenges in the form of antigen escape, variable patient responses, toxicities, limited CAR T cell persistence, and high cost, particularly against solid tumors. This Review discusses the potential role of the endogenous T cell receptor (TCR) as either a hindrance or partner to CAR T cell function. Specifically, we discuss the differences and similarities between CAR and TCR structure and function, findings supporting the value of TCR elimination in CAR T cells, and, in contrast, data in support of retaining and utilizing the endogenous TCR in CAR T cell therapy. We make the case that, while TCR-knockout systems may improve aspects such as the universality, cost, and CAR expression of CAR therapies, the endogenous TCR continues to play a significant role in maintaining CAR T cell persistence and can be used to augment CAR T cell therapeutic phenotypes. Overall, we highlight the uncertainties that persist within the field of CAR T cell therapy and outline emerging evidence and directions regarding the CAR T cell TCR that have the potential to transform patient outcomes.

DOI: https://doi.org/10.1038/s41417-026-01018-7
Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2026 Feb;48(1): 162-169

Advances in Chimeric Antigen Receptor T Cell Therapy in Neuroimmune Diseases.

Bian-Jun Ma, Fu-Wen Yang, Yan-Hong Wang, Xin Wang.

  Antibody therapy is a crucial modality for the treatment of neuroimmune diseases.While it can regulate disease activity in the majority of patients,several individuals remain unresponsive to antibody therapy;additionally,the blood-brain barrier restricts the bioavailability and effectiveness of antibodies within the central nervous system.Unlike antibody therapies,emerging chimeric antigen receptor(CAR)-T cell therapies integrate the biological functions of antibodies that target specific molecules with the potent immune capabilities of T cells,resulting in enhanced therapeutic efficacy,improved tissue permeability,and a more pronounced capacity to eliminate target cells.This study encapsulated the advancements in CAR-T cell therapy for neuroimmune illnesses,aiming to furnish novel insights for the enhancement of CAR-T cell therapy to facilitate its practical use.

Keywords:  chimeric antigen receptor-T cell therapy; multiple sclerosis; myasthenia gravis; myelin oligodendrocyte glycoprotein antibody-associated disease; optic neuromyelitis optica spectrum disorder

DOI:  https://doi.org/10.3881/j.issn.1000-503X.16568
Front Immunol. 2026 ;17 1746673

Smart control of CAR-T cells: emerging strategies for safer and more effective cancer immunotherapy.

Guo-Kai Zhang, Hai-Mei Wang, Fang Zhou.

  Chimeric Antigen Receptor (CAR)-T cell therapy has developed cancer immunotherapy but remains restricted by severe toxicities, antigen escape, and loss of efficacy in solid tumors. Recent advances in smart control systems aim to enhance the safety and precision of CAR-T therapies through tunable, reversible, and context-dependent mechanisms. These include the importance of inducible CAR expression, logic-gated receptors, and external control systems using drugs, light, or biomaterials. Synthetic biology approaches integrating sensor circuits and feedback loops are paving the way for programmable immunity, enabling dynamic adjustment of CAR-T activity in real time. The aim of this study is to review recent advances in strategies that enable smart controlled and designed activity of CAR-T cells for safer and more effective cancer immunotherapy. It seeks to summarize key molecular, genetic, and synthetic approaches designed to regulate CAR-T cell activation, persistence, and cytotoxicity with high precision.

Keywords:  CAR-T cells; antigen escape; cancer immunotherapy; cytokine release syndrome; logic gating; safety switches; smart control; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1746673
Trends Cancer. 2026 Mar 25. pii: S2405-8033(26)00007-5. [Epub ahead of print]

In vivo CAR T cell engineering: design principles and open questions.

Amin Aalipour, Ariana Barreiro, Andrea Garmilla, Michael E Birnbaum.

  Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, leading to seven FDA-approved products, but widespread adoption has been limited by costly and complex manufacturing and administration. Several methods have emerged to directly reprogram T cells within patients, with the potential to simultaneously improve potency, reduce costs, and broaden accessibility. While early clinical studies demonstrate safety and therapeutic activity, critical questions remain regarding long-term efficacy, the interplay between means of delivery and host biology, and optimal disease indications for each delivery approach. This review summarizes the preclinical and clinical data for state-of-the-art viral and nonviral approaches for in vivo CAR-T engineering, discusses their opportunities and limitations, and highlights key open questions that will shape the maturation of this emerging field.

Keywords:  CAR T cell; adoptive cell therapy; in vivo engineering; lipid nanoparticle; off-the-shelf gene therapy; targeted lentivirus

DOI:  https://doi.org/10.1016/j.trecan.2026.01.007
Bull Math Biol. 2026 Mar 25. pii: 67. [Epub ahead of print]88(5):

Integrating Mechanistic Modeling and Machine Learning to Study CD4+/CD8+ CAR-T Cell Dynamics with Tumor Antigen Regulation.

Saranya Varakunan, Melissa Stadt, Mohammad Kohandel.

  Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematological malignancies, yet patient responses remain highly variable and the roles of CD4+ and CD8+ subsets are not fully understood. We present an extended mathematical framework of CAR-T cell dynamics that explicitly models CD4+ helper and CD8+ cytotoxic lineages and their interactions with tumor antigen burden. Building on a recent model of antigen-regulated memory-effector-exhaustion transitions in CAR-T cells, our system of differential equations incorporates CD4+-mediated modulation of CD8+ proliferation, cytotoxicity, and memory regeneration through biologically grounded, saturating interactions. Sensitivity analyses identify effector proliferation, antigen turnover, and CD8+ expansion rates as dominant drivers of treatment outcome. Virtual patient simulations recover reported qualitative trends in CAR-T composition, including enhanced expansion and tumor clearance for defined CD4:CD8 products relative to CD8-only formulations, while also revealing inter-patient variability and time-dependent effects. To assess the practical limits of patient-level prediction under parameter uncertainty, we introduce controlled noise into key parameters and show that direct mechanistic classification rapidly degrades. We then demonstrate that a simple feed-forward neural network can partially recover predictive signal from noisy inputs, outperforming a naïve baseline while remaining consistent with mechanistic sensitivities. This work positions the extended model as a hypothesis generator, and illustrates how data-driven methods can complement mechanistic modeling when parameter uncertainty constrains predictive confidence.

Keywords:  CAR-T therapy; Immunotherapy; Machine learning; Mechanistic modeling

DOI:  https://doi.org/10.1007/s11538-026-01633-3
CPT Pharmacometrics Syst Pharmacol. 2026 Apr;15(4): e70213

Modeling and Simulation in Development and Regulatory Approval of Chimeric Antigen Receptor T-Cell Therapies: An Analysis of European Medicines Agency Centralized Procedures From 2018 to 2024.

Lisa Hanquet, Jean-Michel Dogné, Flora T Musuamba.

  Chimeric antigen receptor (CAR) T-cell therapies represent a major advancement in oncology. These therapies have demonstrated therapeutic potential, particularly in hematological malignancies where patients have relapsed or are refractory to prior treatments. Despite their promise, the development of CAR-T cell therapies is challenging. Manufacturing processes are complex and individualized for each patient, the eligible patient population is small, and conventional clinical trial designs are often not well suited. This study investigates the use of modeling and simulation for CAR-T cell therapies approved in Europe between 2014 and 2024. Regulatory documents for six authorized products were analyzed to identify and categorize regulatory questions relating to pharmacokinetics, efficacy, safety, and benefit-risk assessment. These questions were systematically organized into a structured repository spanning multiple biological levels. Fewer than half of these questions were addressed at initial marketing authorization, with additional data submitted through post-marketing commitments. Most modeling efforts were devoted to pharmacokinetics, with fewer relating to efficacy and safety being rarely explored. A structured credibility framework was employed to benchmark these modeling approaches against conventional analytical methods. The study revealed inconsistent methodological maturity for modeling and simulation approaches used across submissions. Compared with models described in the scientific literature, those used in regulatory applications were generally simpler and lesser, indicating a more limited implementation of M&S approaches in regulatory contexts so far. The repository developed herein may facilitate improved consistency and transparency in regulatory evaluation and support the broader adoption of model-based approaches throughout the development lifecycle of complex therapies.

Keywords:  CAR‐T cells; Pharmacometrics; hematological cancer; regulatory science

DOI:  https://doi.org/10.1002/psp4.70213
Ther Adv Neurol Disord. 2026 ;19 17562864261429570

The prospects of CAR T-cell therapies in changing the therapeutic algorithm of neurologic autoimmunities.

Marinos C Dalakas.

  T cells, genetically modified to express chimeric antigen receptors (CAR T), successfully used in hemato-oncologic malignancies, are showing promising and sustained benefits in refractory autoimmune neurological diseases, including Myasthenia Gravis, stiff-person syndrome, neuromyelitis optica, myositis, autoimmune neuropathies, and multiple sclerosis. Several reported patients with a steadily progressive disease and evolving disability unresponsive to available therapies, including rituximab and new biologics, after 2-3 months of treatment with CARs targeting CD19-positive, antibody-secreting, long-lived plasma cells, and plasmablasts exhibit impressive, long-lasting, and drug-free clinical improvements with the potential for immune reset shifting immunity to a healthy state without the need for continuing more immunotherapy cycles. The review discusses what the unmet needs are with the present neuroimmunotherapeutics pointing out the disease stage and patient subsets for which CAR T-therapy is most suitable highlighting that CAR T should be applied in the early stages of disability development when patients reach early-active/refractory status rather than waiting for very late disease progression when neurological deficits might be irreversible. The future trajectory of CAR T cells is also described as a promising means destined to change the present therapeutic algorithm in all neuro-autoimmunites, even offering a promising path toward a cure, pointing out that, in contrast to currently approved biologics that selectively target one immunoregulatory factor, CD19 CAR T cells exert effects even beyond B cells, cross the blood-brain barrier and lymphoid tissues, and expand as "living cells" to memory cells ensuring sustained long-term benefits. Key therapeutic uncertainties and practicalities are however highlighted, including the exact duration of CAR T-cell therapy-induced drug-free remissions, logistical challenges, economic limitations, and the need for extensive collaborative efforts with experts in specialized clinical centers.

Keywords:  CAR T-cell therapies; CIDP; Stiff-person syndrome; autoimmune neurological diseases; inflammatory myopathies; multiple sclerosis; myasthenia gravis; neuromyelitis optica

DOI:  https://doi.org/10.1177/17562864261429570
Clin Transl Oncol. 2026 Mar 24.

Epigenetic insights and innovations for overcoming barriers in CAR-T cell therapy for cancer.

Viktoria B Poluektova, Svetlana N Zuevskaya, Yarmatov Suvon, Sharipova Gulnihol, Rustam Turakulov, Feruza Umirkulova.

  Over the past several decades, chimeric antigen receptor (CAR)-T cell therapy has revolutionized cancer immunotherapy, particularly for hematological cancers. However, its effectiveness against solid tumors is often hindered by numerous barriers. Advances in modern epigenomic profiling technologies have deepened our understanding of how epigenetic regulation shapes CAR-T cell behavior. Epigenetic mechanisms act as an unseen force that governs CAR-T cell fate by modulating key genes involved in metabolism, differentiation, phenotype, migration, persistence, and overall function. Recent innovations in epigenetic monitoring and manipulation have provided new strategies to address the challenges that restrict CAR-T cell performance. In this review, we examine the epigenetic landscape of CAR-T cells and discuss potential epigenetic-based strategies to enhance CAR-T cell function and overcome limitations in CAR-T cell therapy. Trial registration number: not applicable.

Keywords:  CAR-T; Epigenome editing; Epigenome profiling; Solid tumors; T-lymphocyte

DOI:  https://doi.org/10.1007/s12094-026-04310-y
Int J Technol Assess Health Care. 2026 Mar 27. 42(1): e30

Establishing a Consumer Panel to Inform Health Technology Assessment Processes and Policy: impact and insights from Singapore's experience.

Sok Huang Teo, Fiona Pearce, Tang Ching Lau, Ritu Jain, Ping-Tee Tan.

  Patient involvement in health technology assessment (HTA) at the organizational level remains relatively underreported in Asia. In 2022, Singapore's Agency for Care Effectiveness (ACE) established a Consumer Panel to provide strategic advice on strengthening patient participation in HTA processes and policy development. The Panel comprises representatives from local patient organizations, collectively covering a range of health conditions and bringing extensive lived experience within Singapore's healthcare system. This Perspective outlines ACE's approach to forming the Panel and highlights its contributions during the inaugural term, including co-developing patient involvement processes, supporting health literacy efforts, and fostering collaboration between ACE and patient communities. Panel members' reflections on their role and future directions for advancing patient partnership in HTA are also discussed. Beyond improving the quality and relevance of ACE's work, the Consumer Panel's achievements provide a valuable example for health authorities in other countries seeking to meaningfully involve patients at the organizational level.

Keywords:  health; patient engagement; patient involvement; technology assessment

DOI:  https://doi.org/10.1017/S0266462326103481
Curr Protoc. 2026 Mar;6(3): e70346

Optimized High-Titer Lentivirus Production and Efficient CAR-T Cell Generation.

Atul Kumar Roy, Ashwani Singh, Jyotsna Dandotiya, Rucha R Chandwaskar, Srikanth Sadhu, Amit Awasthi.

  Chimeric antigen receptor (CAR)-T cell treatment has shifted the paradigm of cancer immunotherapy, especially in B-cell malignancies, with around an 80% response rate in acute lymphoblastic leukemia. Emerging data on the use of CAR-T cells in the treatment of autoimmune diseases, such as lupus, indicate another significant advance in this therapeutic field and highlight its promising potential for the future. Despite its remarkable therapeutic potential, the manufacturing of CAR-T cells, including the production of critical components such as high-titer lentiviral vector (LV), remains a significant challenge, limiting the broader accessibility and the ease of manufacturing and administration of this therapy. Lack of optimized and harmonized protocols makes the manufacturing of CAR-T cells cumbersome. To ease some of the challenges of CAR-T cell manufacturing, we optimized LV production, with an emphasis on enhancing viral titers using different transfer-to-helper plasmid ratios, optimizing transfection efficiency in HEK293T cells, and fine-tuning peripheral blood mononuclear cell activation and transduction conditions. We present a set of optimized protocols for the scalable production of third-generation LVs for CAR-T cell generation. This approach facilitates preclinical and translational research by providing a framework for the reproducible, economical, and effective production of CAR-T cells. © 2026 Wiley Periodicals LLC. Basic Protocol 1: Plasmid ratio screening Basic Protocol 2: Viral concentration via ultracentrifugation Basic Protocol 3: FACS-based titration assay Basic Protocol 4: Peripheral blood mononuclear cell (PBMC) isolation Basic Protocol 5: PBMC activation for effective transduction Basic Protocol 6: CAR-T cell generation with lentivirus Support Protocol: Flow cytometry gating strategies.

Keywords:  CAR‐T cells; adoptive cellular immunotherapy; lentivirus; transduction; transfection

DOI:  https://doi.org/10.1002/cpz1.70346
Kidney Int. 2026 Apr;pii: S0085-2538(26)00065-7. [Epub ahead of print]109(4): 624-629

Nobel prize-winning Treg cells in autoimmune kidney diseases and transplantation.

Griffith B Perkins, Maarten Naesens.

  The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary E. Brunkow, Fred Ramsdell, and Shimon Sakaguchi for their research into mechanisms by which the immune system avoids attacking the body's own tissues. At the heart of this research was the discovery of the regulatory T cell, a peculiar immune cell with the capacity to shut down autoimmunity. This Editorial: Special Report looks at the tenacious science and scientists behind the discovery of the regulatory T cell, and the clinical progress of regulatory T-cell therapies to treat autoimmune kidney diseases and transplant rejection.

Keywords:  CAR Tregs; autoimmunity; cell therapy; regulatory T cells; tolerance; transplantation

DOI:  https://doi.org/10.1016/j.kint.2026.01.005
Ther Innov Regul Sci. 2026 Mar 26.

RWE Submission for European Regulators and Payers: Challenges, Uncertainties, and Opportunities.

Lockwood Taylor, Blythe Adamson.

  The new European Union Joint Clinical Assessment (JCA) process, effective January 2025, requires pharmaceutical companies to submit evidence within 100 days of notification. Key challenges include uncertainty about PICO (Population, Intervention, Comparator, Outcomes) parameters prior to PICO notification, limited timeframe for evidence generation, and need to reconcile differences between regulatory versus health technology assessment (HTA) evidence standards. Uncertainties involve predicting PICOs accurately and determining real-world evidence's (RWE) appropriate role. However, opportunities exist for integrated evidence planning across clinical development, regulatory, and health economics and outcomes research (HEOR) teams, leveraging real-world data to inform or address PICOs as well as support regulatory evidence requirements. Early alignment between key functional teams, combined with proactive RWE use, is essential for generating fit-for-purpose evidence that satisfies the dual scrutiny of regulatory approval and HTA relative effectiveness assessment.

Keywords:  Europe; European Medicines Agency (EMA); Evidence generation; Health technology assessment (HTA); Joint clinical assessment (JCA); Real world evidence (RWE)

DOI:  https://doi.org/10.1007/s43441-026-00958-4
Regen Ther. 2026 Jun;32 101102

Pathing the way from regulatory approval to market access for gene therapy products (GTPs): An integrative review in the US, EU5, Japan and China.

Junnan Shi, Hao Hu, Carolina Oi Lam Ung.

   Background: This study aimed to summarize the current practices and mechanisms of market access, pricing and reimbursements for gene therapy products (GTPs) in major jurisdictions, and to identify the key barriers and facilitators affecting the translation of GTPs from regulatory approval to market access across the countries.
Methods: An integrated scoping review was conducted to identify publicly available literature and documents on the marketing access, pricing and reimbursement of GTPs under the PRISMA-ScR guidelines. Key barriers and potential enablers were identified and thematically analyzed using the Consolidated Framework for Implementation Research (CFIR).
Results: Thirty-four studies published between 2020 and May 2025 were included in this study. A total of 21 GTPs had received market authorization from the FDA, EMA, PMDA, or NMPA, targeting four major disease areas: genetic diseases (n = 8), hematologic disorders (n = 7), cancer-related indications (n = 5), and vascular diseases (n = 1). Despite growing approvals, substantial variation exists across jurisdictions in terms of access, pricing, and reimbursement pathways. Commonly reported challenges include concerns over budget impact and affordability (n = 25), uncertainty in clinical evidence (n = 24), limited value assessment frameworks (n = 17), lack of clearly defined reimbursement pathways (n = 17), misalignment between regulatory requirements and real-world implementation capacity (n = 15), and insufficient delivery infrastructure (n = 12). To address these barriers, 15 studies proposed potential solutions involving five areas: cross-country regulatory alignment and processes streaming (n = 3), pricing and reimbursement reform including budget caps, annuity payments and patent buyouts (n = 12), enhanced evidence generation through RWE and adaptive trial designs (n = 5), institutional infrastructure and workforce capacity building (n = 4), and early multi-stakeholder engagement among regulators, HTA bodies, payers, healthcare providers, and patients to align expectations and accelerate access (n = 7).
Conclusion: By adopting the CFIR framework, this study has systematically identified the key challenges and potential solutions in translating GTPs from regulatory approval to patient access. To ensure effective access, it is essential to adopt context-adapted value assessment models, diversified payment mechanisms, and coordinated policy strategies to guide the implementation processes. Building on international experiences, advancing localized implementation strategies encompassing tailored value frameworks, innovative payment models, regional pilots and institutional readiness offer actionable pathways for developing forward-looking access and reimbursement systems for GTPs.

Keywords:  Advanced therapy medicinal products; Gene therapy products; Market access; Market entry agreements; Payment; Reimbursement

DOI:  https://doi.org/10.1016/j.reth.2026.101102
Elife. 2026 Mar 24. pii: RP106470. [Epub ahead of print]14

The 1000+ mouse project for large-scale spatiotemporal parametrization and modeling of preclinical cancer immunotherapies.

Adam L Kenet, Sooraj Achar, Alka Dwivedi, John Buckley, Marie Pouzolles, Haying Qin, Christopher Chien, Naomi Taylor, Grégoire Y Altan-Bonnet.

  Preclinical studies of chimeric antigen receptor (CAR)-T cell immunotherapies are often based on monitoring bioluminescent tumors implanted in mice to assess anti-tumor cytotoxicity. Here, we introduce maRQup (murine automatic Radiance Quantification and parametrization), an easy-to-use method that automatically processes bioluminescent tumor images for quantitative analysis. We demonstrate the ability of maRQup to analyze CAR-T cell treatments over >1000 tumor-bearing mice. We compare CD19-targeting CAR-T cells comprising either a CD28 or a 4-1BB costimulatory domain, and found the former controlled the tumor burden better initially, while the latter reduced the frequency of tumor relapse. We also applied maRQup to demonstrate faster tumor growth during the initial growth phase as compared to the relapse phase and to spatiotemporally analyze the high variability in immunotherapeutic control of tumors, based on their anatomical location. maRQup provides quantitative and statistically-robust insights on preclinical experiments that will contribute to the optimization of immunotherapies.

Keywords:  CAR-T cells; bioluminescent image processing; cancer biology; immunology; inflammation; mathematical modeling; mouse

DOI:  https://doi.org/10.7554/eLife.106470
J Mark Access Health Policy. 2026 Mar 09. pii: 15. [Epub ahead of print]14(1):

Addressing Unmet Medical Needs in Drug Development: Assessment and Implications for Regulatory and Clinical Development Strategies.

Carla Domingo-Esteban, Inka Heikkinen, Nanco Hefting.

  Unmet need is a core component of many Health Technology Assessment (HTA) processes at EU and national level. Most visibly, it is a core selection criterion for Joint Scientific Consultations (JSC) and Joint Clinical Assessment (JCA) for medical devices. This qualitative study explored how Unmet Medical Needs (UMNs) are understood and applied in drug development, with an emphasis on the European regulatory, HTA and access context, and examined their impact on regulatory and clinical development strategies. Twenty semi-structured interviews were conducted with representatives from regulatory authorities, HTA bodies, clinical development, industry, and patient insight roles. Data was analyzed using a thematic content approach combining deductive and inductive coding. Thematic analysis revealed general agreement on the importance of addressing UMNs, but also substantial variation in how they are defined and prioritized. Regulators often stressed disease severity and clinical evidence, while patients and clinicians emphasized quality of life. HTA representatives highlighted comparative benefit and long-term outcomes. These differing perspectives shaped how UMNs were integrated into development strategies, trial design, and regulatory planning. The findings indicate that clearer yet adaptable criteria could support earlier and more consistent alignment. Based on the analysis, a five-part roadmap to guide drug development is proposed, focusing on internal coordination, structured stakeholder engagement, collaboration between regulators and HTA bodies, adaptable definitions, and transparent decision-making. Together, these elements aim to support more systematic and predictable approaches to identifying and addressing unmet needs in drug development.

Keywords:  drug development; health technology assessment; patient engagement; qualitative research; regulatory science; unmet medical need

DOI:  https://doi.org/10.3390/jmahp14010015
BMJ Neurol Open. 2026 ;8(1): e001491

Neurological implications of chimeric antigen receptor-T cell therapy.

Daniel G Raffoul, Izanne Roos, Matthias Mulazzani, Mary Ann Anderson, Mastura Monif, Justin Garber, Anneke van der Walt, Jennifer Massey, Valeriya Kuznetsova, Cassie Nesbitt, Mark Dowling, Irene Ruderman, Arian Lasocki, Constantine S Tam, Simon J Harrison, Tomas Kalincik.

  Chimeric antigen receptor (CAR)-T cell therapies have transformed the management of relapsed or refractory haematological malignancies and are now being adapted for severe B-cell mediated autoimmune disease, including neuroimmunological disorders. Their appeal lies in deep and durable B-cell depletion within lymphoid tissues and target organs, with the potential to induce long-lasting, treatment-free remission. At the same time, broader application is constrained by serious toxicities, in particular, neurological complications such as immune effector cell-associated neurotoxicity syndrome (ICANS) and more recently recognised movement, cerebellar, cranial nerve and peripheral nerve syndromes. In this review, we outline the biological principles of CAR-T cell therapy and summarise the emerging experience in neuroimmunology. We draw on data from both oncology and early autoimmune trials to describe the clinical spectrum, timing and proposed mechanisms of CAR-T cell-related neurotoxicity and to distinguish ICANS from later and more focal toxicities. As CAR-T cell therapies move from cancer centres into the care of patients with refractory neuroimmunological disease, neurologists will need a detailed understanding of both their therapeutic promise and their neurological risks, and close collaboration within multidisciplinary teams will be essential to deliver these treatments safely.

Keywords:  HAEMATOLOGY; MULTIPLE SCLEROSIS; MYASTHENIA; NEUROIMMUNOLOGY

DOI:  https://doi.org/10.1136/bmjno-2025-001491
Value Health. 2026 Mar 20. pii: S1098-3015(26)00104-X. [Epub ahead of print]

Fast Science, Slow Evaluation: What Makes Health Technology Assessment of Genetic and Genomic Technologies So Complicated? A Systematic Review of Methodological Challenges and Identified Suggestions.

Valentina Baccolini, Leonardo Maria Siena, Claudia Isonne, Antonio Sciurti, Carolina Marzuillo, Corrado De Vito, Giuseppe La Torre, Marcello Arca, Giuseppe Migliara, Paolo Villari.

   OBJECTIVES: The implementation of new applications into healthcare systems and practices frequently relies on health technology assessment (HTA). Given their complexity, HTA of genetic and genomic technologies (GGTs) faces multiple challenges, yet no comprehensive synthesis exists. We systematically reviewed and summarized HTA challenges for GGTs, overall and by HTA domain.
METHODS: Following PRISMA guidelines, we searched three databases (OSF protocol h4qg2). Eligible studies primarily discussed HTA challenges/barriers for GGTs across any HTA domain. Issues were classified into nine EUnetHTA's Core Model domains plus a "framework" category. Results were synthesized narratively.
RESULTS: Twenty records published between 2007-2025 were included: heterogeneous in structure, most discussed multiple HTA domains, and some reported suggestions. Economic (n=12), clinical (n=9), and social (n=8) considerations predominated, whereas safety and organizational aspects were under-represented. Across domains, we identified a persistent mismatch between the rapid evolution of GGTs and the slower generation of evidence, along with insufficient standardization and validation of key procedures that hinder cross-study comparability. Other major issues included defining clear healthcare pathways, valuing genomic testing, and strengthening regulatory frameworks to protect patient rights, data integrity, and equity of access. Suggested remedies were adopting living/rapid HTA, defining core outcome sets, harnessing real-world data sources, standardizing guidelines, engaging stakeholders, and enhancing national commitment.
CONCLUSIONS: Fast-moving science and inadequate methods hamper HTA of GGTs. Adopting flexible HTA methods, standardized outcomes and procedures, and multi-stakeholder engagement, supported by national infrastructures, can shift HTA toward a more agile, resource-enabled system that better supports timely, generalizable, and equitable decision-making in genomics.

Keywords:  HTA; challenges; evaluation; genetic; genomic; systematic review

DOI:  https://doi.org/10.1016/j.jval.2026.03.004
Cells. 2026 Mar 19. pii: 547. [Epub ahead of print]15(6):

Empowerment of CAR-T Cells by IL-7 and IL-15 Boosts Their Efficacy Against HER2-Positive Tumors with Enhanced Expansion and Persistence.

Zhehong Cheng, Henning Kirchgessner, Beate Jahraus, Emre Balta, Yvonne Samstag.

  Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable clinical success in B cell malignancies. However, its efficacy in solid tumors remains limited, in part due to suboptimal expansion, persistence, and restrained effector function. Strategies that promote durable CAR-T cell fitness are therefore required to overcome these barriers. In this study, we generated HER2-CAR-T cells targeting human breast cancer cells and evaluated the impact of different cytokine supplementation strategies on CAR-T cell phenotype and function. We analyzed gene expression patterns and performed repetitive tumor killing assays to assess the ability of CAR-T cells expanded with IL-2 + IL-7 + IL-15 compared with IL-2 alone to maintain proliferation and cytotoxic function across multiple rounds of tumor cell exposure. Compared with IL-2 alone, supplementation with IL-7 and IL-15 significantly enhanced CAR-T cell expansion, preserved stem cell-like features prior to antigen encounter, and promoted superior proliferative capacity. Moreover, CAR-T cells cultured with IL-7+15 or IL-2+7+15 maintained sustained cytotoxicity and exhibited increased antitumor cytokine production during repeated tumor challenges. Notably, IL-7 and IL-15 supplementation induced a CD57+ CAR-T cell population that, unlike the immunosenescent CD57+ cells reported previously, retained full proliferative and cytotoxic capacity, with CD57 expression being dynamically downregulated upon antigen stimulation. Collectively, these findings demonstrate that incorporation of IL-7 and IL-15 into CAR-T cell manufacturing protocols substantially improves expansion, persistence, and effector function, supporting their use as a strategy to enhance CAR-T cell performance against solid tumors.

Keywords:  CAR-T cells; HER2; IL-15; IL-7; immunotherapy of cancer

DOI:  https://doi.org/10.3390/cells15060547
Mol Cancer. 2026 Mar 26.

CAR-NK cell therapy for hematologic malignancies: advances, challenges and optimization strategies.

Weitong Liu, Huilei Miao, Li Weng, Xinxin Cao.



Keywords:  CAR-NK cells; Challenges; Clinical strategy; Clinical trend; Efficacy; Hematologic malignancies; Optimization strategies

DOI:  https://doi.org/10.1186/s12943-026-02648-z
Global Health. 2026 Mar 26.

Patient organizations involvement in healthcare: a rapid review and conceptual framework.

Arianna Gentilini, Iva Parvanova, Samra Ghazi, Kristy M Scarfone, Jillian Kohler.

   BACKGROUND: Patient organizations have become increasingly influential in the healthcare sector, offering unique insights into unmet health needs, disease impact, and patients' quality of life. These groups have evolved from advocates for access to treatment, as seen during the HIV/AIDS crisis, to active participants in the research and policy-making processes. Despite growing recognition of their critical role, a comprehensive understanding of their interactions with various healthcare actors remains limited.
MAIN BODY: This rapid review aims to map the landscape of patient organization involvement in healthcare, particularly in high-income settings. We conducted a systematic search of MEDLINE, focusing on literature published between 2000 and 2024, and identified 61 relevant articles. The analysis revealed that patient organizations interact with a range of actors, including pharmaceutical companies, healthcare professionals, payers, health technology assessment bodies, and regulatory agencies. Key themes were identified around conflicts of interest, especially with regards to the pharmaceutical industry, where concerns about transparency and independence were prevalent. The review also highlighted the vital role patient organizations play in research and development, regulatory approval processes, and reimbursement decisions. The conceptual framework developed from this review outlines these interactions across the pharmaceutical lifecycle, emphasizing the varied and significant contributions of patient organizations.
CONCLUSION: This review underscores the need for more transparency and meaningful engagement of patient organizations in healthcare decision-making. While their involvement has been primarily studied in the context of pharmaceutical industry relations, further research is needed to explore their interactions with other relevant actors. Addressing funding challenges and expanding research beyond well-studied regions are crucial for fully understanding and optimizing the role of patient organizations in healthcare.
CLINICAL TRIAL NUMBER: Not applicable.

Keywords:  Conflicts of interest; Health technology assessment; Healthcare; Patient organizations

DOI:  https://doi.org/10.1186/s12992-026-01205-z
Clin Exp Rheumatol. 2026 Mar 12.

Central memory T cells: stem-like biology, pathogenic roles in autoimmunity, and therapeutic applications.

Dalin Di, Yanyan Zhang, Haixia Li, Qingxiang Zhang, Yuxia Li.

Central memory T (TCM) cells are a cornerstone of the adaptive immune system, serving as a long-lived, self-renewing stem-like population that provides durable immunological protection. Primarily residing in secondary lymphoid organs, TCM cells are characterised by robust proliferative potential, multipotent differentiation capacity, and metabolic reliance on oxidative phosphorylation. These attributes are crucial for mediating rapid and effective secondary immune responses.Recent advances have elucidated the complex molecular circuitry governing TCM cells' fate decisions, focusing on the transcription factor networks and epigenetic modifications that preserve their characteristic stemness. In the context of disease, TCM cells play a dual role: they are a vital source of effector cells for combating infections and malignancies, yet they can also contribute to the chronic inflammation that drives autoimmune disorders including systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, and Sjögren's disease.This functional dichotomy underlies their considerable clinical significance. Notably, TCM cells represent a preferred cellular source for chimeric antigen receptor T (CAR-T) cell therapy in both oncology and emerging autoimmune indications, serve as a predictive biomarker for the efficacy of immune checkpoint inhibitors, and act as a key indicator of vaccine effectiveness.This review comprehensively examines TCM cells, covering their biological features, developmental mechanisms, and recent clinical applications in cancer immunotherapy, autoimmune diseases, and cellular therapies, while outlining future therapeutic directions.

DOI: https://doi.org/10.55563/clinexprheumatol/0bkrx5
Front Immunol. 2026 ;17 1740144

Real-world safety profile of T-cell engagers: evidence from multi-database analysis with CAR-T comparisons.

Jinman Zhong, Chang Chen, Yunman Xu, Yueping He, Jingwen Luo, Changxiu Zhang, Jiewen Tan, Dan Xiong.

   Background: T-cell engagers (TCEs), "off-the-shelf" immunotherapies are seeing widespread clinical application, yet their real-world safety profile is not fully defined. This study aimed to characterize the comprehensive adverse event (AE) profile of TCEs, using chimeric antigen receptor T-cell (CAR-T) therapy as a contextual benchmark.
Methods: A pharmacovigilance study was conducted on AE reports for TCE and CAR-T therapies from FAERS and VigiBase. A multi-level analytical framework integrated disproportionality analysis, time-to-onset modeling, occurrence network analysis, and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) analysis to characterize signals, temporal dynamics, and clinical syndromes.
Results: The proportion of fatal outcomes reported with TCEs significantly increased from 14.3% in 2015 to 23.5% in 2025 (P<0.001). Compared to CAR-T, TCEs showed stronger signals for Infection and Tumor Lysis Syndrome (TLS), while CAR-T showed stronger signals for Cytokine Release Syndrome (CRS) and ICANS. TLS and CRS occurred significantly earlier with TCEs. Network analysis quantified the co-occurrence and clinical severity of the CRS-ICANS-infection triad. The TCE class showed profound drug-specific heterogeneity, including severe oral/nail toxicities with talquetamab (oral toxicity ROR = 6066.40) and extramedullary relapse/infiltration with blinatumomab. TCE-associated ICANS revealed a strong overall signal (ROR 197.08), with fatal outcomes reported in 26% of cases, an early-peaking reporting pattern (WSP α = 0.63), and key risk factors including age, indication, target and concurrent CRS.
Conclusion: TCEs are characterized by rapid early CRS/TLS AEs, elevated infection reporting, and target-specific toxicities, while CAR-T exhibits stronger CRS/ICANS signals. These findings support early monitoring and molecule-specific, syndrome-based risk management, advancing precision pharmacovigilance for T-cell redirecting therapies.

Keywords:  T-cell engager; chimeric antigen receptor t-cell therapy; immune effector cell-associated neurotoxicity syndrome; pharmacovigilance; real-world evidence

DOI:  https://doi.org/10.3389/fimmu.2026.1740144
J Immunother Cancer. 2026 Mar 23. pii: e013668. [Epub ahead of print]14(3):

γδ T cells at the interface of innate and adaptive immunity in cancer.

Arnau Solé Casaramona, Martin F Bachmann, Eva Sevick-Muraca, Mona O Mohsen.

  γδ T cells are unconventional lymphocytes that bridge innate and adaptive immunity by combining recognition of stress-induced ligands independently of classical major histocompatibility complex molecules with the capacity to undergo clonal expansion and long-term adaptation. Their unusual ability to detect malignant transformation using semi-invariant T-cell receptors, butyrophilin recognition and natural killer-like receptors positions them as powerful effector cells in tumors that evade classical immune escape mechanisms. Furthermore, distinct γδ subsets have distinct phenotyping and specific tissue-residencies, which could be leveraged to modulate immunological responses. We evaluate engineered therapies and different experimental platforms for studying γδ T cell biology. We conclude that next-generation cancer treatments should strategically integrate γδ T cells into synthetic immunology, individualized modeling, and combinatorial regimes.

Keywords:  Adaptive; Education; Immunotherapy; Innate; T-Lymphocytes

DOI:  https://doi.org/10.1136/jitc-2025-013668
Cytometry B Clin Cytom. 2026 Mar 23.

Flow cytometry-based monitoring of chimeric antigen receptor (CAR) T cells: Reagent selection, assay design, and clinical utility.

Jianhua Ling, Wei Wang, Sa A Wang.

  Accurate quantification of chimeric antigen receptor (CAR) T cells is essential for monitoring post-infusion CART expansion and persistence and for real-time clinical decision-making. Multiparameter flow cytometry (MFC) enables rapid, live-cell detection with absolute quantification and concurrent immunophenotypic characterization. This review focuses on the practical and technical aspects of flow cytometry-based CAR T-cell monitoring, including selection of CAR detection reagents (target-specific, construct-specific, and target-agnostic strategies), assay optimization, purpose-driven panel design, and matrix-appropriate validation for peripheral blood and other clinically relevant specimens. We also address assay considerations unique to gene-edited allogeneic CAR T-cell products, including the use of surrogate immunophenotypic approaches when construct-specific reagents are unavailable. Finally, we discuss the role of MFC in identifying CAR T-cell clonal expansions and in evaluating suspected secondary hematolymphoid neoplasms in the post-CAR T setting.

Keywords:  BCMA; CD19; ICE enterocolitis; T‐cell lymphoma; allogeneic CART; chimeric antigen receptor T cells (CART); flow cytometry; linker; scFv

DOI:  https://doi.org/10.1002/cyto.b.70026
J Immunother Cancer. 2026 Mar 27. pii: e014450. [Epub ahead of print]14(3):

Locoregional delivery of CAR T cells in high-grade gliomas: a systematic analysis of safety, efficacy, and emerging biomarkers of response.

Christian K Ramsoomair, Manav Daftari, Rami Benchouia, Dagoberto Estevez-Ordonez, Anurag Aka, Vratko Himic, Manuela Aramburu-Berckemeyer, Daniel Kreatsoulas, Vaidya Govindarajan, Jay S Chandar, Michael E Ivan, Ricardo J Komotar, Ashish Shah.

   BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy represents a promising frontier in oncology, but its application to high-grade gliomas (HGG) is challenged by the blood-brain barrier, limited efficacy, and significant toxicities associated with systemic administration. Locoregional delivery has the potential to address these shortcomings. This systematic review evaluates the safety and efficacy of locoregional vs systemic CAR-T cell delivery for HGG.
METHODS: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a total of 112 studies were identified from three separate databases between 2015 and 2024. Of these, 19 articles were assessed for eligibility, resulting in 16 articles meeting the inclusion criteria with 194 treated patients across 14 clinical trials. A comparative meta-analysis was performed to compare the safety and efficacy outcomes of locoregional administration (eg, intracerebroventricular, intratumoral) with systemic (intravenous) delivery. Severe (grade ≥3) adverse event rates and therapeutic responses were pooled to calculate crude incidence, rate ratios, and relative risks (RRs) with 95% CIs. Both fixed-effect and random-effects models were used to evaluate incidence rate ratios.
RESULTS: Locoregional delivery was associated with a markedly improved safety profile, demonstrating an over 60% reduction in the incidence of grade ≥3 adverse events compared with systemic infusion (RR=0.39; 95% CI 0.30 to 0.52; p<0.001). Furthermore, locoregional strategies demonstrated encouraging signals of antitumor activity, including rates of disease responses not widely observed with systemic approaches (RR=3.79; 95% CI 1.23 to 11.70; p<0.05). Locoregional delivery also enables the analysis of cerebrospinal fluid to monitor T-cell trafficking and emerging biomarkers of immune activation.
CONCLUSION: Intracranial delivery of CAR-T cells helps overcome key barriers that limit the efficacy and safety of systemic therapy in brain tumors. These findings support a paradigm shift that integrates locoregional delivery techniques as a pivotal component in the design of future CAR-T cell trials, offering a safer and potentially more effective therapeutic approach with greater opportunities for longitudinal sampling for patients with HGG.

Keywords:  Chimeric antigen receptor - CAR; Immunotherapy; Neurotoxicity; T cell

DOI:  https://doi.org/10.1136/jitc-2025-014450
J Pers Med. 2026 Mar 03. pii: 147. [Epub ahead of print]16(3):

From Immunobiology to Clinical Application: Tumor-Infiltrating Lymphocytes in Melanoma.

Mislav Mokos, Mirna Šitum.

  Background: Tumor-infiltrating lymphocytes (TILs) play a key role in the immune response against melanoma. They act as both markers of an active tumor environment and as treatments in adoptive cell therapy. This narrative review covers what is currently known about TIL biology, their prognostic and predictive value, and the use of TIL-based adoptive cell therapy (TIL-ACT) in advanced melanoma. Methods: We searched PubMed/MEDLINE, Web of Science and clinicaltrials.gov through January 2026 using terms related to melanoma, TILs, adoptive cell therapy, immune checkpoint inhibitors, neoantigens, T-cell receptor clonality, and spatial transcriptomics. We included original research, major clinical trials, translational studies and key reviews. Results: Melanoma often has many neoantigens, which leads to a high number of tumor-resident TILs. These TILs, their arrangement, and their interactions with myeloid cells influence how well they fight tumors. Features of TILs seen under the microscope and through other tests can help predict patient outcomes, even before treatment. Studies show that TIL-ACT leads to objective responses in about 30-50% of patients whose melanoma did not respond to immune checkpoint inhibitors. Some patients achieve lasting complete remissions, though the treatment can cause significant, mostly short-term side effects from lymphodepletion and interleukin-2. New research points to factors related to the patient, tumor, and TIL product that affect treatment success, supporting the use of biomarkers and combination strategies. Conclusions: TIL-based adoptive cell therapy is now a promising, personalized treatment for advanced melanoma after anti-PD-1 therapy has failed. Future studies should focus on identifying reliable biomarkers, improving TIL products, combining therapies to change the tumor environment, and making manufacturing more efficient to ensure more patients can safely access TIL therapy.

Keywords:  adoptive cell therapy; biomarkers; immune checkpoint inhibitors; immunotherapy; lifileucel; melanoma; personalized medicine; tumor microenvironment; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.3390/jpm16030147
Pharmaceutics. 2026 Mar 13. pii: 356. [Epub ahead of print]18(3):

Artificial Intelligence and the Transformation of Cell and Gene Therapy Development.

Jared R Auclair, Jeewon Joung, Maya A Singh, Gaël Debauve, Rominder Singh.

  Cell and Gene Therapy (CGT) represents a paradigm shift in medicine, offering curative potential for previously intractable diseases. However, the complexity, high cost, and manufacturing challenges inherent in developing, producing, and administering these therapies hinder their widespread accessibility. This review examines the critical and increasingly synergistic role of Artificial Intelligence (AI) and Machine Learning (ML) in overcoming these barriers across the entire CGT lifecycle, from discovery and construct design to smart manufacturing, clinical translation, and regulatory applications. We analyze how AI-driven approaches fundamentally differ from conventional methods, facilitating rapid construct optimization, generating highly predictive translational models, enabling the vision of autonomous, digital-twin-driven manufacturing, and establishing new paradigms for pharmacovigilance and regulatory oversight. The integration of AI is not merely an incremental improvement but a foundational transformation, positioning CGT to move from niche, bespoke treatments to scalable, accessible, and highly personalized medical modalities. We conclude by discussing current gaps, particularly data scarcity and regulatory uncertainty, and outlining a roadmap to realize the full potential of AI-enabled CGT.

Keywords:  CGT development; CGT manufacturing; artificial intelligence; cell and gene therapy; machine learning

DOI:  https://doi.org/10.3390/pharmaceutics18030356
J Mark Access Health Policy. 2026 Mar 06. pii: 14. [Epub ahead of print]14(1):

Can We Trust PAICs in Rare Diseases? Methodological Challenges and Limitations.

Mikolaj Parkitny, Samuel Aballéa, Piotr Wojciechowski, Mondher Toumi.

  Population-adjusted indirect comparisons (PAICs), including Matching-Adjusted Indirect Comparison and Simulated Treatment Comparison, are increasingly used to inform health technology assessments. These methods offer a pragmatic approach to generating comparative evidence between treatments when head-to-head trial data are unavailable and standard indirect treatment comparison methods are unfeasible. In rare diseases, however, PAICs often face substantial methodological challenges arising from small sample sizes, limited covariate overlap, and the frequent use of unanchored comparisons that rely on unverifiable assumptions. These limitations can lead to unstable estimates, reduced precision, and bias that may undermine the reliability of findings. Methodological refinements-such as optimized weighting, Bayesian approaches, and doubly robust estimators-provide some improvements but do not resolve these fundamental issues. Current European Joint Clinical Assessment guidance recommends that anchored PAICs be applied with great caution, while unanchored PAICs are considered highly problematic, and other methods should be used instead. We argue that PAICs can play a supportive role within a multidimensional and deliberative HTA process, contributing to comparative assessment alongside other evidence sources when available data are limited. However, their results require careful interpretation and transparent communication of uncertainty. Future research should prioritize the further development of formal frameworks to quantify bias and systematically assess robustness, thereby preventing overstatement of the credibility of PAIC-derived evidence in rare disease contexts.

Keywords:  matching-adjusted indirect comparison; rare diseases; simulated treatment comparison

DOI:  https://doi.org/10.3390/jmahp14010014
Forensic Sci Int Synerg. 2026 Jun;12 100672

Organizational culture and forensic science reliability: A lifecycle analysis of latent error pathways.

Michael P Kessler.

  Reliability in forensic science is often inferred from accreditation and standards compliance. These controls are necessary, but they do not, by themselves, demonstrate stable performance under routine casework conditions. This conceptual synthesis treats reliability in the scientific systems sense: the capacity of a forensic science system to maintain stable performance and to interrupt error under ordinary operating constraints. Drawing on forensic science, safety science, and organizational research, it describes three mechanism-consistent pathways by which reliability can erode without overt nonconformance: latent conditions embedded in workload and review design; attenuation of weak signals as concerns are summarized or administratively closed; and lifecycle propagation, where early constraints shape later analysis, interpretation, reporting, and testimony. The Marshall Hale wrongful conviction is used as an illustrative mechanism map of how procedural completion can coexist with reduced corrective leverage across institutional boundaries.

Keywords:  Forensic science governance; Forensic science reliability; Latent error pathways; Organizational culture; Quality systems

DOI:  https://doi.org/10.1016/j.fsisyn.2026.100672
BMC Health Serv Res. 2026 Mar 27.

Exploring alternative funding mechanisms to improve patient access to innovative medicines.

Teerapat Ungtrakul, Jomtana Siripaibun, Puree Anantachoti, Omar Akhtar, Pichaya Suthipinijtham, Malvin Kang, Adrien Gras, Jeonghoon Ahn, Nithi Mahanonda, Chirayu Auewarakul.



Keywords:  Cancer therapy; Financial strategies; Health technology assessment; High-cost innovation; Patient access; Thailand

DOI:  https://doi.org/10.1186/s12913-026-14438-w
Front Immunol. 2026 ;17 1792164

Tunable CAR-NK-92 activity in the tumor microenvironment via a dual ATF4-responsive circuit.

Enzo Manchon, Nell Hirt, Aravindhan Soundiramourty, Benjamin Versier, Yves Christen, Dominique Charron, Jacques Mallet, Nabila Jabrane-Ferrat, Che Serguera, Reem Al-Daccak.

  Chimeric antigen receptor-engineered NK-92 (CAR-NK-92) cells emulate activated natural killer cells, combining potent innate cytotoxicity with CAR-driven antigen specificity. Their scalability and FDA approval make them attractive for universal use. However, their application in solid tumors remains limited by the immunosuppressive tumor microenvironment (TME), which is often characterized by hypoxia and nutrient deprivation. We recently demonstrated that an ATF4-inducible promoter, 2xAARE-YB, enables spatial and temporal control of CAR expression in T cells, enhancing safety by restricting expression to amino acid-deprived TME while reducing exhaustion to improve persistence. In this study, we adapted the 2xAARE-YB system for CAR-NK-92 cells. Under glucose-limited conditions, a hallmark of the TME, the system effectively regulated CAR expression, enabling potent antigen-specific cytotoxicity. In xenograft models, the nutrient-responsive 2xAARE-YB system achieved regulated intratumoral CAR expression in vivo, supporting its potential for the development of safer therapeutic strategies. Additionally, the clinically approved ER stress-inducing drug artesunate also reliably activated the circuit, offering a drug-inducible regulation of CAR expression. Collectively, these findings establish 2xAARE-YB as a dual-mode regulatory platform that enables tunable, context-dependent CAR expression in NK-92 cells. Although this approach may be more effective in HLA I-negative tumors than in HLA I-positive tumors, it represents a promising path toward safer and more adaptable CAR-NK-92 therapies tailored for the dynamic metabolic constraints of solid tumors.

Keywords:  CAR-NK cell therapy; ER stress-inducing drugs; FDA-approved NK-92 cells; GCN2-ATF4 pathway; regulatable systems; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1792164
Inflamm Regen. 2026 Mar 25.

Natural killer cells: gatekeepers of healthy aging in longevity medicine.

Joanna Y Yang, Doris T Tu, Jun-Cheng Liao, Oscar K Lee.

Natural killer (NK) cells are innate lymphocytes that provide rapid immune surveillance through the recognition and elimination of virally infected, malignant, and stressed cells. Beyond their established roles in host defense, accumulating evidence indicates that NK cells undergo profound age-associated remodeling affecting subset distribution, receptor balance, metabolic programming, and effector function. These changes, collectively referred to as NK immunosenescence, contribute to impaired clearance of senescent cells, dysregulated inflammation, and increased susceptibility to cancer, infection, and metabolic disease. In this review, we integrate current knowledge of NK cell aging into the emerging framework of longevity medicine. Rather than introducing NK cells as a newly identified determinant of aging, we synthesize evidence positioning them as key immune effectors whose functional state reflects and influences biological aging processes. We highlight how NK cells participate in senescence surveillance, tissue homeostasis, and immunometabolic regulation across organs, and how their dysfunction intersects with multiple hallmarks of aging. We further discuss the potential utility of NK-related phenotypic and functional metrics as complementary biomarkers of immune aging, while acknowledging current limitations in specificity and prognostic validation. Finally, we examine therapeutic strategies aimed at preserving or restoring NK competence, ranging from lifestyle and nutritional interventions to cytokine-based therapies, immune checkpoint modulation, and emerging cellular platforms. While many advanced NK-targeted approaches remain investigational-particularly outside oncology settings-we outline a translational roadmap linking NK biology to actionable interventions and measurable outcomes relevant to healthspan. By situating NK cells within a systems-level view of immune aging, this review frames them as a tractable component of precision longevity medicine rather than a singular regulator of aging.

DOI: https://doi.org/10.1186/s41232-026-00414-8
J Autoimmun. 2026 Mar 23. pii: S0896-8411(26)00027-2. [Epub ahead of print]160 103549

TCR recognition of peptide-HLA class II complexes in autoimmunity: Structural insights for therapeutic targeting.

Zhanrong Cui, Joshua D Ooi, Yi-Tian Ting.

  Autoimmune diseases encompass a broad spectrum of disorders in which self-reactive T and B cells breach immune tolerance and drive chronic tissue inflammation. Although broad immunosuppressants and cytokine-targeted biologic therapies have improved disease management, many patients still fail to achievement drug-free remission and often relapsed once medication is withdrawn. Human Leukocyte Antigen (HLA) class II genes, the most polymorphic in the human genome, are major determinants of autoimmune disease risk. Polymorphism in HLA class II, concentrated in the peptide-binding groove, shapes the repertoire of self-peptides that can be presented to the immune system. This peptide-HLA complexes (pHLA) therefore influences which autoreactive CD4+ T-cell clones escape central and peripheral tolerance, yet these mechanistic insights have so far only partially been translated into therapeutic design. In this review, we first summarize key features of self-reactive versus pathogen-specific pHLA II recognition in autoimmune diseases. We compiled all 38 currently resolved human ternary TCR-pHLA II complexes that are directly linked to autoimmune disease, 19 of these involve celiac diseases, whereas only a handful represent other autoimmune indications. Even with the relatively sparse structural dataset for this axis, current knowledge has helped shape emerging therapeutic strategies such as pHLA II-based nanomedicines, engineered regulatory T cells and TCR-like antibodies. We further discuss how artificial intelligence and machine-learning frameworks could integrate each patient's HLA class II genotype, peptide-presentation profile and autoreactive T-cell repertoire to design genuinely personalised, HLA II-stratified therapies, outlining this as a key future direction for the field.

Keywords:  Antigen-selective immunotherapy; Autoimmune specificity; HLA polymorphism; Self-antigen recognition; Structural immunology

DOI:  https://doi.org/10.1016/j.jaut.2026.103549
Annu Rev Biomed Data Sci. 2026 Mar 24.

Privacy and Security Throughout the Health Data Life Cycle: From Primary Care to Research Networks.

Bradley A Malin, Chao Yan, Luca Bonomi.

Health data are increasingly generated, shared, and analyzed across an ever-growing collection of settings. While these developments enable new forms of biomedical discovery and clinical decision support, they also introduce evolving privacy, security, and trust challenges that extend beyond traditional regulatory and technical frameworks. In this review, we characterize the various risks and protections throughout the health data life cycle, from data generation and primary use in healthcare to secondary use in research and artificial intelligence (AI) model development. We discuss how regulation, organizational practices, and technological choices shape data protection requirements, and we discuss and contextualize emerging threats, such as incidental disclosures through AI tools. We further review technical approaches for mitigating these risks, including access control and auditing, reidentification risk assessment and statistical mechanisms for risk mitigation (e.g., differential privacy), and synthetic data generation. We also consider how collaboration across disparate organizations may be achieved through federated learning mechanisms and cryptographic technologies, such as secure multiparty computation. Throughout, we highlight trade-offs between privacy protection and data utility, and we articulate practical challenges in deploying these methods at scale. We conclude by identifying open issues for the field, including the need for standardized metrics and greater transparency to support trust in data-driven healthcare and research.

DOI: https://doi.org/10.1146/annurev-biodatasci-092724-031932
Am J Crit Care. 2026 Mar 26. e1-e9

Silence Kills 2.0: How Communication Failures Stifle Innovation and Harm Patients.

Joseph Grenny, Vicki Good, Ramón Lavandero, Elizabeth Scruth.

BACKGROUND: In health care organizations in which silence is the norm, questionable competence, rule-breaking, and mistakes ("crucial moments") often persist, putting patients and clinicians at risk. Silence may also impede an organization's behavioral agility-the speed at which care teams adopt new technologies and evidence-based practices.
OBJECTIVES: Twenty years after the Silence Kills study, this study addressed these questions: Does silence still happen? Does silence kill innovation?
METHODS: In a quantitative cross-sectional descriptive study, clinicians across the United States, including nurses, other care providers, and leaders, completed an online instrument incorporating the 2005 Silence Kills survey and other measures to understand how often clinicians perform 4 behaviors related to crucial moments (speaking up, reminding, holding each other accountable, and challenging assumptions) that were hypothesized to increase behavioral agility. Demographic data also were collected.
RESULTS: Of 5163 respondents, 3500 provided analyzable data. Fewer than 10% of respondents spoke up during crucial moments in 2005; in 2025, it was 32%, suggesting significant progress in overcoming the culture of silence. A continued strong relationship between speaking up and health care outcomes was found. A culture of candid communication also strongly correlated with behavioral agility (r = 0.71), patient safety, patient experience, and employee engagement and retention (P < .001).
CONCLUSIONS: Improvements in patient care, employee satisfaction, and adoption of evidence-based practices are possible when clinicians are empowered to speak up in crucial moments. Artificial intelligence use is expected to accelerate progress toward improved patient outcomes, reduced costs, and increased access to care, but only if the human systems required for implementation increase their capacity to absorb new ideas.

DOI: https://doi.org/10.4037/ajcc2026203
Curr Mol Med. 2026 Mar 18.

Microbiota-driven Immunopathogenesis in Systemic Lupus Erythematosus: Cross-site Mechanisms and Intervention Strategies.

Shuqing Feng, Qin Huang.

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease whose pathogenesis involves intricate interactions with the human microbiota. Accumulating evidence reveals significant compositional and functional dysbiosis in the gut, oral, skin, and vaginal microbiota of SLE patients compared to healthy individuals. These dysbioses actively contribute to disease development and progression through a multitude of mechanisms. These include impaired epithelial barrier integrity, exemplified by the "leaky gut" phenomenon, which facilitates the translocation of microbial antigens. Molecular mimicry, where microbial antigens share structural similarities with host self-antigens, triggers the production of cross-reactive autoantibodies. Furthermore, dysregulated production of microbial metabolites, such as short-chain fatty acids, tryptophan derivatives like tryptamine, and histamine, directly modulates host immune cell function, promotes inflammatory responses, and influences epigenetic regulation. The causal role of specific microbiota in SLE is substantiated by experimental models, including fecal microbiota transplantation studies where transfer of SLE-associated microbiota can recapitulate autoimmune features in recipient germ-free mice, and mono-colonization with pathobionts like Ruminococcus gnavus or Staphylococcus aureus can drive specific aspects of the disease. This growing understanding has paved the way for novel microbiota-targeting interventions. Strategies such as dietary modifications, probiotic and prebiotic supplementation, and fecal microbiota transplantation show considerable promise in preclinical and early clinical studies for restoring microbial homeostasis, rebalancing dysregulated immune responses, and alleviating disease activity. However, challenges in patient-specific variability, understanding precise mechanisms, and ensuring longterm safety remain. Future research must focus on delineating detailed causal pathways, validating efficacy in large-scale trials, and ultimately developing personalized microbiota-targeting interventions to improve SLE management and patient outcomes.

Keywords:  Systemic lupus erythematosus; gut microbiota; immune system.; oral microbiota; skin microbiota; vaginal microbiota

DOI:  https://doi.org/10.2174/0115665240433654260209063544