bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–04–05
forty-five papers selected by
Luca Bolliger, lxBio
  1. Potential Application of CAR-NK Cells as an Ex Vivo Therapy for T-cell-related Diseases.
  2. Non-viral and mRNA-based strategies for next-generation CAR-T cell therapy.
  3. Cellular therapies in systemic Sclerosis: immunopathogenesis-informed precision targeting with CAR-T and CAR-NK approaches.
  4. CAR T cell therapy: Autoimmune neurological uses and neurotoxicities.
  5. Application and Challenges of Chimeric Antigen Receptor T Cell Therapy in Systemic Rheumatic Diseases and Autoimmune Disorders.
  6. CAR T-Cell Therapy for Solid Tumors: Clinical Challenges and Current Advancements.
  7. Recent advances in CAR T and CAR NK cell therapy for AML.
  8. Combining CRISPR/Cas9-mediated TRAC knockout with mRNA-based CAR expression enables flexible generation of allogeneic CAR T cells.
  9. Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.
  10. Highlights in IO: next-generation CAR-T therapy for glioblastoma.
  11. Shaping cell therapy manufacturing with metabolic understanding and control.
  12. Economic value of anti-CD20 therapies in multiple sclerosis: a systematic review of cost-effectiveness studies.
  13. CLO26-108: Efficacy of CAR T Cell Therapy in Extranodal and Nodal Large B-Cell Lymphoma.
  14. T-Cell Receptor Engineered T-Cell Therapy: A Rapidly Evolving Treatment Paradigm for Solid Tumors.
  15. Review of advances in CAR-T therapies in malignant hematology.
  16. CAR T cells engineered against LAG-3: Unleashing potency in the tumor microenvironment of breast cancer.
  17. Value‑Based Contracting for Cell and Gene Therapies: A Scoping Review of Payer-Manufacturer Agreements and Treatment‑Center Considerations in USA.
  18. Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
  19. CAR T-cell therapy and indications for pediatric rheumatology: Structured overview of applications, risks, and considerations.
  20. Health technology assessment in Eastern Europe and Central Asia: an updated SWOT analysis.
  21. Addressing clinical uncertainties in ATMP reimbursement: a review of methodological guidelines and European practice.
  22. Access to CAR T-cell therapy across diverse global markets.
  23. IFNγ-induced antigen loss in chimeric antigen receptor-T cell therapy.
  24. Programmable CAR immunotherapies for neurodegenerative proteinopathies.
  25. What is the Value of Developing an HTA Process?
  26. A roadmap to embedding real-world evidence into Health Technology Assessment processes for cancer medicines: experiences from Scotland.
  27. Seven subsets, two fates: mouse γδ T cells in cancer immunity.
  28. In vivo CAR-T therapy: from molecular design to precision delivery.
  29. Real-World Evidence in Action: A Comprehensive Environmental Scan of Real-World Evidence Use in Health Technology Assessments Submitted to Canada's Drug Agency From 2020 to 2024.
  30. Perfusion microbioreactor for CAR-Treg manufacturing.
  31. China's Growing Importance in Global Cancer Medicines.
  32. Futuristic global cell and gene therapy regulations based on a review of today's leading frameworks.
  33. Bright side of the dark genome: antigens for next-gen cancer vaccines.
  34. Real-world data and evidence in the development of cell and gene therapies.
  35. Structural determinants of effective academic-industry technology transfer in biomedical engineering.
  36. Next-generation interleukin-enhanced immunotherapies: From molecular engineering to armored T-cell architectures.
  37. Shifting sands in Saudi Arabian healthcare system towards value-based care: navigating the changing landscape.
  38. Regulatory Frameworks for the Integration of Quantum Computing in Pharmaceutical R&D: Implications for Drug Development and Compliance Monitoring.
  39. Divergent Paths, Convergent Goals: Institutional Experiments in Cell and Gene Therapy Regulation and Payment Between China and the United States.
  40. Human Cytomegalovirus Infection in Haematopoietic Stem Cell Transplant Recipients and CAR-T Cell Recipients-PART 2: Antiviral Therapy and Virus-Specific T Cell Therapy for HCMV in Allo-HSCT.
  41. Towards a Harmonized Definition of Digital Health Technologies For Use in Health Technology Assessment: A Scoping Review and Modified Delphi Consensus Study.
  42. Inhibitory receptor agonists: Emerging strategies in immune modulation.
  43. LAG-3 at the crossroads: A context-dependent regulator of Tregs and autoimmunity inflammatory disorders.
  44. Foundation models and AI agents in oncology drug discovery.
  45. Could an outcome-based agreement be operationalized using real-world data from the Canadian Neuromuscular Disease Registry? Perspectives from an expert-led assessment in spinal muscular atrophy.
  1. Front Biosci (Landmark Ed). 2026 Mar 11. 31(3): 48704
    Potential Application of CAR-NK Cells as an Ex Vivo Therapy for T-cell-related Diseases.
    Daekee Kwon, Kyung-Sun Kang.
      Anticancer therapeutics have evolved from small-molecule drugs to monoclonal antibodies and, more recently, to cell and gene therapies (CGTs). This progress has been driven by the pursuit of greater drug specificity, potency, and safety. Recent breakthroughs in chimeric antigen receptor T-cell (CAR-T) therapy for B-cell hematologic malignancies have accelerated the development of CAR-X CGTs, including CAR-T, CAR-natural killer (CAR-NK), and CAR-macrophage approaches. In this article, we compare candidate CAR-X platforms for T-cell-related diseases, such as T-cell hematologic malignancies, and propose the most suitable modality. Therefore, we analyzed the advantages and limitations of CAR-T, CAR-NK, and CAR-macrophage therapies. In T-cell-related diseases, CAR-T therapy faces multiple challenges, including fratricide, T-cell aplasia, and substantial barriers to the generation of allogeneic CAR-T products. CAR-macrophage therapies, in contrast, are constrained by relatively limited efficacy. In contrast, CAR-NK cells do not cause fratricide or T-cell aplasia and can be manufactured efficiently as allogeneic, "off-the-shelf" products. Collectively, to sustain and extend the advances in CGT initiated by CAR-T cells in B-cell malignancies, prioritizing CAR-NK research infrastructure for T-cell-related diseases represents a rational and strategic approach.
    Keywords:  adoptive immunotherapy; allogeneic cell; aplasia; cell therapy; chimeric antigen receptor therapy; hematologic neoplasms
    DOI:  https://doi.org/10.31083/FBL48704
  2. Pathol Res Pract. 2026 Mar 25. pii: S0344-0338(26)00106-8. [Epub ahead of print]282 156455
    Non-viral and mRNA-based strategies for next-generation CAR-T cell therapy.
    Taiping Wang, Feng Jin, Wenzheng Xing, Shujuan Yu.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for hematologic malignancies, but its broader application remains limited by the complexity, cost, manufacturing time, and integration-related risks associated with viral vector-based engineering. These constraints have become increasingly important as CAR-T strategies are being extended to solid tumors, autoimmune diseases, and in vivo CAR-T generation, while mRNA therapeutics and non-viral delivery technologies continue to advance. However, non-viral platforms and mRNA engineering are often discussed separately, and a unified translational perspective is still lacking. In this review, we examine how mRNA engineering can be integrated with non-viral delivery systems, including lipid nanoparticles, electroporation, and exosome-based platforms, to support safer and more flexible ex vivo and in vivo CAR-T generation. We further discuss key barriers to clinical translation, including limited expression durability, cell-selective delivery, manufacturing scalability, and regulatory considerations, and highlight the emerging contribution of computational approaches to sequence and carrier optimization. Together, these advances support a timely reassessment of non-viral mRNA-based CAR-T engineering as a practical framework for the development of next-generation cell therapies.
    Keywords:  Adoptive T-cell therapy; CAR-T cells; In vivo engineering; LNPs; MRNA; Non-viral platforms
    DOI:  https://doi.org/10.1016/j.prp.2026.156455
  3. Best Pract Res Clin Rheumatol. 2026 Apr 02. pii: S1521-6942(26)00024-0. [Epub ahead of print] 102139
    Cellular therapies in systemic Sclerosis: immunopathogenesis-informed precision targeting with CAR-T and CAR-NK approaches.
    Gerard Convey, Masataka Kuwana, Mandana Nikpour.
      Systemic sclerosis (SSc) is a rare, heterogeneous systemic autoimmune rheumatic disease characterized by immune dysregulation, vasculopathy, and excessive fibrosis. SSc is associated with high morbidity and mortality despite current immunosuppressive and anti-fibrotic therapies. Emerging cellular therapies, particularly chimeric antigen receptor (CAR) T-cell and natural killer (NK) cell approaches offer potential for deep immune reset and long-term remission. This review examines the immunobiological rationale for these therapies in SSc and evaluates their early clinical evidence, including comparisons to other autoimmune diseases.
    Keywords:  B-Cell depletion; BCMA-Targeted therapy; CAR-NK cell therapy; CAR-T cell therapy; CD19-Targeted therapy; Cellular therapy; Precision therapy; Scleroderma; Systemic Sclerosis (SSc)
    DOI:  https://doi.org/10.1016/j.berh.2026.102139
  4. Best Pract Res Clin Rheumatol. 2026 Apr 02. pii: S1521-6942(26)00030-6. [Epub ahead of print] 102145
    CAR T cell therapy: Autoimmune neurological uses and neurotoxicities.
    Alec R Friedman, Sara Gil-Perotin, Sarah Flanagan Wesley.
      Chimeric antigen receptor T cell therapy (CAR-T) represents a growing field of cell therapy for the treatment of a range of oncological and autoimmune conditions. From the neurological perspective, it remains limited by immunotoxicities, in particular immune effector cell-associated neurotoxicity syndrome (ICANS) and non-ICANS neurotoxicities, such as movement disorders (parkinsonism) and neurocognitive toxicity, neuropathies, myelopathies, and tumor inflammation-associated neurotoxicity. Despite these potential adverse effects, CAR-T remains promising for the treatment of refractory autoimmune neurological conditions, including myasthenia gravis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathies, stiff person syndrome, and others. CAR-T use for autoimmune neurological disorders marks an exciting paradigm shift from immune suppression to immune reprogramming. Moreover, given success in several T-cell mediated autoimmune conditions, these successful results extend the therapeutic scope of B-cell-targeted CAR-T approaches.
    Keywords:  Autoimmune neurological disease; Chimeric antigen receptor T cell therapy; Immune effector cell-associated neurotoxicity syndrome; Neurotoxicity
    DOI:  https://doi.org/10.1016/j.berh.2026.102145
  5. MedComm (2020). 2026 Apr;7(4): e70658
    Application and Challenges of Chimeric Antigen Receptor T Cell Therapy in Systemic Rheumatic Diseases and Autoimmune Disorders.
    Zhidan Fan, Li Zhang, Haiguo Yu.
      Chimeric antigen receptor T (CAR-T) cell therapy, originally developed for hematologic malignancies, has emerged as a transformative candidate for systemic rheumatic diseases and autoimmune disorders (AIDs). Its unique efficacy in refractory AIDs relies on depleting autoreactive B cells and driving antigen-naïve immune reconstitution, achieving durable drug-free remission in early-phase trials. Despite promising clinical and serological responses lasting 2-5 years without long-term immunosuppression, the field faces unmet needs: complex manufacturing, limited tissue penetration, antigen escape, immunological sequelae, and lack of predictive biomarkers. Existing reviews predominantly focus on oncology adaptations or isolated technical aspects, lacking systematic integration of mechanisms, challenges, and precision-oriented innovations for rheumatic diseases. This review comprehensively summarizes CAR-T's action mechanisms in AIDs, analyzes core clinical challenges, and highlights emerging strategies-including universal/in vivo-generated CAR-T cells, multitargeted/logic-gated designs, organ-homing engineering, and rational combinations with tolerance-enhancing agents. It further emphasizes multiomics integration (single-cell transcriptomics, spatial mapping, B-cell receptor/T-cell receptor repertoire analysis) for patient stratification and relapse prediction. By bridging mechanism-driven engineering with clinical translation, this work provides an actionable framework to advance CAR-T toward functional immune reset, enabling precision immunotherapy for refractory rheumatic diseases and AIDs.
    Keywords:  CAR‐T cell therapy; autoimmune disorders (AIDs); biomarker discovery; immune reconstitution; in vivo CAR‐T; multiomics integration; precision immunology; universal CAR‐T
    DOI:  https://doi.org/10.1002/mco2.70658
  6. Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00085-7. [Epub ahead of print]35(2): 207-222
    CAR T-Cell Therapy for Solid Tumors: Clinical Challenges and Current Advancements.
    Anthony Gutierrez, Robert Eil.
      Chimeric antigen receptor (CAR T-cell) therapy has revolutionized outcomes in hematologic cancers, yet translation to solid tumors remains limited by safety and efficacy barriers. Antigen overlap between malignant and normal tissues leads to on-target, off-tumor toxicity, while the immunosuppressive tumor microenvironment restricts trafficking, persistence, and cytotoxicity. Locoregional approaches further aim to optimize delivery. This review highlights that improved antigen selection, rigorous trial design, and multidisciplinary collaboration will be required to successfully integrate CAR T-cell therapy into the care of patients with solid tumors.
    Keywords:  CAR T-Cell; Engineering; Immunotherapy; Microenvironment; Neoplasm; Solid tumors
    DOI:  https://doi.org/10.1016/j.soc.2025.10.001
  7. Int J Hematol. 2026 Apr 04.
    Recent advances in CAR T and CAR NK cell therapy for AML.
    Makiko Suga, Naoki Hosen.
      CAR T cell therapy has demonstrated remarkable efficacy in treating haematological malignancies, including B-cell lymphomas, B-cell leukaemias, and multiple myeloma. CAR T cell therapy for acute myeloid leukaemia (AML) is also urgently needed. One of the major challenges is identifying AML-specific antigens, since many potential candidates (e.g. CD33, CD123, CLL-1, CD70, TIM-3 and FLT3) are also expressed on normal haematopoietic progenitors. This can lead to 'on-target/off-tumour' toxicity and bone marrow aplasia. CAR NK cell therapy for AML shows promise as a lower-toxicity, off-the-shelf alternative. NK cells have a lower inherent risk of GVHD and may cause milder CRS/ICANS. In this review, we will describe the current status of CAR T/NK cell development for AML. We will also introduce a new CAR T-cell or NK-cell therapy that targets mismatched HLA-DRB1 in patients with AML who have relapsed following an allogeneic haematopoietic stem cell transplant.
    Keywords:  AML; CAR NK cells; CAR T cell
    DOI:  https://doi.org/10.1007/s12185-026-04203-4
  8. Biomed Pharmacother. 2026 Mar 30. pii: S0753-3322(26)00333-1. [Epub ahead of print]198 119300
    Combining CRISPR/Cas9-mediated TRAC knockout with mRNA-based CAR expression enables flexible generation of allogeneic CAR T cells.
    Thanyaporn Buakaew, Rattapoom Thaiwong, Thananya Inthanachai, Tanapat Palaga, Drew Weissman, Koramit Suppipat, Chatchanan Ausavarungnirun, Supannikar Tawinwung.
       BACKGROUND: Autologous chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in hematologic malignancies but remain limited by complex manufacturing processes. Allogeneic, off-the-shelf CAR T cells derived from healthy donors represent a promising alternative; however, safe implementation requires elimination of endogenous T-cell receptor (TCR) expression and flexible CAR expression strategies.
    OBJECTIVE: This study aimed to develop an optimized manufacturing workflow for allogeneic CAR T cells by combining CRISPR/Cas9-mediated TCR knockout with mRNA-based CAR expression, and to evaluate cryopreservation strategies enabling on-demand CAR T-cell generation.
    METHODS: Healthy donor T cells were edited at the TRAC locus using CRISPR/Cas9 to generate TCR-deficient T cells. These cells were cryopreserved and subsequently transfected with mRNA encoding CD117, BCMA, or CD19 CARs. CAR expression, cell viability, immunophenotype, cytokine secretion, and antigen-specific cytotoxicity were assessed under different cryopreservation-transfection conditions.
    RESULTS: TCR knockout T cells exhibited efficient TCR disruption with reduced alloreactive proliferation. CD117 mRNA CAR T cells derived from TCR-deficient T cells demonstrated CAR expression kinetics, immunophenotypic profiles, and antigen-specific cytotoxicity comparable to wild-type CAR T cells. Evaluation of two cryopreservation strategies revealed that cryopreservation prior to mRNA electroporation preserved cell viability, phenotype, and cytotoxic function, whereas cryopreservation after mRNA transfection was associated with reduced functional activity. The optimized protocol was successfully extended to CD19- and BCMA-targeting CAR mRNAs.
    CONCLUSION: Collectively, these findings establish a modular platform for producing allogeneic CAR T cells using mRNA technology, offering a practical approach for rapid, on-demand CAR T-cell therapy.
    Keywords:  CAR-T cells; CRISPR/Cas9; MRNA; TCR-negative T cells
    DOI:  https://doi.org/10.1016/j.biopha.2026.119300
  9. Chin Med J (Engl). 2026 Mar 30.
    Chimeric antigen receptor T-cell therapies related to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: Diagnosis, high-risk factors, and management.
    Yixuan Zhang, Jilong Yang, Huiqi Xin, Kexin Ai, Mengsu Yang, Yuhua Li, Yanjie He.
       ABSTRACT: Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a life-threatening complication of chimeric antigen receptor T cell (CAR-T) therapy. Despite its high mortality rate, IEC-HS remains underrecognized due to overlapping clinical and laboratory features with severe cytokine release syndrome (CRS), leading to delayed diagnosis and suboptimal management. This review systematically analyzes key strategies to distinguish IEC-HS from severe CRS in the literature. The analysis focuses on temporal patterns, such as the delayed onset of IEC-HS after CAR-T infusion. It also examines dynamic laboratory trends, including persistently elevated ferritin and lactate dehydrogenase levels and a slower decline in C-reactive protein (CRP). In addition, distinct cytokine profiles are discussed, such as prolonged interferon-gamma (IFN-γ) elevation and surges in chemokines and growth factors. We further identify high-risk factors for IEC-HS, including patient-specific factors (baseline inflammation, low natural killer [NK] cell counts), disease-related factors (high B-cell acute lymphoblastic leukemia [B-ALL] burden and prior high-grade CRS), and CAR-T-related factors (CD22 target, CD28 costimulation, T-cell selection, high CAR-T cell dose, excessive CAR-T cell expansion, and TET2 gene mutation). For management, we evaluate conventional therapies (corticosteroids, etoposide) and emerging immunomodulatory agents (anakinra, ruxolitinib, emapalumab), emphasizing the 2023 treatment regimen by the American Society of Transplantation and Cellular Therapy (ASTCT). By integrating risk stratification, early diagnostic criteria, and tailored therapeutic approaches, this review aims to improve clinical outcomes for IEC-HS patients.
    Keywords:  Adverse events; Chimeric antigen receptor T cell; Cytokine antagonists; Cytokine release syndrome; Hemophagocytic lymphohistiocytosis; Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome; Immune-related adverse events
    DOI:  https://doi.org/10.1097/CM9.0000000000004066
  10. J Immunother Cancer. 2026 Apr 01. pii: e014670. [Epub ahead of print]14(4):
    Highlights in IO: next-generation CAR-T therapy for glioblastoma.
    Junya Yamaguchi, Hideho Okada.
      Over the past few years, outcomes and findings from several phase 1 clinical trials evaluating chimeric antigen receptor (CAR)-T cell therapies for glioblastoma (GBM) have been reported. For CAR-T cell therapy to succeed in GBM, several challenges must be overcome, including the immunosuppressive microenvironment (immunosuppressive cells, hypoxia, and metabolic constraints), antigen heterogeneity, and the anatomically isolated environment. To address these challenges, next-generation CAR-T cells-those engineered with additional functionalities-have been developed, and phase 1 clinical trials evaluating these next-generation CAR-T therapies for GBM have now been initiated. The development of CAR-T therapy for GBM has entered a new chapter. To date, the antitumor efficacy of CAR-T therapies still needs to be improved, and the high frequency of neurotoxicity remains a major issue that needs to be addressed; however, there is a growing anticipation that next-generation CAR-T therapies may provide clinical benefit to patients.
    Keywords:  Adoptive cell therapy - ACT; Central Nervous System Cancer; Chimeric antigen receptor - CAR; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2025-014670
  11. Trends Biotechnol. 2026 Apr 01. pii: S0167-7799(26)00091-0. [Epub ahead of print]
    Shaping cell therapy manufacturing with metabolic understanding and control.
    Constança M Costa, Ana Paula Terrasso, Marta H G Costa, Paula M Alves, Margarida Serra.
      The clinical efficacy of cell therapy products is intrinsically related to their state of differentiation and maturity. However, current approaches to target cell phenotype and potency lack efficacy, scalability, and cost-effectiveness. Metabolism is a key driver of cell fate, a characteristic that can be explored to design bioprocesses yielding functional cell therapy products. Here, we review recent studies focused on exploring metabolic shifts to improve cell potency and discuss how these strategies can contribute to accelerating bioprocess development and benefit from their translation into scalable, tightly controlled, and affordable manufacturing workflows.
    Keywords:  cell therapy; immunotherapy; manufacturing; metabolic control; process analytical technology
    DOI:  https://doi.org/10.1016/j.tibtech.2026.03.006
  12. Ther Adv Neurol Disord. 2026 ;19 17562864261426816
    Economic value of anti-CD20 therapies in multiple sclerosis: a systematic review of cost-effectiveness studies.
    Johannes Heinemann, Marco Zirkel, Oliver Schoeffski, Rick Dersch, Heinz Wiendl.
       Background: Disease-modifying therapies (DMTs) have transformed multiple sclerosis (MS) care but are associated with substantial costs. Among high-efficacy DMTs, anti-CD20 antibodies are widely used, yet their economic value, particularly compared with different classes of DMTs, has not been comprehensively synthesized.
    Objective: To systematically review evidence on the cost-effectiveness of anti-CD20 antibodies compared with other DMTs or best supportive care (BSC) in MS.
    Data sources and methods: We searched PubMed, Embase, Web of Science, and International Network of Agencies for Health Technology Assessment (July 2025) for cost-effectiveness analyses comparing rituximab, ocrelizumab, ofatumumab, or ublituximab with other DMTs or BSC. Two reviewers independently screened studies, extracted data, and assessed reporting quality using the Consolidated Health Economic Evaluation Reporting Standards 2022 checklist. All costs were converted to 2024 US dollars and adjusted for inflation.
    Results: Of 92 records screened, 20 studies met inclusion criteria. Analyses were conducted in diverse but mostly high-income regions, most commonly using Markov models with long time horizons. Anti-CD20 antibodies were dominant (more effective, less costly) or cost-effective in the majority of studies, particularly when compared with platform therapies. In contrast, comparisons with other high-efficacy DMTs yielded more heterogeneous results, with immune reconstitution therapies more cost-effective in several studies. Reporting quality was generally high, although patient involvement, assessment of heterogeneity, and a health economic analysis plan were rarely addressed.
    Conclusion: These findings support the use of anti-CD20 antibodies as an economically reasonable option in many healthcare settings, particularly when compared with platform therapies, while underscoring that cost-effectiveness relative to other high-efficacy treatments is context-dependent. The lack of data from low- and middle-income countries and limited transparency in Health Technology Assessment reports represent major limitations. Future research should prioritize context-specific evaluations and promote full disclosure of economic data to strengthen the evidence base for clinically and economically informed reimbursement decisions in MS.
    Trial registration: The study was prospectively registered with PROSPERO (ID: CRD420251109958).
    Keywords:  anti-CD20 antibodies; cost-effectiveness; health technology assessment; multiple sclerosis; ocrelizumab; ofatumumab; rituximab
    DOI:  https://doi.org/10.1177/17562864261426816
  13. J Natl Compr Canc Netw. 2026 Mar 31. pii: CLO26-108. [Epub ahead of print]24(3.5):
    CLO26-108: Efficacy of CAR T Cell Therapy in Extranodal and Nodal Large B-Cell Lymphoma.
    Salman J Khan, Hamza Usman, Seemab Sheikh, Mahuri Yalamanchili.
      
    DOI:  https://doi.org/10.6004/jnccn.2025.7213
  14. Surg Oncol Clin N Am. 2026 04;pii: S1055-3207(25)00098-5. [Epub ahead of print]35(2): 191-205
    T-Cell Receptor Engineered T-Cell Therapy: A Rapidly Evolving Treatment Paradigm for Solid Tumors.
    Stav Leibou, Aaron J Dinerman, Nicholas D Klemen.
      Peripheral blood lymphocytes can be engineered to express T-cell receptors (TCRs) that recognize human leukocyte antigen (HLA)-restricted cancer antigens and subsequently administered systemically as TCR-T cell therapy. A growing repertoire of tumor-exclusive antigens including cancer germline antigens, viral oncoproteins, and neoantigens has led to a broadening potential applicability of this targeted approach in patients with solid tumors. While TCR-T cell therapy has already demonstrated clinical efficacy in trials of patients with metastatic melanoma and certain sarcomas, it is now emerging as a promising investigational therapy for mismatch repair proficient epithelial cancers.
    Keywords:  Adoptive cell transfer; Cancer immunotherapy; Immuno-oncology; TCR-T cells
    DOI:  https://doi.org/10.1016/j.soc.2025.12.001
  15. Front Oncol. 2026 ;16 1768614
    Review of advances in CAR-T therapies in malignant hematology.
    Neda Amirmokhtari, Forat Lutfi.
      There have been numerous advancements in immune cell effector therapies in the malignant hematology space. This review article explores the pivotal studies that led to the approval of chimeric antigen receptor T-cell (CAR-T) therapies for hematologic malignancies and highlights available associated long-term and real-world data. It also examines the mechanisms of resistance and potential novel therapies to overcome these mechanisms.
    Keywords:  AES; acute lymphoblastic B-cell leukemia; adverse events; anti-CD19 CAR-T therapy; auto-CARTs; lymphoma - diagnosis
    DOI:  https://doi.org/10.3389/fonc.2026.1768614
  16. Am J Med Sci. 2026 Mar 27. pii: S0002-9629(26)00119-9. [Epub ahead of print]
    CAR T cells engineered against LAG-3: Unleashing potency in the tumor microenvironment of breast cancer.
    Mohammad A I Al-Hatamleh, Mahasin Hamid, Monika Vashisht, Ma'mon M Hatmal, Ali Mussa.
      Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematologic malignancies but faces significant challenges in solid tumors such as breast cancer. A primary obstacle is the immunosuppressive tumor microenvironment (TME), which drives T-cell exhaustion and limits therapeutic efficacy. Lymphocyte-activation gene 3 (LAG-3) is a key mediator of this exhaustion, suppressing antitumor immunity upon engagement with ligands such as MHC class II. This review examines the rationale for targeting the LAG-3 pathway to enhance CAR T cell potency within the breast cancer TME. We critically evaluate emerging bioengineering strategies designed to counteract LAG-3-mediated suppression, focusing on two complementary approaches: (1) armored CAR T cells engineered to secrete anti-LAG-3 antibody fragments locally within the TME, and (2) CAR T cells modified to express dominant-negative LAG-3 receptors or with LAG-3 genetically ablated, conferring intrinsic resistance to this inhibitory axis. By combining precise tumor recognition with localized or intrinsic checkpoint disruption, these next-generation therapies aim to enhance T-cell persistence, proliferative capacity, and cytotoxic function. Interrupting LAG-3 signaling represents a transformative strategy to reverse TME-driven immunosuppression, offering the potential for more durable clinical responses in breast cancer. Translating this promise into reality will require rigorous preclinical validation and innovative clinical trial designs.
    Keywords:  CAR T cell therapy; Cancer immunotherapy; Chimeric antigen receptor; LAG-3; Personalized medicine; TME
    DOI:  https://doi.org/10.1016/j.amjms.2026.03.016
  17. Transplant Cell Ther. 2026 Mar 31. pii: S2666-6367(26)00253-8. [Epub ahead of print]
    Value‑Based Contracting for Cell and Gene Therapies: A Scoping Review of Payer-Manufacturer Agreements and Treatment‑Center Considerations in USA.
    Pranav M Patel, Amy Heck Sheehan, Cynthia Wan, Jason B Reed, Iulia Opran, Amber Small, Chelsea Phillips Renfro.
       BACKGROUND: Cell and gene therapies (CGTs) offer the potential for durable or curative outcomes, but come with high upfront costs and uncertainty about long-term safety and effectiveness. To address these challenges, manufacturers and payers have expressed sustained interest in value-based contracts (VBC), which tie reimbursement to real-world outcomes. While publicly disclosed VBCs have been most visible around earlier CGT launches, details on their structure, assessed outcomes, and operational execution remain limited. For treatment centers, understanding this landscape is important because they are well positioned to support data collection, outcome measurement, and validated reporting in the future. These areas represent some of the most commonly cited challenges among manufacturers and payers, suggesting a potential opportunity for treatment centers as uptake of VBCs is anticipated to increase.
    OBJECTIVE: To review publicly reported VBCs between payers and CGT manufacturers in the United States and characterize outcomes assessed, implementation features, reporting gaps, and implications for treatment center involvement.
    STUDY DESIGN: A scoping review of peer-reviewed publications and press releases (January 2017-January 23, 2026) describing VBCs involving CGTs was conducted across seven databases - PubMed, Embase, International Pharmaceutical Abstracts, ABI/INFORM, Factiva, Newspaper Source Plus, and Regional Business News. Included articles described real-world VBCs between manufacturers and payers in the United States (US) and written in English. Exclusion criteria included VBCs between stakeholders other than manufacturers and payers, and VBCs implemented in countries other than the US. Extracted elements included therapy type, payer/manufacturer involvement, outcome measures, contract structure, and any disclosed adjudication.
    RESULTS: Of 1,324 screened records, 16 studies/ press releases met inclusion criteria, describing 23 VBCs across conditions such as spinal muscular atrophy, sickle cell disease, beta-thalassemia, inherited retinal disorders, hemophilia, acute lymphoblastic leukemia, and rare metabolic and dermatologic diseases. Most VBCs involved Medicaid and commercial payers (e.g. Cigna, Harvard Pilgrim Health Care). Reported outcomes focused on patient-level milestones tied to clinical benefit; for example, early remission status, improvement in functional visual testing, sustained transfusion independence, or the need to resume prophylaxis over pre-specified time windows (ranging from one month to five years). Considerable variability was observed across contracts in terms of outcome definitions, assessment time horizons, and contractual structures. Additionally, no contracts disclosed how these outcomes were assessed; adjudication processes, third-party roles, or contract performance results, leaving practical implementation details largely unknown.
    CONCLUSION: Current VBCs for CGTs show substantial variability and minimal reporting, offering limited insight into outcome definitions, assessment timing, or how models are implemented in practice. As broader interest in VBCs continues, treatment centers may have an opportunity to help address implementation and outcome-measurement challenges frequently cited by payers and manufacturers. Their experience with clinical assessment, longitudinal follow-up, and existing CGT program operations could help inform feasible, clinically meaningful approaches to scale adoption of VBCs.
    Keywords:  Cell and gene therapy; outcomes-based agreements; payer–manufacturer agreements; treatment centers; value-based contracting
    DOI:  https://doi.org/10.1016/j.jtct.2026.03.037
  18. Cancer Immunol Immunother. 2026 Apr 02. pii: 133. [Epub ahead of print]75(4):
    Metformin drives HIF-1α-mediated dual metabolic reprogramming to enhance γδ T cell therapy in triple-negative breast cancer.
    Xuping Qin, Haowen Zhong, Meize Liu, Tiantian Yu, Rong Ma, Ying Zhou, Jingyu Chen, Fen Liu, Xiwei Wang, Jianting Long.
      Triple-negative breast cancer (TNBC) lacks effective targeted treatments, rendering γδ T cell immunotherapy a promising therapeutic strategy. However, the function of these immune cells is often limited by exhaustion and immunosuppression. This study investigated whether metformin can enhance γδ T cell-mediated immunity against TNBC. Results demonstrated that metformin increased the cytotoxicity, proliferation, and cytokine production of γδ T cells while reducing their exhaustion markers. It differentially modulated cellular metabolism by enhancing oxidative phosphorylation (OXPHOS) and glycolysis in γδ T cells while suppressing these pathways in cancer cells through AMPK-HIF1-α signaling. Metformin also upregulated stress ligands on tumor cells, thereby improving immune recognition. In chemoresistant models, metformin restored γδ T cell function. Clinical data further showed that high AMPK activity and increased γδ T cell infiltration were associated with improved patient survival. These findings indicate that metformin remodels immunometabolism and enhances tumor immunogenicity, supporting its potential as a combinatory agent in γδ T cell-based immunotherapy for TNBC.
    Keywords:   γδ T cells; Metabolic reprogramming; Metformin; TNBC
    DOI:  https://doi.org/10.1007/s00262-026-04351-w
  19. Best Pract Res Clin Rheumatol. 2026 Apr 01. pii: S1521-6942(26)00028-8. [Epub ahead of print] 102143
    CAR T-cell therapy and indications for pediatric rheumatology: Structured overview of applications, risks, and considerations.
    Kali Chiriboga, Pooja N Patel, Hermine I Brunner.
      This chapter offers an overview of CAR T-cell therapy and its emerging role in pediatric rheumatology, particularly the potential impact on severe refractory autoimmune conditions in children. It examines criteria for patient eligibility, safety concerns, and potential long-term effects for young rheumatology patients, while stressing the importance of personalized and prolonged follow-up. The possibility of achieving drug-free remission in pediatric cases appears to be a possible in refractory patients; however, further studies should focus on standardizing pre-treatment protocols for children with rheumatic diseases, reducing the intensity of conditioning regimens, and implementing extended surveillance to assess therapy duration and lasting outcomes.
    Keywords:  Autoimmune diseases; CAR T-cell therapy; Childhood onset systemic lupus erythematosus; Drug free remission; Juvenile dermatomyositis; Juvenile systemic sclerosis; Pediatric rheumatology
    DOI:  https://doi.org/10.1016/j.berh.2026.102143
  20. Int J Technol Assess Health Care. 2026 Mar 30. 42(1): e31
    Health technology assessment in Eastern Europe and Central Asia: an updated SWOT analysis.
    Rabia Sucu, Antonio Migliore, Nicola Vicari, Esra Meltem Koç, Alima Almadiyeva.
      Health technology assessment (HTA) is increasingly recognized as a critical tool for evidence-informed decision-making in Eastern Europe and Central Asia (EECA), a region characterized by substantial diversity in health system maturity, financial resources, and institutional capacities. Building on the previous Eurasian HTA Initiative conducted a decade earlier, this study aimed to update the regional assessment of HTA implementation, expand country representation, and identify evolving strengths, weaknesses, opportunities, and threats affecting the advancement of HTA across the region. An online multilingual survey, informed by the original SWOT framework, was disseminated between August and October 2025 to experts from national authorities, HTA agencies, academia, and health sector stakeholders across eleven EECA countries. Twenty-two responses were analyzed descriptively. Key strengths included strong regional collaboration interest, growing availability of online HTA resources, and sustained global support. Major weaknesses centered on the limited trained HTA/EBM personnel and the absence of standardized national training programs. Opportunities reflected expanding interest in EBM, pressure from rising healthcare costs, and prospects for regional advocacy, educational exchanges, and international collaboration. Principal threats involved insufficient funding for capacity building, low policy-maker and clinician awareness, commercial influence from industry, and limited incentives for EBM uptake. Overall, respondents emphasized gradual progress in selected areas but persistent structural barriers requiring coordinated national and regional action.
    Keywords:  EECA; Health technology assessment; SWOT; evidence-based decision making; regional collaboration
    DOI:  https://doi.org/10.1017/S0266462326103614
  21. Front Pharmacol. 2026 ;17 1749386
    Addressing clinical uncertainties in ATMP reimbursement: a review of methodological guidelines and European practice.
    Lotte Delemarre, Isabelle Huys, Walter Van Dyck, Steven Simoens.
       Introduction: Advanced Therapy Medicinal Products (ATMPs) often present substantial clinical uncertainties at the time of reimbursement evaluation, particularly due to the lack of appropriate comparators and the absence of long-term clinical endpoints. This study primarily examined two methodological areas relevant to these challenges: indirect treatment comparisons (ITCs) and surrogate endpoints. In addition, the review was supplemented with an assessment of innovative trial designs to explore how emerging approaches may contribute to evidence generation for ATMPs.
    Methods: A structured literature review was conducted using PubMed and Embase, combining keywords such as "Health Technology Assessment," "ATMP," "Indirect Treatment Comparison," and "Surrogate Endpoint," supplemented with grey literature searches. European pharmacoeconomic guidelines were analyzed using the ISPOR database and referenced national documents.
    Results: By April 2025, 27 ATMPs had received European Medicines Agency approval; 20 relied on single-arm trials, and 19 used surrogate endpoints. Single-arm trials limit direct comparative effectiveness assessment, requiring alternative approaches such as ITCs. Conventional ITCs need a common comparator, which is unavailable in single-arm evidence, while population-adjusted indirect comparisons (PAICs) offer a potential solution but depend on strong assumptions and are sensitive to unmeasured confounding. Guidelines generally accept the use of ITCs when direct comparative evidence is unavailable. However, they provide limited guidance on the separate question of when RCTs should be considered infeasible. Surrogate endpoints are widely used due to curative aims of ATMPs, but their validation typically requires RCT evidence and is highly context-specific. Guideline acceptance criteria for surrogate endpoints vary. Some require robust validation demonstrating a causal relationship, while others allow correlation-based or context-specific justification, particularly when direct evidence is limited or the technology addresses rare or serious conditions. Innovative trial designs may help generate more robust evidence in these challenging contexts.
    Discussion: The study highlights the need to refine methods for handling single-arm trials, projecting long-term outcomes, and using surrogate endpoints in ATMP evaluations. While some clinical uncertainty is inevitable, healthcare systems must manage it effectively to ensure timely, equitable access without creating additional barriers.
    Keywords:  advanced therapy medicinal products; health technology assessment; indirect treatment comparison; reimbursement; surrogate endpoint
    DOI:  https://doi.org/10.3389/fphar.2026.1749386
  22. Blood. 2026 Apr 02. 147(14): 1509-1510
    Access to CAR T-cell therapy across diverse global markets.
    Kristina Jenei.
      
    DOI:  https://doi.org/10.1182/blood.2025032585
  23. Front Immunol. 2026 ;17 1772472
    IFNγ-induced antigen loss in chimeric antigen receptor-T cell therapy.
    Miao Cao, Jasmine Alvarez, Ramkrishna Mitra, Michael Xu, Trevor R Baybutt, Zhengyang Sun, Oluwatobiloba Taylor, Allison S Doermann, Ross E Staudt, Scott A Waldman, Adam E Snook.
       Introduction: FDA-approved chimeric antigen receptor (CAR)-expressing T cell therapies (CARTs) have revolutionized the treatment of blood cancers. Yet none have been successful for "solid" tumors, such as colorectal cancer (CRC), the 2nd leading cause of cancer deaths. Guanylyl cyclase C (GUCY2C) has emerged as a clinical-stage target for CART and bispecific T-cell engager (BiTE) therapies in CRC. IFNγ has been canonically recognized as beneficial for the effector functions of T cells by enhancing antigen processing and HLA presentation and is essential for CART targeting of solid malignancies by inducing adhesion molecule expression for synapse stabilization.
    Methods: Using in vitro co-culture systems, conditioned media experiments, cytokine screening, pharmacologic inhibition, CRISPR-Cas9 knockout, and transcriptomic analyses, we investigated mechanisms of GUCY2C antigen loss in CRC cells exposed to activated CART cells.
    Results: We identified a novel antigen loss mechanism that limits the efficacy of CART in CRC, in which IFNγ secreted by activated CART cells causes bystander cancer cells to lose GUCY2C. This previously unexplored antigen loss mechanism is mediated through IFNγ receptor, JAK, and cellular stress signaling pathways. This mechanism of antigen loss can be rescued with anti-IFNγ neutralizing antibody, the JAK inhibitor ruxolitinib, or 4-phenylbutyrate (an ER stress reliever).
    Discussion: We revealed a negative effect of IFNγ that uniquely interferes with immunotherapies targeting native surface antigens, such as CART and BiTE therapies, which may be reversed by disrupting stress signaling pathways to enhance solid tumor CART and BiTE immunotherapies.
    Keywords:  CAR-T cell; GUCY2C; IFNγ; antigen escape; colorectal cancer; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1772472
  24. Trends Pharmacol Sci. 2026 Apr 01. pii: S0165-6147(26)00042-8. [Epub ahead of print]
    Programmable CAR immunotherapies for neurodegenerative proteinopathies.
    Giulia Pesce, Marc Estivill-Alonso, Salvador Ventura.
      Abnormal protein aggregation and a dysregulated neuroimmune environment are defining features of many neurodegenerative disorders. In Alzheimer's disease, systemic monoclonal antibodies against amyloid-β provide proof of principle that immunotherapy can modify disease trajectory. However, clinical benefit is limited by low brain exposure, short-lived activity, the need for repeated dosing, and inflammation-linked toxicity. Building on transformative clinical success in oncology, chimeric antigen receptor (CAR) immunotherapies offer a complementary approach to address these limitations, combining the molecular precision of antibody-derived binders with the versatility and persistence of engineered immune cells. These technologies are being explored for central nervous system (CNS) proteinopathies, where they can couple the selective recognition of pathogenic proteoforms to immune programs that are compatible with the CNS's low tolerance for collateral inflammation. Here, we review CAR strategies for aggregate-selective targeting and explore how to incorporate tunable controls and safety mechanisms. Finally, we examine how distinct CAR-engineered effector cell types may modulate key processes in neurodegeneration, from aggregate clearance to immune rebalancing. Together, these advances define CAR design principles for durable, programmable, and targeted immunomodulation in neurodegenerative disease.
    Keywords:  CAR design; cell-based therapies; chimeric antigen receptors; disease-modifying therapies; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.tips.2026.02.009
  25. Pharmacoeconomics. 2026 Apr 02.
    What is the Value of Developing an HTA Process?
    Peter Murphy, Simon Walker, Septiara Putri, Mark Sculpher, Susan Griffin.
      Health technology assessment (HTA) processes are becoming increasingly established and embedded in healthcare decision making around the world. Yet, there is limited evidence on whether HTA processes at the system level offer value for money to those presiding over their creation, such as governments and ministries of health. That is, whether the value of improvements in the health system exceed the costs. To address this issue, we outline the approaches adopted in a sample of recent evaluations of HTA systems and propose a set of considerations for measuring and valuing HTA processes. The scale and remit of the process can help identify the relevant system-level impacts of HTA such as those on productive efficiency and population health, health equity, guiding innovation and care pathways, and broader impacts. We further describe the methodological challenges and potential approaches to evaluating HTA including the appropriateness of approaches. The considerations discussed can reveal the potential for ill-designed HTA processes to generate less social value than intended.
    DOI:  https://doi.org/10.1007/s40273-026-01613-4
  26. Value Health. 2026 Mar 30. pii: S1098-3015(26)00113-0. [Epub ahead of print]
    A roadmap to embedding real-world evidence into Health Technology Assessment processes for cancer medicines: experiences from Scotland.
    Cancer Medicines Outcomes Programme-Public Health Scotland team
       OBJECTIVES: To describe the development of a robust, sustainable pathway for the generation of real-world evidence (RWE) for cancer medicines, and how this was embedded into routine Health Technology Assessment (HTA) processes in Scotland to support decision-making.
    METHODS: Requirements were agreed between Scotland's HTA body (Scottish Medicines Consortium, SMC) and Cancer Medicines Outcomes Programme-Public Health Scotland (CMOP-PHS). Nationally held administrative healthcare data is used to estimate patient numbers and identify comparator treatments. An educational workshop was held for SMC staff to explain CMOP-PHS reports. Feedback was sought from SMC assessors via an online form aimed at understanding the informativeness of CMOP-PHS reports and findings.
    RESULTS: Out of 13 requests made by SMC between February and July 2025, CMOP-PHS provided RWE reports for eight (61.5%) cancer medicine assessments: seven initial assessments, and one reassessment. Reports provided information on the number of patients being treated for the indication of interest in the last 12 months; the regimens used for treatment; and patient characteristics. Reasons for not providing RWE related to data completeness/granularity and insufficient patient numbers. Feedback indicated positive experiences; all responses (n=13) confirmed that CMOP-PHS's work was informative. Respondents most strongly agreed that information on the number of patients treated for the same conditions in the last 12 months, and information on current comparator treatments, were helpful.
    CONCLUSIONS: CMOP-PHS has developed a rigorous, standardised approach for providing RWE to inform cancer HTA, which is now firmly embedded into SMC processes. Future developments are aimed at further improving data availability and quality.
    Keywords:  Health technology assessment; Scotland; cancer; real-world data; real-world evidence
    DOI:  https://doi.org/10.1016/j.jval.2026.03.011
  27. Trends Immunol. 2026 Mar 27. pii: S1471-4906(26)00040-2. [Epub ahead of print]
    Seven subsets, two fates: mouse γδ T cells in cancer immunity.
    Abhiram C T Mallu, Natalie Z Phinney, Federico Lupo, Seth B Coffelt.
      The importance of γδ T cells in cancer, as defenders against tumorigenesis, was established more than 2 decades ago. Since that time, research using mouse models of cancer has brought to light a nonuniform view of tumor-associated γδ T cells by providing granularity into the role of individual γδ T cell subsets in specific cancer types. In this review, we discuss data that highlight the unique contributions of Vγ1+, Vγ4+, Vγ5+, Vγ6+, and Vγ7+ cells throughout cancer progression. We delve into their responses to tumors, including both protective and pathogenic functions. We examine how the mechanisms by which these mouse immune cell subsets shape tumor development and spread can be exploited for therapeutic purposes in people with cancer.
    Keywords:  cancer; metastasis; mouse models; γδ T cells
    DOI:  https://doi.org/10.1016/j.it.2026.02.009
  28. J Nanobiotechnology. 2026 Apr 02.
    In vivo CAR-T therapy: from molecular design to precision delivery.
    Huixian Li, Wenjing Wen, Xuan Zhao, Gaofeng Liang.
      In 2017, the United States Food and Drug Administration (FDA) granted the inaugural approval of chimeric antigen receptor T cell (CAR-T) therapy, marking the advent of a new era in cancer immunotherapy. However, the conventional ex vivo CAR‑T cell manufacturing workflow is complex and time consuming, resulting not only in high treatment costs and limited patient access, but also in effector differentiation of T cells and upregulation of exhaustion markers during prolonged in vitro expansion, which may impair the durability and antitumor activity of the cell product and reduce therapeutic efficacy. To enhance the efficacy and accessibility of CAR-T therapy, the strategy of in vivo generation of CAR cells has emerged as a prominent research focus, notwithstanding substantial technical challenges and its broad prospects. This review systematically summarizes the latest advances, technical challenges, and future trends of in vivo CAR-T therapy, with an emphasis on CAR mRNA molecular design, structural modifications, advancements in gene delivery technologies, and clinical applications, aiming to provide a comprehensive reference for related research.
    Keywords:  Construction; Gene Delivery; Immunotherapy; In vivo CAR-T
    DOI:  https://doi.org/10.1186/s12951-026-04232-5
  29. Value Health Reg Issues. 2026 Mar 31. pii: S2212-1099(26)00030-0. [Epub ahead of print] 101616
    Real-World Evidence in Action: A Comprehensive Environmental Scan of Real-World Evidence Use in Health Technology Assessments Submitted to Canada's Drug Agency From 2020 to 2024.
    Ghayath Janoudi, Russanthy Velummailum, Cal Shephard, Eon Ting, Paul Arora, Winson Y Cheung.
       OBJECTIVES: To characterize real-world evidence (RWE) in Canada's Drug Agency (CDA-AMC) submissions, describe its designs and purposes, and summarize the agency/committee views on its use.
    METHODS: We conducted a comprehensive environmental scan of the CDA-AMC website to retrieve all reports and recommendations of reimbursement review submissions published between January 2020 and June 2024. RWE utilization was classified by therapeutic area, study design, geographic data source, and intended purpose. Reviewer and committee comments were thematically coded.
    RESULTS: Of the 294 submissions screened, 274 were included in this study. A total of 70 submissions (25.5%) contained RWE. These submissions cited 113 distinct real-world data/RWE sources, namely: retrospective cohorts (58%), prospective cohorts (20%), and other designs (22%). Geographic origin was predominantly the United States (39%) or Europe (38%); only 12 sources (11%) were Canadian. RWE often informed comparative effectiveness (54%) and evidence gaps (52%). Reviewer critiques focused on data quality (70%) and generalizability (61%); lack of Canadian data was identified in 50% of submissions. Within the Canadian subgroup, generalizability concerns decreased (40%), but data quality issues remained common (70%). A total of 83% of submissions received "reimburse with conditions" recommendations.
    CONCLUSIONS: RWE has become routine in CDA-AMC submissions, yet remains largely non-Canadian and limited in its applicability. More formal guidance on transportability analyses, quantitative bias assessment, and improved standards across clinical and economic domains could enhance evidence generation, submission quality, and health technology assessment confidence in clinical and pharmacoeconomic information. These findings may inform ongoing refinement of RWE checklists and expectations, providing a benchmark against which future use of RWE can be measured and tracked.
    Keywords:  CDA-AMC; drug reimbursement; environmental scan; health technology assessment; real-world evidence
    DOI:  https://doi.org/10.1016/j.vhri.2026.101616
  30. iScience. 2026 Apr 17. 29(4): 115246
    Perfusion microbioreactor for CAR-Treg manufacturing.
    William Edwards, Ningjia Sun, Yikai Wang, Yuhan Lu, Cong Wang, Daniela Mastronicola, Cristiano Scottà, Marco Romano, Cesare M Cejas, Antoine Espinet, Giovanna Lombardi, Ciro Chiappini.
      Manufacturing cell and gene therapies (CGTs) at scale presents challenges in cost, product consistency, and adaptability to personalized treatments. Traditional large-volume bioreactors are designed to support cell growth through controlled nutrient delivery and gas exchange, but are poorly suited to the decentralized, small-batch production required for personalized therapies such as chimeric antigen receptor (CAR) T cells. To address this, we have developed the KCL-Microbioreactor (K-MBR), a closed microbioreactor platform based on microfluidic principles. Engineered in polydimethylsiloxane (PDMS), the K-MBR combines spatial confinement, semi-continuous perfusion, and integrated viral transduction in a compact footprint, enabling efficient gene delivery and robust expansion of therapeutic cells. We demonstrate the platform's utility by generating functional CAR-Tregs targeting HLA-A2, achieving a 92% increase in yield compared to conventional methods. The K-MBR offers a streamlined solution for CGT manufacturing, with potential to reduce production costs and enhance scalability across a broad range of cell therapies.
    Keywords:  Biological sciences
    DOI:  https://doi.org/10.1016/j.isci.2026.115246
  31. JCO Glob Oncol. 2026 Apr;12(4): e2500524
    China's Growing Importance in Global Cancer Medicines.
    Zhihao Xu, Richard Sullivan, Kristina Jenei, Jian Wang, Jialong Tan.
      Following the global shift toward innovation-driven cancer care, China has rapidly transformed its cancer medicine research, development, regulation, and financing systems over the past decade. This review aims to provide a comprehensive understanding of these transformations from the perspective of China's unique market-government coordination. This review applies an integrative framework that combines historical development, regulatory reforms, market access mechanisms, and affordability strategies. It traces the evolution of China's cancer medicine research and development-from sporadic imitation in the mid-20th century to a globally competitive innovation ecosystem-accelerated by the 2015 drug regulatory reform and subsequent international harmonization. It further examines the interaction among regulatory oversight, pricing mechanisms, and health insurance coverage and evaluates policy tools such as self-evaluation scoring, National Reimbursement Drug List negotiations, and volume-based procurement. China's reform-driven policies have enhanced both innovation and accessibility. Pricing and procurement mechanisms have expanded patient access while containing costs, and multilayered financing arrangements-combining basic medical insurance, targeted medical aid, and city-based private insurance-have improved affordability and sustainability for high-cost cancer medicines. Despite substantial progress, China continues to face challenges in balancing innovation incentives with equitable access, optimizing therapeutic value assessment, and ensuring long-term fiscal sustainability. The Chinese experience offers policy-relevant insights for countries seeking to enhance cancer medicine accessibility and innovation capacity through integrated regulatory and financing reforms.
    DOI:  https://doi.org/10.1200/GO-25-00524
  32. Cytotherapy. 2026 Jan 21. pii: S1465-3249(26)00020-4. [Epub ahead of print]28(6): 102064
    Futuristic global cell and gene therapy regulations based on a review of today's leading frameworks.
    Shahrukh K Hashmi, M Abdullah Jamil, Josu de la Fuente, Johnny Mahlangu, Margareth C Ozelo, Mark C Walters, Asma Almannaei, Alok Srivastava, Hazza Alzahrani, Peihua Lu, Gili Kenet, Kaori Nomura, Philippe Leboulch.
      The advancement of cell and gene therapies (CGT) represents a pivotal shift in the treatment model for cancers and a broad spectrum of other diseases, particularly rare and orphan disorders. Despite major advances, information regarding global regulatory pathways is scarce and often perplexing. Essential technicalities to approval, such as current good manufacturing practice, good laboratory practices, critical process parameters and pathways that accelerate the approval process (like orphan drug designation), are often inadvertently marginalized or overcomplicated. Furthermore, the globalization of these therapies is crucially hampered by fragmented, economically unsustainable and unreliable regulatory pathways. These regulatory challenges and the high cost of the traditional clinical trial model create significant bottlenecks for developers. We analyze the current frameworks in major jurisdictions, highlighting the technicalities in each and propose a new, harmonized global blueprint for development and approval. Key components of this proposed framework include a shift toward advanced preclinical models, adaptive trial design and patient-centric endpoints. Along with simplifying the processes for CGT developers (whether industry or academia), adopting this framework could increase the efficiency of CGT approvals, and lower the development costs. Such changes would help in achieving the goal of bench to bedside to globalization, directly translating into a more robust research atmosphere that benefits all by increasing the efficiency of CGT trial and product approvals in both developed and developing countries.
    Keywords:  adaptive-trial-design; cell-and-gene therapy; global regulations; pivotal-trial; platform-trials
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102064
  33. J Immunother Cancer. 2026 Apr 02. pii: e014075. [Epub ahead of print]14(4):
    Bright side of the dark genome: antigens for next-gen cancer vaccines.
    Xiao-Song Wang, Bernard A Fox.
      The discovery of cancer's hidden antigen landscape-comprising non-canonical 'dark matter' antigens-has unveiled a vast, untapped reservoir of immune targets for next-generation cancer immunotherapy. While most cancer vaccine strategies of the past decade have focused on mutation-derived neoantigens, studies applying sensitive mass spectrometry methods fail to identify the majority of predicted neoepitopes being presented by tumor human leukocyte antigen (HLA) molecules, potentially explaining negative results of several recent neoantigen vaccine trials. By contrast, peptides from non-canonical open reading frames, aberrant splice products, and non-coding RNAs that derive from short-lived proteins (SLiPs) are readily stabilized in class I HLA, and as a consequence of frequently being undetected in the thymus, have demonstrated strong immunogenicity. Early reports suggest some non-canonical immunopeptides are shared within and sometimes across multiple cancer histologies, with early evidence that some have tumor-promoting functions. Because these SLiPs are degraded so quickly and are stabilized in HLA-I, the intact proteins are postulated to not be accessible to antigen-presenting cells and are not efficiently processed and cross-presented-positioning this 'junk DNA'-derived antigen class as an attractive foundation for off-the-shelf vaccines. Here, we trace four phases of cancer vaccine evolution, review the technological advances that enabled the discovery of the dark immunopeptidome and discuss how these findings challenge established paradigms and reinvigorate interest in shared tumor antigens. By embracing this expanded antigenic universe, the field is poised to overcome key limitations of neoantigen-focused immunotherapy and move toward more universally effective cancer vaccines.
    Keywords:  Antigens, Neoplasm; Antigens, Viral, Tumor; DNA, Intergenic; Immunotherapy; Vaccine
    DOI:  https://doi.org/10.1136/jitc-2025-014075
  34. J Biopharm Stat. 2026 Mar 29. 1-16
    Real-world data and evidence in the development of cell and gene therapies.
    Yeonhee Kim, Shihua Wen, Khadija Rerhou Rantell, Zhenzhen Xu, Patricia Anderson.
      Cell and gene therapies (CGTs) are rapidly growing fields in regenerative medicine with the potential to tackle the most difficult-to-treat diseases. Despite their transformative potential, the development of CGTs is inherently complex, resource-intensive, and associated with high costs, posing substantial barriers in development and commercialization. As a feasible approach to address these challenges, real-world data (RWD) and real-world evidence (RWE) are gaining increasing recognition as powerful tools to potentially support and accelerate CGT development. This manuscript aims to identify the potential role of RWE and RWD in CGT development, with a focus on its application in regulatory licensure to date. Furthermore, we discuss current challenges, limitations, and evolving regulatory landscape pertaining to the use of RWE in regulatory decision-making.
    Keywords:  Real-world data; cell and gene therapy; external control; historical control; hybrid trial; real-world evidence
    DOI:  https://doi.org/10.1080/10543406.2026.2648311
  35. Technol Health Care. 2026 Mar 30. 9287329251381507
    Structural determinants of effective academic-industry technology transfer in biomedical engineering.
    Jolanta Pauk, Konrad Pauk, Anna Stec.
      BackgroundWhile macro-level factors influencing collaboration are well-studied, the daily operational processes between academia and industry remain unclear, especially in biomedical engineering, where coordination is complex and critical. This study fills this gap by analyzing decision-making, governance, and coordination practices from both perspectives to improve technology transfer and innovation outcomes.MethodsThis study employed a mixed-methods approach, including a structured questionnaire distributed among academic and industrial stakeholders, complemented by detailed case studies illustrating practical examples of collaboration in biomedical technology transfer.ResultsFindings reveal both converging and diverging motivations: academia values access to new technologies and societal impact, while industry prioritizes rapid market implementation and competitiveness. Key barriers include time constraints, conflicting publication and confidentiality demands, and challenges in intellectual property negotiations. Support mechanisms such as long-term funding, administrative support, and hybrid work models facilitate collaboration. Case studies demonstrate that successful partnerships hinge on clear regulatory frameworks and mutual understanding of objectives.ConclusionsFuture university-industry partnerships should prioritize clear communication, joint IP frameworks, and inclusive governance from the start. Involving clinical practitioners and end-users early improves product relevance, while proactive regulatory planning, supported by institutional guidance, helps avoid delays and compliance issues.
    Keywords:  Technology transfer; academic-industry collaboration; biomedical engineering; healthcare technologies; innovation
    DOI:  https://doi.org/10.1177/09287329251381507
  36. Curr Opin Chem Biol. 2026 Mar 30. pii: S1367-5931(26)00019-0. [Epub ahead of print]92 102670
    Next-generation interleukin-enhanced immunotherapies: From molecular engineering to armored T-cell architectures.
    Wenzhe Li, Wenjing Wang.
      Interleukins-based immunotherapy has been adopted clinically and is actively investigated for the treatment of tumors. Current FDA-approved interleukin therapies are significantly limited by the short half-lives and systemic toxicities. Recent advances include interleukin fusion proteins with enhanced target specificity and effector function. Additionally, integration of synthetic interleukin signaling into chimeric antigen receptor (CAR)-T or T cell receptor (TCR)-T cells augments their activation and sustains effector persistence within the immunosuppressive tumor microenvironment (TME). Together, these strategies aim to potentiate anti-tumor immunity, enhance the specificity while minimizing systemic toxicity. Here, we review recent developments in interleukin-enhanced cancer immunotherapy and discuss existing challenges and potential research opportunities.
    DOI:  https://doi.org/10.1016/j.cbpa.2026.102670
  37. Front Public Health. 2026 ;14 1765428
    Shifting sands in Saudi Arabian healthcare system towards value-based care: navigating the changing landscape.
    Ahmed Al-Jedai, Hajer Almudaiheem, Wejdan Ibrahim Said Aburas, Eid Almutairi, Maysa Tariq Eshmawi, Khalid Al Sulaiman, Essam Tawfik, Mohammed Al-Luhidan, Mohammad Alowairdhi, Nancy Awad, Rita Ojeil, Mohammed Ahmed Alshennawi.
      The KSA's healthcare system is undergoing substantial transformation under Vision 2030, with a strategic shift toward value-based healthcare (VBHC). This perspective paper examines the national reform initiatives and implementation readiness using five interrelated domains: data interoperability and governance, health technology assessment (HTA) capacity and availability of local data, policy fragmentation across high-cost therapeutic areas, operational burden of managed entry and risk-sharing agreements, and equity and stakeholder trust. Evidence was synthesized from peer-reviewed literature, policy documents, and institutional sources from the Saudi Ministry of Health. The analysis highlights progress in digital health integration, formulary modernization, pharmacoeconomic evaluation, real-world data infrastructure, and expanding use of value-linked reimbursement mechanisms. However, persistent challenges include fragmented digital systems, limited technical capacity for advanced HTA, heterogeneous policy implementation in specialized therapeutic areas, administrative complexity associated with performance-based agreements, and ongoing equity and trust considerations. Emerging methodological advances, including cost-effectiveness thresholds, development of multi-criteria decision analysis frameworks, and establishment of a Saudi-specific EQ-5D-5L valuation, strengthen the foundation for VBHC implementation. In this paper, we have recommended an implementation-oriented assessment of system enablers and constraints and identifies priority areas to support scalable, evidence-based, and sustainable adoption of VBHC in the KSA.
    Keywords:  Kingdom of Saudi Arabia; Saudi Ministry of Health; Saudi Vision 2030; health technology assessments; public-private partnership; value-based healthcare
    DOI:  https://doi.org/10.3389/fpubh.2026.1765428
  38. Curr Pharm Des. 2026 Mar 26.
    Regulatory Frameworks for the Integration of Quantum Computing in Pharmaceutical R&D: Implications for Drug Development and Compliance Monitoring.
    Simran Nayan, Shikha Baghel Chauhan, Indu Singh, Chirag Jain.
       BACKGROUND: Quantum computing (QC) is rapidly developing as an enabling technology that could potentially have major impacts in pharmaceutical drug research and development, but also faces significant challenges in terms of regulation in drug development and drug control contexts.
    OBJECTIVE: The purpose of this review is to assess different ways that existing pharmaceutical regulations, both within and outside regions such as the EU and US, enable, limit, or necessitate modification for applications throughout the drug development process.
    METHODS: A regulatory science-based analytical approach was used to examine how existing regulatory instruments, such as the FDA's Emerging Technology, EMA's DARWIN EU, and ICH, measure up to the validation, transparency, and reproducibility imperatives it is believed would emerge from drug development involving quantum technology. Relevant case studies were reviewed to provide context for new governance structures and global regulatory precursors.
    RESULTS: Although regulators have implemented various flexible pathways-including regulatory sandboxes, model-informed drug development, and adaptive licensing-these mechanisms currently still fail adequately to address the challenges of verification and auditability and the integrity of quantum algorithms for molecular modeling, pharmacogenomics, and pharmacovigilance. The main gaps were identified in ethical oversight, cybersecurity, and model validation standards.
    CONCLUSION: Coordinated regulatory science will help enable the safe, effective, and regulatory-acceptable use of quantum computing for pharmaceutical R&D. The combination of established standards in guidelines such as ICH E6(R3), GAMP 5, and GDPR with quantum-specific validation and governance pathways could enable responsible innovation while maintaining patient safety, data integrity, and public trust.
    Keywords:  Quantum computing; drug discovery; machine learning.; regulatory framework; regulatory sandboxes
    DOI:  https://doi.org/10.2174/0113816128428517260204145600
  39. Clin Pharmacol Ther. 2026 Apr 03.
    Divergent Paths, Convergent Goals: Institutional Experiments in Cell and Gene Therapy Regulation and Payment Between China and the United States.
    Jiajv Chen, Wei Li.
      With the continuous advancement of CGT technologies, therapeutic regimens worldwide are confronting dual challenges: accelerated regulation and innovation in payment models. The United States has established a regulatory framework characterized by early-stage acceleration and late-stage evidence supplementation based on the 21st Century Cures Act, matching a market-driven payment model supported by commercial insurance and Medicare pilots. China adheres to technology-first with strict risk control, experiencing three regulatory phases and forming a government-led payment model via prudent national medical insurance and local supplementary coverage. Both countries face common dilemmas of long-term evidence shortage, payment system adaptation, and regional accessibility inequality. This study objectively clarifies the institutional differences between the two countries and subjectively proposes targeted solutions including risk-adapted hierarchical regulation, cross-border collaborative payment sharing, and industrial synergy, aiming to provide a reference for global CGT universal access.
    DOI:  https://doi.org/10.1002/cpt.70279
  40. Rev Med Virol. 2026 May;36(3): e70135
    Human Cytomegalovirus Infection in Haematopoietic Stem Cell Transplant Recipients and CAR-T Cell Recipients-PART 2: Antiviral Therapy and Virus-Specific T Cell Therapy for HCMV in Allo-HSCT.
    Gaurav Sutrave, Michelle K Yong, Danya Kaplan, David J Gottlieb, Allison Abendroth, Barry Slobedman, Emily Blyth, Lauren Stern.
      Human cytomegalovirus (HCMV) reactivation is a common and significant complication after allogeneic haematopoietic stem cell transplantation (allo-HSCT), causing potentially life-threatening disease. Antiviral therapy approaches for HCMV are often limited by toxicities and the risk of developing antiviral drug resistance. This review article (Part 2) provides an overview of current antiviral pharmacotherapies for HCMV and the application of virus-specific adoptive T cell therapies for the prevention or treatment of HCMV reactivation in allo-HSCT recipients. The number of available antiviral drugs for HCMV is expanding, and letermovir primary prophylaxis is increasingly being adopted due to its favourable safety profile. Treatment resistant/refractory infections, end-organ disease, and late HCMV reactivations after antiviral therapy withdrawal continue to pose challenges. Adoptive HCMV-specific T cell therapies are a promising strategy for promoting immune-mediated control of HCMV reactivation in allo-HSCT recipients. The administration of HCMV-specific T cell products, generated through ex vivo expansion of donor-derived or partially HLA matched, third party HCMV-specific T cells, have demonstrated efficacy in combatting clinically significant HCMV infection in clinical trials. Adoptive HCMV-specific T cell therapies represent a powerful alternative approach for managing drug resistant HCMV infections in allo-HSCT recipients and reducing the reliance on antiviral pharmacotherapies.
    Keywords:  HCMV; VST; antivirals; cytomegalovirus; haematopoietic stem cell transplant; virus‐specific T cell
    DOI:  https://doi.org/10.1002/rmv.70135
  41. Value Health. 2026 Mar 28. pii: S1098-3015(26)00111-7. [Epub ahead of print]
    Towards a Harmonized Definition of Digital Health Technologies For Use in Health Technology Assessment: A Scoping Review and Modified Delphi Consensus Study.
    Annapoorna Prakash, Marcia Tummers, Joan Segur-Ferrer, Rosa Maria Vivano Hidalgo, Rossella Di Bidino, Emmanouil Tsiasiotis, Dario Sacchini, Americo Cicchetti, Wija J Oortwijn.
       OBJECTIVE: The objectives of this study are to map definitions of digital health, eHealth, mHealth, telehealth, telemedicine and artificial intelligence to further expand an existing conceptual map to distinguish between these terms, and propose a harmonized definition for "digital health technologies" METHODS: A scoping review was conducted to identify definitions of digital health, eHealth, mHealth, telehealth, telemedicine and artificial intelligence. PubMed/MEDLINE, Embase, Cochrane Library, and EconLit were searched between January 2015 and May 2024. A two-round modified Delphi, informed by the scoping review, was undertaken to develop a harmonized definition of DHTs. Numerical summary analyses were performed for identified definitions and Delphi responses, and thematic and content analyses were applied to the definitions and free-text responses.
    RESULTS: The search yielded 11,041 records, of which 482 articles were included after screening and snowballing. A total of 328 definitions were identified for digital health, eHealth, mHealth, telehealth, telemedicine and artificial intelligence. Higher number of definitions were identified for the term telehealth/telemedicine. Across definitions, three key components consistently emerged: purpose, users, and underlying technology. Round 1 of the Delphi received 118 complete responses, and Round 2 received 54. Consensus was achieved on the key components, their sub-components, and the final definition of DHTs.
    CONCLUSION: This study proposes a unified definition of DHTs, grounded in the components of purpose, users, and technology. Recognition of AI within the definition reflects its growing role in digital health. This definition provides a foundation for developing classification criteria that support consistent health technology assessment (HTA) of DHTs.
    Keywords:  EDiHTA; definition; digital health technologies; eHealth; health technology assessment; mHealth; telemedicine
    DOI:  https://doi.org/10.1016/j.jval.2026.03.009
  42. J Exp Med. 2026 Apr 06. pii: e20241217. [Epub ahead of print]223(4):
    Inhibitory receptor agonists: Emerging strategies in immune modulation.
    Kieran R Adam, Aamir Suhail, Vijay K Kuchroo, Dario A A Vignali.
      Inhibitory receptors (IRs) such as CTLA-4, PD-1, LAG3, TIM-3, and TIGIT are critical regulators of immune homeostasis, functioning to restrain excessive immune activation and prevent autoimmunity. While the blockade of IRs has transformed cancer immunotherapy by reinvigorating antitumor T cell responses, emerging strategies aim to harness the immunosuppressive potential of these receptors for treating autoimmune and inflammatory diseases. Agonistic antibodies that activate IR signaling have demonstrated promising results in preclinical models by promoting immune tolerance and suppressing pathological effector T cell functions. This review highlights recent progress in the development of agonistic IR-targeted therapies, examining their mechanisms of action, therapeutic efficacy, and the translational challenges that must be addressed to bring these innovative approaches into clinical practice for the management of autoimmunity and inflammatory disorders.
    DOI:  https://doi.org/10.1084/jem.20241217
  43. Life Sci. 2026 Mar 27. pii: S0024-3205(26)00168-2. [Epub ahead of print]394 124359
    LAG-3 at the crossroads: A context-dependent regulator of Tregs and autoimmunity inflammatory disorders.
    Zengyang Yu, Xinyi Tang, Yuling Shi, Yu Gong.
       AIMS: This review aims to systematically examine the regulatory mechanisms of Lymphocyte Activation Gene 3 (LAG3) in modulating T regulatory cell (Treg) function and its context-dependent implications in major inflammatory and autoimmune diseases.
    MATERIALS AND METHODS: We conducted a comprehensive literature review synthesizing findings from basic research, preclinical animal models, and clinical studies investigating LAG3 expression and function across autoimmune conditions, including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, autoimmune diabetes, inflammatory bowel disease, and psoriasis.
    KEY FINDINGS: LAG3 exhibits dual, context-dependent roles in autoimmunity. In multiple sclerosis and rheumatoid arthritis, LAG3+ Tregs exert protective immunosuppressive functions via IL-10 and TGF-β. Conversely, in systemic lupus erythematosus and psoriasis, LAG3 expression can mark unstable Tregs transitioning to pathogenic IL-17-producing phenotypes. LAG3 also modulates Treg metabolic programming, IL-2/STAT5 signaling, and cooperates with other checkpoints like PD-1. Soluble LAG3 (sLAG-3) is elevated in several autoimmune diseases, but its functional significance remains unclear.
    SIGNIFICANCE: Understanding LAG3's context-dependent regulation of Tregs is crucial for developing precision immunotherapies. Future strategies should move beyond broad LAG3 blockade toward subset-specific modulation to restore immune tolerance in autoimmune diseases.
    Keywords:  Inflammation and autoimmune diseases; LAG-3; Treg
    DOI:  https://doi.org/10.1016/j.lfs.2026.124359
  44. Drug Discov Today. 2026 Mar 31. pii: S1359-6446(26)00060-7. [Epub ahead of print] 104655
    Foundation models and AI agents in oncology drug discovery.
    Yashwardhan Ghanwatkar, Pankaj Rajdeo, Ram I Mahato.
      Oncology drug discovery remains limited by high attrition, slow experimental iteration and weak translation from preclinical models to clinical benefit. This review examines how AI is restructuring that process through three connected layers: biological foundation models that reduce uncertainty in molecular and cellular systems; generative design methods that improve candidate quality and compress medicinal chemistry cycles; and autonomous discovery platforms that integrate reasoning, experimentation and feedback. We analyze targeted protein degradation, emerging clinical validation and evolving regulatory frameworks; and argue that future progress will depend on causal inference, context generalization, interpretability and regulatory-grade evidence generation rather than model scale alone.
    Keywords:  AI agents; Foundation AI; diffusion models; drug discovery; generative AI; oncology
    DOI:  https://doi.org/10.1016/j.drudis.2026.104655
  45. Ther Adv Rare Dis. 2026 Jan-Dec;7:7 26330040261433035
    Could an outcome-based agreement be operationalized using real-world data from the Canadian Neuromuscular Disease Registry? Perspectives from an expert-led assessment in spinal muscular atrophy.
    Arif Mitha, Victoria Hodgkinson, Susi Vander Wyk, Chris Cameron, Allison Wills.
       Background: Outcome-based agreements (OBAs) may facilitate earlier patient access to promising therapies, particularly when evidence is limited. The authors of this paper investigated how to operationalize an OBA using real-world data (RWD) from the Canadian Neuromuscular Disease Registry (CNDR).
    Objective: The first objective of this research was to determine which spinal muscular atrophy (SMA) health outcomes in the CNDR are suitable for an OBA. The second objective was to evaluate the current process of data collection in the CNDR and explore how to operationalize data processes to support an OBA, including identifying gaps and proposing solutions.
    Design: This qualitative expert-led assessment was conducted through a series of focus group discussions with selected experts.
    Methods: A selected group of experts participated in 17 focus group meetings. The ability of the CNDR to generate real-world evidence (RWE) for an OBA was evaluated for eight SMA health outcomes. The criteria used were data readiness, interpretability, and timeframe within the CNDR. Next, the processes involved were evaluated, specifically to determine how data tracking within the CNDR could be operationalized for an OBA, including identifying gaps and possible solutions. Based on the findings, the group proposed a future state for an OBA process using the CNDR. The group followed up with stakeholder feedback interviews to validate the findings of this research and to gather insights.
    Results: Five SMA outcomes within the CNDR were identified as potentially suitable outcomes for OBA. Three process gaps were identified in the current state of the CNDR, and corresponding solutions were proposed. A proposed future-state process flow for CNDR was developed to support RWE generation for OBA.
    Conclusions: Expert consultations suggest that operationalizing an OBA using CNDR RWD is feasible.
    Keywords:  Canadian Neuromuscular Disease Registry; access to medications; outcomes-based agreements; rare disease; real world data; reimbursement; spinal muscular atrophy
    DOI:  https://doi.org/10.1177/26330040261433035
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