bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–07–12
fifty-six papers selected by
Luca Bolliger, lxBio
  1. Beyond Conventional CARs: Expanding the Targetable Antigen Landscape in CAR-T Cell Therapy.
  2. Fundamentals of engineered T cell therapies: From basic design to bells and whistles.
  3. In vivo transduction of CAR T cells: Pharmacological principles, delivery platforms, and the road to clinical translation.
  4. Transient T cell therapies.
  5. Next-generation CAR-T engineering for colorectal cancer: integrating targets, tumor microenvironment barriers, and emerging strategies.
  6. CAR T cell therapy for solid cancer scores first approval in China.
  7. Rewiring cellular immunotherapy: From CAR evolution to circuit innovations across diseases.
  8. Enhancing the persistence of therapeutic T cells.
  9. Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.
  10. The future of TCR-Treg therapies is renewables.
  11. CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.
  12. Optimizing Clinical Study Designs for CAR-T Cell Therapy: Development of an Efficient Sampling Strategy Through Optimal Experimental Design.
  13. Chimeric antigen receptor T cell therapy cardiotoxicity: a narrative review.
  14. Next Generation Methods in Health Technology Assessment (HTA): Need, Rigor, and Implementability.
  15. Engineering T cell metabolism to enhance therapeutic efficacy.
  16. Chimeric Antigen Receptor-Macrophages in Pancreatic Cancer: Promise, Pitfalls, and the Path Ahead.
  17. The German National Strategy for Gene- and Cell-Based Therapies: Generating Impact by Employing a Novel Multi-Stakeholder Approach.
  18. Beyond the algorithm: health technology assessment frameworks for AI in cardiology under the European Union Health Technology Assessment Regulation: a systematic review.
  19. Tracking therapeutic T cells in vivo.
  20. Manufacturing as biology: How T-cell processing shapes therapeutic outcomes.
  21. Precision Immunoregulation in transplantation: The rise of engineered Treg therapies.
  22. Optimizing CAR-T Therapy in Diffuse Large B-Cell Lymphoma: Biological Determinants and Translational Strategies Across the Therapeutic Continuum.
  23. Developing an early scientific advice framework for health technology assessment in Saudi Arabia: insights from global practices and expert consultations.
  24. Divergent Regulatory and Reimbursement Pathways for Digital Therapeutics: A Scoping Review With Implications for Korea.
  25. Point-of-Care Manufacturing of Anti-CD19.1-Chimeric Antigen Receptor-T Cells Using CliniMACS Prodigy: Real-World Experience From Jordan.
  26. Validation of AI-enabled surrogate models in quantitative systems pharmacology: a practical, context-of-use-driven review.
  27. A Critical Review of PET/CT Assessment After CAR-T Cell Therapy in Large B-Cell Lymphoma, Limitations of Current Criteria, Emerging Biomarkers, and a Framework for Standardised Evaluation.
  28. Impact of prior CAR T-cell treatment on graft-vs-host disease and non-relapse mortality after allogeneic transplantation.
  29. Smarter rules for digital health: How the digital omnibus can simplify without sacrificing patient rights.
  30. Construction and Functional Evaluation of Cyclic Peptide-Based CAR T Cells in Tumor Models.
  31. AI-driven neoantigen identification: a comprehensive review from somatic variant calling to T cell recognition.
  32. An Ontology for the Adoption of Medical Devices in Health Care Organizations: Design and Development Study.
  33. Human digital twins in personalized and predictive healthcare: a comprehensive review of technologies, applications, and future directions.
  34. Bridging preclinical development and clinical manufacturing: a translational GMP-Platform for lentiviral vector production in academic CAR T-Cell therapy.
  35. Modeling TCR-Epitope Recognition Specificity: What We Should Learn to Succeed.
  36. Single-Cell Transcriptomic Analysis Reveals γδ T-Cell Infiltration and Presence of Immune Regulatory Molecules in Biliary Tract Cancer Microenvironment.
  37. Are the Current Preclinical Models Adequate to Evaluate CAR-T Cell Therapy in Paediatric High-Grade Gliomas?
  38. CAR-Macrophage therapy for digestive system tumors: mechanisms, engineering and translational prospects.
  39. What population-based databases reveal about equity in access to hematopoietic cell transplant and cellular therapy.
  40. Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.
  41. MIDD Evidence to Support Drug Regulatory Decisions in China.
  42. A Bayesian Optimal Interval Design Considering Efficacy and Toxicity in Early Phase Basket Trials.
  43. Discordance in orphan drug approvals between the U.S. Food and Drug Administration and the European Medicines Agency: A retrospective observational analysis.
  44. A Lung-Targeted γδ T Cell Nanovaccine Couples Pulmonary Immune Priming to Systemic Antitumor Immunity in Non-Small-Cell Lung Cancer.
  45. CD137 in cancer therapy - bench to bedside.
  46. Immune regulation in mitochondrial transfer: knowledge structure and emerging trends from a bibliometric perspective.
  47. Health Data Quality Skill Gaps and Training Needs Among European Health Data Stakeholders: Cross-Sectional Survey.
  48. Organoid-AI platforms need integrated governance in drug discovery.
  49. FDA approves novel cell therapy made with haematopoietic stem cells, Tregs and T cells.
  50. Autoantigen mRNA-LNP Vaccination Drives Therapeutic Efficacy in Preclinical Models for Autoimmunity.
  51. Microbiota and immunotherapy: The birth of a new paradigm?
  52. Advancing the relevance of clinical trials for older patients.
  53. The Role of Contract Manufacturing in Antibody-Drug Conjugate (ADC) Drug Substance Development - Strategies for Successful Engagement.
  54. From Donation to Innovation: New Blood-Derived Products.
  55. Effects of diffusion, affinity, and permeation rate on drug cell therapy.
  56. Alternative Conditioning Regimens for Hemoglobinopathy Gene Therapy: Balancing Efficacy, Toxicity, and the Next Frontier.
  1. Transplant Cell Ther. 2026 Jul 08. pii: S2666-6367(26)00535-X. [Epub ahead of print]
    Beyond Conventional CARs: Expanding the Targetable Antigen Landscape in CAR-T Cell Therapy.
    Umida Yoziyeva, Alexey Yumashev, Shakhodat Kobilova, Dildora Khaydarova, Dildor Numonova, Nilufar Akhmedova, Matlyuba Saidkarimova, Zebo Khudoykulova.
      Chimeric antigen receptor (CAR)-T cell therapy has emerged as a central pillar of immunotherapy, with astonishing achievements in the treatment of CD19-positive B cell malignancies and multiple myeloma. In recent years, substantial efforts have been made to translate CAR-T cell therapy into other hematologic malignancies, solid tumors, and also non-malignant disorders, such as autoimmune diseases. Nonetheless, several challenges constrain the broader application of CAR-T cell therapy. Conventional CARs can only recognize extracellular protein antigens, which severely limits the range of targetable antigens. Moreover, extracellular disease-associated proteins are often shared with healthy cells, increasing the risk of on-target, off-tumor toxicities. Consequently, expanding the targetable antigen repertoire in parallel with reducing off-tumor toxicities has become a focus of current research. This review aims to provide a comprehensive overview of recent advances in the design of innovative CAR architectures to expand the targetable antigen landscape. In this regard, we discuss innovative CARs in four main categories: I) peptide-MHC-targeting CARs capable of recognizing intracellular proteins; II) Ultra-precision CARs capable of recognizing pathogenic cells while sparing healthy counterparts; III) Ligand/receptor-based CARs; IV) Non-protein antigen-targeting CARs.
    Keywords:  CAR-T cell therapy; Cancer; Chimeric antigen receptor (CAR); Immunotherapy
    DOI:  https://doi.org/10.1016/j.jtct.2026.07.003
  2. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00031-1. [Epub ahead of print]106 1-64
    Fundamentals of engineered T cell therapies: From basic design to bells and whistles.
    Janna C Minehart, Eric W Cross, Praise S Oo, Vijay G Bhoj.
      T cells endowed with defined antigen specificity by provision of monoclonal T cell receptors (TCR) or synthetic Chimeric Antigen Receptors (CAR) have established themselves as a potent drug class with several such products now commercially available. This review addresses fundamental aspects of the design of engineered TCR and CAR T therapies. Beyond the basic design features, we touch upon several additional strategies that have been developed or are currently in pre-clinical development to enhance the efficacy or safety of such therapies. Within the vast and quickly growing space of T cell engineering, this discussion is not all-encompassing but aims to lay a foundation for other reviews in the series that delve into more focused aspects of T cell therapy.
    Keywords:  Chimeric antigen receptor; Immunotherapy; T Cell therapy
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.002
  3. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00032-3. [Epub ahead of print]106 213-251
    In vivo transduction of CAR T cells: Pharmacological principles, delivery platforms, and the road to clinical translation.
    Saar I Gill.
      Chimeric antigen receptor (CAR) T cell therapy has fundamentally altered the treatment landscape for hematological malignancies, yet the autologous ex vivo manufacturing process that underpins commercially available products imposes severe constraints on access, scalability, and cost. In vivo CAR T cell generation can be achieved by direct systemic administration of gene delivery vehicles engineered to selectively transduce endogenous T lymphocytes. This approach reconceives the patient's own lymphoid organs as a bioreactor. Two major platforms are now entering clinical testing: engineered viral vectors that stably integrate a CAR transgene, and lipid nanoparticles (LNPs) that deliver CAR-encoding RNA for transient expression. This review examines the biological rationale, delivery engineering, immunological barriers, CAR payload design, early clinical evidence, and future directions of this field. Particular emphasis is placed on the pharmacological principles that distinguish in vivo from ex vivo approaches, and on the transformative potential for indications that lie beyond the current reach of conventional CAR T cell therapy.
    Keywords:  Adoptive immunotherapy; Chimeric antigen receptor; Immunotherapy; In vivo gene delivery; In vivo transduction; Lentiviral vector; Lipid nanoparticle; MRNA therapeutics; T cell engineering
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.003
  4. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00036-0. [Epub ahead of print]106 179-212
    Transient T cell therapies.
    Yudian Xiao, Mingliang Bai, Melgious Jin Yan Ang, Michael J Mitchell, Xuexiang Han.
      Chimeric antigen receptor (CAR) T cell therapy has achieved clinical success in hematological malignancies, but its reliance on viral vectors and complex ex vivo manufacturing poses challenges related to safety, cost, and scalability. Next-generation strategies, including universal ("off-the-shelf") and in vivo CAR-T cell therapies, have emerged to address these limitations. The latter strategy employs targeted delivery systems to directly program patients' T cells in situ, bypassing ex vivo manipulation and offering a more streamlined, scalable, and safer therapeutic paradigm. The success of in vivo CAR-T cell therapy relies on targeted delivery systems. While engineered lentiviruses enable stable integration, non-viral vectors for transient CAR expression offer superior pharmacological control. This approach, exemplified by lipid nanoparticles in combination with mRNA, avoids risks of insertional mutagenesis and enables titratable, short-lived CAR expression, thereby enhancing safety management and suitability for applications beyond oncology. In this chapter, we first delineate the pharmacological imperative for transient CAR expression. Next, various delivery strategies are systematically reviewed, including ex vivo electroporation, in vivo non-viral systems, and engineered virus-like particles. Afterwards, we summarize the ongoing clinical trials of transient CAR-T cell therapy for oncology and non-oncology indications. Finally, we provide perspectives on the development of next-generation transient CAR-T cell therapies.
    Keywords:  Autoimmune diseases; Cancer immunotherapy; Chimeric antigen receptor (CAR) T cell therapy; In vivo CAR-T; Lipid nanoparticles (LNPs); MRNA therapeutics; Transient CAR expression
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.007
  5. Front Immunol. 2026 ;17 1829723
    Next-generation CAR-T engineering for colorectal cancer: integrating targets, tumor microenvironment barriers, and emerging strategies.
    Yajuan Yang, Zongyue Gao, Ping Song, Chao Wang, Kai Wang, Zuowu Xi, Ruirui Jing.
      Chimeric antigen receptor (CAR)-T cell therapy for colorectal cancer (CRC) faces three major barriers: antigen heterogeneity, off-tumor toxicity, and the efficacy-safety trade-off. To overcome these obstacles, next-generation engineering strategies have emerged, including: (1) novel CRC-associated targets with improved tissue restriction; (2) architectural innovations such as armored CARs, optimized signaling (1XX, 28-ΔIL2RB-z(YXXQ)), and cytokine-arming; (3) combinatorial antigen-sensing circuits (AND/OR/NOT gates, SUPRA, synNotch); and (4) CRISPR-based editing for exhaustion-related knockouts (e.g., PD-1, Fas, TGFBR2) and site-specific CAR knock-in. Clinical evidence has demonstrated objective responses and disease stabilization in subsets of patients. However, the immunosuppressive tumor microenvironment-including inhibitory cells, dense stroma, and metabolic dysfunction-remains a critical hurdle limiting CAR-T persistence. Future directions should prioritize molecular typing-guided intervention, universal CAR-T, multicellular platforms (CAR-NK, CAR-M), and interdisciplinary collaboration. This review provides a framework for designing next-generation CAR-T therapies capable of achieving durable remissions in advanced CRC.
    Keywords:  CAR-T cell therapy; CRISPR/Cas9; antigen heterogeneity; colorectal cancer; next-generation engineering; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1829723
  6. Nat Rev Drug Discov. 2026 Jul 08.
    CAR T cell therapy for solid cancer scores first approval in China.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-026-00117-2
  7. Biotechnol Adv. 2026 Jul 09. pii: S0734-9750(26)00186-2. [Epub ahead of print] 108980
    Rewiring cellular immunotherapy: From CAR evolution to circuit innovations across diseases.
    Jiayi Chen, Yaxin Cui, Keyi Du, Jiangshan Liu, Jing Xie, Simiao Wang, Zhaogang Yang.
      Chimeric antigen receptor (CAR)-based immunotherapy has evolved from early linear receptor designs into increasingly sophisticated biological signal processing systems. While conventional CAR-T cell therapies have achieved remarkable clinical success, particularly in hematologic malignancies, their broader application is constrained by limited scalability, manufacturing complexity, and treatment-related toxicities. These challenges have driven the expansion of CAR engineering beyond T cells to alternative immune cell types, including natural killer (NK) cells and macrophages, as well as the diversification of genetic delivery and control strategies. Concurrently, advances in synthetic biology have reframed CARs not merely as static receptors but as programmable immune circuits capable of integrating multiple inputs, executing logical operations, and generating context-dependent outputs. Such circuit-based designs enable precise regulation of immune activation, improved discrimination between tumor and healthy tissues, and enhanced functional persistence within heterogeneous and immunosuppressive microenvironments. In this review, we conceptualize CAR-based immunotherapy as a form of biological signal processing and systematically trace its transition from linear CAR architectures to programmable immune circuits. We summarize engineering strategies for both ex vivo and in situ reprogramming of immune cells, compare viral and nonviral gene delivery platforms, and discuss key design principles underlying circuit CARs across different disease contexts.
    Keywords:  CAR-T; CAR-immune cells; Circuit CAR; Immunotherapy; synNotch CAR
    DOI:  https://doi.org/10.1016/j.biotechadv.2026.108980
  8. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00037-2. [Epub ahead of print]106 101-116
    Enhancing the persistence of therapeutic T cells.
    Gregory M Chen, Joseph A Fraietta.
      Therapeutic T cells show enormous promise for the treatment of cancer and other diseases, and an intriguing attribute of T cells for cellular therapy is their ability to have persist and perform cytotoxic function for years. With the advances in T-cell therapies such as CAR T-cell therapy for cancer, long-persisting therapeutic T cells have now been studied in clinical settings and revealed unexpected T-cell poulations. Based on these studies, an emerging framework of long-lived cytotoxic T cells may guide the rational design of new therapies optimized for long-lasting efficacy. The ideal duration of therapeutic T-cell persistence varies by clinical context, and the design of T-cell therapies should follow the therapeutic objective. This chapter highlights the central objective of enhancing the persistence of therapeutic T cells in various clinical contexts, and discusses the ways in which our growing knowledge of long-persisting T cells can guide the next generation of cell therapies.
    Keywords:  CAR T-cell therapy; Cancer immunotherapy; T-cell persistence; T-cell therapy
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.008
  9. J Transl Med. 2026 Jul 09.
    Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.
    Ya Li, Chensi Zeng, Sanxiu He, Qing Xiao, Yi Liu, Xuejiao Shu, Xiaoqing Xie, Yaxiao Lu, Huihui Fu, Jun Li, Chunyan Xiao, Jing Wu, Yao Liu, Xiaomei Zhang.
      Chimeric antigen receptor (CAR) T cell therapy is a next generation precision immunotherapy that engineers a patient's own T cells to express synthetic CARs, thereby augmenting tumour cell recognition and cytotoxic activity. Despite transformative clinical success in haematologic cancers, nearly half of treated patients relapse or fail to respond, and the translation of CAR-T therapy to solid tumours remains substantially more challenging. Increasing evidence shows that biomechanical forces, including stretch, compression, shear stress, and extracellular matrix (ECM) stiffness, shape immune activation, trafficking, and effector function through mechanotransduction pathways, ultimately modulating immune responses and disease evolution. Biomechanical cues critically influence CAR-T function, governing target recognition, activation dynamics, and cytotoxic engagement. Furthermore, the mechanical landscape of the tumour microenvironment shapes T cell infiltration, persistence, and exhaustion, thereby constraining CAR-T efficacy. These insights have fueled growing interest in biomechanically informed strategies to optimize CAR-T therapies. Here, we review the biomechanical principles governing CAR-T antitumour responses and highlight how ECM rigidity, shear forces, and other mechanical cues shape CAR-T performance. Biomechanics informed strategies that enhance CAR-T cell antitumour immunity offer a novel conceptual framework for advancing precision cancer immunotherapy. Elucidating how CAR-T cells sense and adapt to the mechanical tumour microenvironment will guide the design of next generation products and accelerate their translation into solid tumour indications.
    Keywords:  Antitumour immunity; Biomechanical cues; CAR-T; Tumour mechanical microenvironment
    DOI:  https://doi.org/10.1186/s12967-026-08563-7
  10. Autoimmun Rev. 2026 Jul 10. pii: S1568-9972(26)00153-9. [Epub ahead of print] 104139
    The future of TCR-Treg therapies is renewables.
    Cheng Rui Peh, Tu Nguyen-Dumont, Yi Tian Ting, Joshua Daniel Ooi.
      Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.
    Keywords:  Allogeneic cell therapy; Antigen-specific cell therapy; Autoimmune disease; CAAR-T cells; CAR-T cells; Decentralised manufacturing; Gene editing; Immune tolerance; Regulatory T cells; TCR-Tregs
    DOI:  https://doi.org/10.1016/j.autrev.2026.104139
  11. Hum Gene Ther. 2026 Jul 10. 10430342261467645
    CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.
    Duc-Hiep Bach, Thanh Liem Nguyen.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.
    Keywords:  CAR-T manufacturing platforms; clonal fitness; epigenomic imprinting; immune reconstitution; nonviral gene delivery
    DOI:  https://doi.org/10.1177/10430342261467645
  12. CPT Pharmacometrics Syst Pharmacol. 2026 Jul;15(7): e70274
    Optimizing Clinical Study Designs for CAR-T Cell Therapy: Development of an Efficient Sampling Strategy Through Optimal Experimental Design.
    Fenja Klima, Anna M Mc Laughlin, Robin Michelet, Wilhelm Huisinga, Katy Haussmann, Annette Künkele, Andrew C Hooker, Charlotte Kloft.
      CAR-T cell therapy is a cellular cancer immunotherapy that has impressively improved outcomes in hematological malignancies compared to conventional treatments. Yet, many patients do not respond permanently. Nonlinear mixed-effects modeling can support a better understanding of the unique and not fully understood dose-exposure and exposure-response relationships for CAR-T cell therapy by integrating available knowledge into a quantitative, physiology-motivated framework. However, to unfold its full potential, it requires informative and efficient study designs for clinical data collection. We aimed to develop an optimal experimental design framework informing a robust and feasible clinical CAR-T cell study design based on a published mechanistic model of CAR-T cell kinetics and tumor dynamics. By considering variability between study populations and parameter uncertainty, we (1) identified the minimal population size required to inform model parameters, (2) assessed different sampling strategies, and (3) informed flexible sampling windows instead of fixed sampling timepoints. The optimized study design consisted of 60 patients, three fixed assessments of tumor burden (days 0, 30 and 90), and three feasible CAR-T cell sampling windows (days 2-4, 12-18 and 32-47 after infusion). In stochastic simulation and estimation, the optimized design with sampling windows showed better performance in informing model parameters, including those characterizing heterogeneous outcomes, than designs with fixed sampling timepoints, confirming its efficiency and robustness. This framework shall facilitate future feasible and resource-efficient CAR-T cell clinical data collection, thus showcasing the potential of optimal experimental design to advance the development and optimization of complex cancer immunotherapies in clinical trials and clinical practice.
    Keywords:  CAR‐T cells; cancer immunotherapy; cellular therapy; clinical study design; modeling; optimal experimental design; simulation
    DOI:  https://doi.org/10.1002/psp4.70274
  13. Cardiooncology. 2026 Jul 08.
    Chimeric antigen receptor T cell therapy cardiotoxicity: a narrative review.
    G Sinigiani, G Scapinello, T Berno, F Piazza, A Cipriani.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the management of some relapsed/refractory hematologic malignancies. However, cardiovascular (CV) toxicity has emerged as a clinically relevant concern, particularly given its increasing use in older patients with CV comorbidities. Cytokine release syndrome (CRS) plays a central role in the development of cardiotoxicity, with interleukin-6 identified as a key mediator. Atrial arrhythmias and heart failure are among the most frequently reported complications. Their management relies on early detection and supportive care, although current strategies are largely extrapolated from general cardio-oncology guidelines. Significant gaps remain in risk stratification, surveillance protocols, and therapeutic approaches tailored to the unique inflammatory profile of CAR T cell-related toxicity. Addressing these gaps is essential to improve CV outcomes in this growing patient population.This narrative review aims to offer clinical cardiologists and hematologists a practical and current framework for the recognition and management of CAR T cell -related cardiotoxicity, with a focus on pathophysiological mechanisms, clinical presentation, and management strategies.
    Keywords:  CAR T cell therapy; Cardio-oncology; Cardiotoxicity
    DOI:  https://doi.org/10.1186/s40959-026-00499-7
  14. Int J Technol Assess Health Care. 2026 Jul 07. 1-24
    Next Generation Methods in Health Technology Assessment (HTA): Need, Rigor, and Implementability.
    Marina Richardson, Federico Augustovski, Melissa Pegg, Cyril Seck, Sitanshu Sekhar Kar, Wim Goettsch.
      
    DOI:  https://doi.org/10.1017/S0266462326103900
  15. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00030-X. [Epub ahead of print]106 117-139
    Engineering T cell metabolism to enhance therapeutic efficacy.
    Laura Anderson, Nicola J Mason, Roddy S O'Connor.
      Adoptive cell therapies, particularly chimeric antigen receptor (CAR) T cells, function as "living drugs" whose efficacy depends not only on target recognition but also on the metabolic state of the infused product. T cell metabolism governs energy production, redox homeostasis, biomass generation, and adaptation to persistent antigen exposure and nutrient stress, thereby shaping expansion, effector function, persistence, and susceptibility to exhaustion. Core metabolic programs relevant to these outcomes include glycolysis and mitochondrial respiration, anaplerosis and amino acid metabolism, lipid metabolism, and NAD- and redox-linked pathways. These programs help determine adoptive cell therapy-relevant phenotypes, including the balance between immediate cytotoxicity and long-term durability. Increasing evidence further suggests that metabolism can be therapeutically manipulated across the lifecycle of adoptive cell therapy through ex vivo manufacturing, receptor and signaling design, direct gene engineering, and post-infusion support. Collectively, these findings support a pharmacologic framework in which metabolic state is not merely a descriptive correlate of product quality, but a controllable determinant of therapeutic performance. A deeper mechanistic understanding of these pathways may enable more precise strategies to improve persistence, function, and long-term antitumor efficacy.
    Keywords:  Adoptive cell therapy; CAR T cells; Ex vivo manufacturing; Metabolic engineering; Metabolic programming; Mitochondrial fitness; T cell exhaustion; T cell metabolism; T cell persistence; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.001
  16. Front Biosci (Elite Ed). 2026 May 28. 18(2): 45762
    Chimeric Antigen Receptor-Macrophages in Pancreatic Cancer: Promise, Pitfalls, and the Path Ahead.
    Palloma Porto Almeida, Leandro Martins de Freitas.
      Chimeric antigen receptor-engineered macrophages (CAR-Ms) are emerging as a transformative frontier in immunotherapy and represent a promising strategy for pancreatic cancer. Unlike chimeric antigen receptor T-cell (CAR-T) or chimeric antigen receptor natural killer cell (CAR-NK) cells, which encounter limitations when applied to solid tumors, CAR-Ms combine innate tumor-homing capabilities with engineered antigen specificity to overcome these barriers. Recent studies have demonstrated encouraging antitumor activity in preclinical pancreatic ductal adenocarcinoma (PDAC) models; however, key questions remain regarding the persistence, safety, and scalability of these models. Nonetheless, despite these uncertainties, CAR-Ms may represent a paradigm shift from immune activation focused solely on direct cytotoxicity to one that also integrates immune orchestration and tumor microenvironmental reprogramming.
    Keywords:  cellular therapy; chimeric antigen receptor; macrophages; tumor microenvironment
    DOI:  https://doi.org/10.31083/FBE45762
  17. Hum Gene Ther. 2026 Jul 06. 10430342261464845
    The German National Strategy for Gene- and Cell-Based Therapies: Generating Impact by Employing a Novel Multi-Stakeholder Approach.
    Christian Gallus, Francis Ayuk, Philipp Beckhove, Daniel Besser, Martin Bornhäuser, Hildegard Büning, Tobias Cantz, Christoph Conrad, Stefan Eichmüller, Thomas Gazlig, Holm Graessner, Annette Grüters-Kieslich, Nathalie Huber, Michael Hudecek, Thekla Kurz, Björn Lamprecht, Elke Luger, Ulrike Protzer, Axel Schambach, Richard Schäfer, Pablo Serrano, Sven Stegemann, Isabelle Stöckert, Christof von Kalle, Joachim Weber, Christopher Baum.
      Gene- and cell-based therapies (GCTs) represent a disruptive and transformative class of biomedical innovations. They address diseases by adding, removing, repairing, or replacing genes and/or by endowing distinct living cells with additional biological functions. Through this plethora of options, numerous conditions-including genetic disorders, cancers, and degenerative diseases-have become potential targets for a curative therapy. Thus, GCTs are considered the "Future of Medicine" as they (i) offer a potential cure, particularly for rare and severe disorders previously considered untreatable, (ii) expand the treatment options for common diseases, and (iii) possess the possibility to complement currently applied conventional treatment options. Recognizing both the scientific promise and translational challenges of GCTs, Germany has launched a coordinated national initiative-the National Strategy for Gene- and Cell-Based Therapies. The Strategy was commissioned by the German Federal Ministry of Research, Technology and Space (BMFTR, formerly the German Federal Ministry of Education and Research [BMBF]) and developed through a multi-stakeholder process. The latter involved more than 150 experts from academia, industry, health care sector, professional associations, and patient organizations, who were nominated by the community and assembled into eight working groups to identify current roadblocks and propose possible solutions. Summarized in the Strategy Paper, which was submitted to the BMFTR and published on June 12, 2024, a comprehensive roadmap was developed in this bottom-up process to accelerate the development and clinical implementation of GCTs in Germany. Although it initially had a national focus, the resulting framework is increasingly contributing to the international GCT landscape through growing exchange with GCT initiatives launched in other European member states and with the European Society of Gene and Cell Therapy (ESGCT).In brief, the initiative is focusing on translation starting from research through all steps to clinical application and beyond. This includes workforce development, regulatory frameworks, manufacturing capacity, patient access, and communication with the general public. Numerous targeted measures have been developed by the participating experts in the working groups and are currently being implemented in this broad, collaborative, and bottom-up multi-stakeholder approach. They encompass, for example, the establishment of a website as central information platform, including the GCT-Atlas, a web-based networking and information tool for stakeholders and actors in the GCT field, tailored communication and outreach formats, a Regulatory Support Unit providing independent regulatory guidance for publicly funded early-stage, nonclinical product development, different funding and entrepreneurship programs offering researchers and clinicians financial, educational, and mentoring support, as well as the establishment of translational infrastructure and exchange formats with investors to specifically foster the necessary scale-up and commercialization.Overall, the main goal of the German National Strategy for GCT is to ensure patient access to advanced therapies while strengthening Germany's position as an international hub for biomedical innovation. To accomplish this, existing resources need to be coordinated, streamlined, and prioritized to increase efficiency and support the long-term sustainability of the system. These objectives are closely aligned with current emerging European initiatives, including the EU Biotech Act and the Horizon Europe work program 2026, which aim to further optimize the framework conditions for this strategically important field and enhance future European competitiveness.
    Keywords:  cell therapy; gene therapy; multi-stakeholder approach; national initiative
    DOI:  https://doi.org/10.1177/10430342261464845
  18. Ann Transl Med. 2026 Jun 30. 14(3): 36
    Beyond the algorithm: health technology assessment frameworks for AI in cardiology under the European Union Health Technology Assessment Regulation: a systematic review.
    Lucía Osoro, Baptiste Vasey, Peter McCulloch, Felix Broghammer, Stephen Gilbert, Juan Carlos Rejon-Parrilla, Dipak Kalra, Rubén Casado-Arroyo.
       Background: Artificial intelligence (AI) is increasingly used in cardiovascular care to support diagnosis, monitoring and clinical decision-making. However, its dynamic and adaptive nature challenges conventional health technology assessment (HTA) frameworks, which are typically designed for static interventions. This review aims to assess how existing literature supports HTA-relevant evaluation of AI-based cardiovascular technologies and examine their alignment with the evidentiary requirements outlined in the European Union Health Technology Assessment Regulation (EU HTAR).
    Methods: A structured literature search was conducted in PubMed, Scopus, and ScienceDirect databases for studies published between January 2020 and December 2025. After screening 223 records, 33 full texts were reviewed and six met inclusion criteria. A narrative synthesis was performed, alongside a comparative analysis of three HTA frameworks.
    Results: Six studies were included in the final synthesis, covering cardiovascular AI applications such as stroke outcome prediction, atrial fibrillation screening and wearable-based monitoring. Supported by 17 documents. Four studies incorporated real-world data, though lifecycle adaptability and post-deployment evaluation were rarely addressed. Most focused on clinical or economic performance, without referencing formal HTA frameworks. Alignment with the EU HTAR was indirect and stakeholder engagement, particularly with cardiologists, was inconsistently reported. These findings indicate increasing clinical adoption of cardiovascular AI but limited integration with structured HTA processes or regulatory foresight.
    Conclusions: While AI tools in cardiology show increasing promise, current HTA practices do not yet fully align with the regulatory and methodological expectations of the EU HTAR. Adapted evaluation models are needed to support the effective, evidence-based adoption of AI technologies in cardiovascular care.
    Keywords:  Artificial intelligence (AI); European Union Health Technology Assessment Regulation (EU HTAR); cardiovascular care; health technology assessment (HTA); lifecycle evaluation
    DOI:  https://doi.org/10.21037/atm-2026-0052
  19. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00033-5. [Epub ahead of print]106 253-281
    Tracking therapeutic T cells in vivo.
    Angela Z Gong, Mark A Sellmyer.
      Engineered cell therapies have shown remarkable promise in treating malignancies and autoimmune diseases. As of 2025, there are seven FDA-approved chimeric antigen receptor (CAR) T therapies, each treating different cancers. Despite rapid progress in developing new therapies, there is a lack of understanding about the in vivo behavior of adoptively transferred cells. Noninvasive methods that monitor CAR T cell dynamics and persistence in vivo are critical to both assess individual patients' responses to therapy in real time and to guiding improvements to engineered cell therapies. Imaging approaches that evaluate persistence, proliferation, functionality, and distribution of T cells will aid in optimizing therapeutic development and adjustment of treatment strategies in the clinic. Molecular imaging can noninvasively track labeled cells on a whole-body level and enable long-term monitoring of adoptively transferred cells in a manner compatible with the proliferation and persistence of therapeutic cells and may someday be able to bypass the need for paired biopsies. In this chapter, we highlight examples of cell tracking and labeling strategies for engineered T cell therapies.
    Keywords:  Direct labeling; Engineered T cell therapies; Molecular imaging; Radiolabeling; Reporter gene imaging
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.004
  20. Adv Pharmacol. 2026 ;pii: S1054-3589(26)00034-7. [Epub ahead of print]106 141-177
    Manufacturing as biology: How T-cell processing shapes therapeutic outcomes.
    Nikolai Przybylski, Qinghe Zeng, Xiao Huang.
      T-cell therapies have transformed the treatment landscape for hematologic malignancies and show growing promise for solid tumors and non-oncologic diseases. Unlike conventional drugs, these living therapeutics are shaped not only by genetic engineering but also by the ex vivo manufacturing process itself, which functions as a powerful biological determinant of cell fate and function. Here, we present a framework that conceptualizes manufacturing as a form of biological programming that governs therapeutic outcomes through its effects on T-cell phenotype, fitness, and functional durability. We review how each major processing step, including isolation, selection, activation, transduction, expansion, and formulation, influences the balance between cell quantity and quality, the two principal determinants of clinical efficacy. Particular emphasis is placed on how extracellular cues encountered during manufacturing, such as physical properties of activation materials, stimulatory ligand presentation, cytokine and nutrient composition, and gene delivery method, shape transcriptional, epigenetic, and metabolic programs that define cell phenotypes directly linked to cell quantity and quality. Emerging strategies to deliberately steer T-cell differentiation toward persistence-associated phenotypes, enhance metabolic fitness, and reduce vein-to-vein time are highlighted as critical avenues for next-generation manufacturing. Additionally, reducing inconsistency and cost remain areas of strategic importance to expand availability. Collectively, this review underscores that optimizing T-cell therapy requires treating manufacturing not as a logistical necessity but as a controllable biological intervention. A mechanistic understanding of how processing decisions program cellular behavior will enable the rational design of more potent, durable, and scalable T-cell products for diverse clinical applications.
    Keywords:  Cell quality; Cell quantity; Ex vivo stimulation; T-cell manufacturing; T-cell phenotype
    DOI:  https://doi.org/10.1016/bs.apha.2026.05.005
  21. Mol Biol Rep. 2026 Jul 08. pii: 1112. [Epub ahead of print]53(1):
    Precision Immunoregulation in transplantation: The rise of engineered Treg therapies.
    Mohammad Asim Azhar, Tanveer Ahmad Mir, Mohammad Afzal Khan, Alaa Alzhrani, Jahan Salma, Shadab Kazmi, Abdullah M Assiri, Dieter C Broering, Ahmed Yaqinuddin.
      Regulatory T cells (Tregs) are key mediators of immune tolerance and play a critical role in limiting excessive immune activation in conditions such as autoimmunity, transplantation, and graft-versus-host disease. Tregs are broadly classified into thymic-derived Tregs (tTregs) and peripherally induced Tregs (pTregs), which differ in lineage stability, epigenetic regulation, and functional plasticity. The suppressive function of tTregs is supported by stable expression of the transcription factor FOXP3, reinforced by demethylation of the Treg-specific demethylated region (TSDR). In contrast, pTregs are more susceptible to inflammatory cytokine signaling, which can destabilize FOXP3 expression and compromise suppressive function. Tregs employ multiple mechanisms of immune regulation, including CTLA-4-mediated inhibition of co-stimulatory signaling, cytokine modulation, metabolic interference, and, in certain contexts, granzyme-dependent cytotoxicity. Advances in cellular engineering have enabled the development of next-generation Treg therapies, including ex vivo expanded polyclonal Tregs, antigen-specific Tregs, and chimeric antigen receptor (CAR)-modified Tregs. Early-stage clinical and preclinical studies indicate that these approaches are feasible and exhibit favorable safety profiles in transplantation and immune-mediated diseases. This review summarizes current understanding of Treg biology, mechanisms governing lineage stability, and emerging strategies to enhance Treg specificity, persistence, and suppressive capacity, while highlighting remaining translational challenges.
    Keywords:  CAR-Tregs; FOXP3; Gene editing; Immune tolerance; Regulatory T cells
    DOI:  https://doi.org/10.1007/s11033-026-12310-y
  22. Crit Rev Oncol Hematol. 2026 Jul 10. pii: S1040-8428(26)00372-0. [Epub ahead of print] 105485
    Optimizing CAR-T Therapy in Diffuse Large B-Cell Lymphoma: Biological Determinants and Translational Strategies Across the Therapeutic Continuum.
    Yishan Wang, Yongxian Hu.
      Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), yet a substantial proportion of patients fail to achieve durable remission. These limitations arise from both inadequate initial response and subsequent disease relapse. Despite the availability of multiple optimization strategies, their clinical implementation remains challenging, partly because these approaches act at different points along the therapeutic continuum and address distinct biological or clinical barriers, resulting in a fragmented clinical implementation landscape that lacks a unified framework. In this review, we provide a clinically oriented synthesis of strategies to improve CAR-T efficacy in DLBCL, focusing on two interconnected objectives: enhancing initial remission and sustaining long-term disease control. We discuss how interventions before leukapheresis, during manufacturing, before infusion, during in vivo expansion, and after remission may shape clinical outcomes. We also discuss in vivo CAR-T technologies as an emerging platform with the potential to expand the therapeutic landscape and improve accessibility. By integrating evidence across studies, this review provides a comprehensive and systematic perspective on optimizing CAR-T efficacy in DLBCL while highlighting current evidence gaps and challenges to clinical implementation.
    Keywords:  CAR-T cell therapy; Diffuse large B-cell lymphoma; in vivo CAR-T; therapeutic resistance; translational strategies; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105485
  23. Cost Eff Resour Alloc. 2026 Jul 07.
    Developing an early scientific advice framework for health technology assessment in Saudi Arabia: insights from global practices and expert consultations.
    Ahmed Al Jedai, Hajer AlMudaiheem, Naif AlOtaibi, Lamia Al Zubaidi, Mohamed Al Shennawi, Nawaf Al Bali, Wejdan Aburas, Hana Alabdulkarim, Afaf Al Shamri, Bandar Al Harbi, Ashraf Al Grain, Ibtissam Al Harbi, Mohamed Khedr, Hind Hajj, Nancy Sayed Awad.
       BACKGROUND: Early Scientific Advice (ESA) is an independent, non-binding guidance from Health Technology Assessment (HTA) bodies or regulatory authorities to manufacturers before market entry. Unlike company sponsored advisory boards focused on commercial purposes. Saudi Arabia lacks a formal ESA framework representing a policy gap as the country adopts value-based care and evidence-driven reimbursement. This study address gap by proposing a Saudi ESA framework informed by global best practices and stakeholder input.
    METHODS: A narrative review literature review was conducted across PubMed, Embase, Scopus, and a grey literature to examine established ESA systems, followed by a roundtable with 15 experts representing policymakers, regulators, clinicians, HTA experts, industry, payers, and academia, ensuring multi-stakeholder input.
    RESULTS: Benchmarking ESA models implemented by National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), and European Medicines Agency (EMA) and integrated roundtable consensus, four key pillars for the Saudi ESA were identified: (1) scope covering both pharmaceuticals and medical devices to support local of new technologies; (2) timing varies for ESA pharmaceuticals, it can be positioned before drug registration during the late stages of clinical development, phase 2 and 3 for diseases of high local relevance, such as rare diseases to align evidence pre-submission while for medical devices ESA would occur primarily in the post-marketing stage; (3) governance positioning the HTA centrally because of its role in value assessment and reimbursement; (4) patients' involvement, facilitated through structured questionnaires, to ensure real-world perspective.
    CONCLUSION: The four ESA pillars (scope, timing, governance, patients' involvement) synthesize current international ESA practices and input from local experts, providing a structured foundation to support efficient evidence generation and alignment between regulatory and reimbursement requirements. Pilot evaluation is still required to validate anticipated benefits.
    Keywords:  Early scientific advice; Health technology assessment; Pharmaceuticals; Saudi Arabia
    DOI:  https://doi.org/10.1186/s12962-026-00783-4
  24. Inquiry. 2026 Jan-Dec;63:63 469580261467451
    Divergent Regulatory and Reimbursement Pathways for Digital Therapeutics: A Scoping Review With Implications for Korea.
    Mincheol Kim, Gaeun Kim.
      IntroductionDigital therapeutics (DTx) represent an emerging class of software-based medical devices delivering evidence-based therapeutic interventions. Several countries have developed regulatory and reimbursement frameworks for DTx, while Korea's evaluation system remains in its early stages. This scoping review compared regulatory and reimbursement frameworks for DTx across the United States, Germany, the United Kingdom, and Korea, and separately derived author-led policy implications for a Korean DTx evaluation framework.MethodsFollowing the Arksey and O'Malley framework and PRISMA-ScR guidelines, we searched 11 databases for literature published between January 2015 and December 2025 (final search: 15 February 2026). DTx was operationalized using the Digital Therapeutics Alliance anchor definition with jurisdiction-specific application rules. Data were synthesized along five analytical dimensions: regulation, evidence assessment, reimbursement, postmarket evidence, and governance linkage.ResultsOf 2,847 records, 42 sources (19 articles, 23 policy documents) were included. Jurisdictions diverged most clearly on statutory codification of DTx, the existence of a dedicated reimbursement pathway, and regulator-payer integration. Germany's DiGA Fast-Track had 61 products listed cumulatively (50 active, 11 removed), exceeding one million prescriptions and €234 million expenditure (GKV-SV reporting period through 31 December 2024). Korea provisionally listed four DTx products since 2023.ConclusionsGermany's DiGA system shares more institutional features with Korea's evolving system than do the US or UK frameworks. We propose, as an author-derived synthesis informed by the review, a five-phase Korean DTx framework, while acknowledging substantive system-level differences (payer pluralism, pricing, benefit design, HTA procedure) that constrain direct transferability.
    Keywords:  digital therapeutics; health technology assessment; insurance reimbursement; medical device legislation; scoping review
    DOI:  https://doi.org/10.1177/00469580261467451
  25. JCO Glob Oncol. 2026 Jul;12(7): e2500648
    Point-of-Care Manufacturing of Anti-CD19.1-Chimeric Antigen Receptor-T Cells Using CliniMACS Prodigy: Real-World Experience From Jordan.
    Khalid Halahleh, Ahmad Abu-Khader, Husam Abu-Jazar, Mohamad Makoseh, Waleed Dana, Rozan Al-Far, Taima' Qabajah, Mohammad Al-Sharairy, Rula Najjar, Ayat Taqash, Yasmin Al Ra'Ee, Mohammad Al-Rawashdeh, Alaa Abu-Fara, Fatena Ajlouni, Walid Naser, Zaid Abdelrahman, Maysa Al-Hussaini, Imad Treish, Hikmat Abdel-Razeq, Asem Mansour.
       PURPOSE: Industry-driven chimeric antigen receptor (CAR)-T cell manufacturing is complex and time-consuming. We hypothesized that decentralized manufacturing of CAR-T cells on an automated closed CliniMACS Prodigy system (Miltenyi Biotec) is feasible and reproducible for patients with relapsed refractory non-Hodgkin's lymphoma (rrNHL) in a developing country.
    MATERIALS AND METHODS: To manufacture anti-MB-19.1-CAR-T cell products, peripheral blood mononuclear cells were collected, enriched into pure T cells by positive selection using CD4 and CD8 magnetic beads, redirected into the chamber of the CliniMACS Prodigy for activation with the T-cell TransAct reagent containing CD3 and CD28, followed by transduction by anti-MB-CD19.1-CAR Lentiviral Vector, and cultured for 12 days followed by cell harvesting. Eleven products were manufactured, three from healthy donors for feasibility evaluation and eight clinical-grade products under a phase II clinical trial. Quality control and release manufacturer standards were set to ensure their identity, viability, purity, sterility, and potency.
    RESULTS: Eleven anti-CD19.1-CAR-T products with reproducible key characteristics were manufactured. Validation run data demonstrated a successful anti-CD19.1-CAR-T cell production with 51-fold T-cell expansion, a robust transduction efficiency of 26%, a viability of 98%, and fulfillment of manufacturer standards for clinical application. Clinical-grade products demonstrated 35-fold T-cell expansion, 44% transduction efficiency, and 99.8% viability, and fulfilling quality checks. The average vein-to-vein time is 15.25 days (range, 15-17). Safety and efficacy of clinical-grade products in the first eight patients enrolled showed reasonable objective responses with no new safety signals.
    CONCLUSION: Our data highlight the feasibility and reproducibility of the point of care of anti-CD19.1-CAR-T cells in a developing country, Jordan.
    DOI:  https://doi.org/10.1200/GO-25-00648
  26. Drug Discov Today. 2026 Jul 06. pii: S1359-6446(26)00134-0. [Epub ahead of print] 104729
    Validation of AI-enabled surrogate models in quantitative systems pharmacology: a practical, context-of-use-driven review.
    Igor Goryanin, Irina Goryanin.
      Quantitative systems pharmacology (QSP) models support model-informed drug development but are computationally expensive, limiting workflows requiring many simulations. Artificial intelligence (AI)-enabled surrogates can accelerate these workflows, but require validation aligned with context of use and regulatory expectations. Here, we present an eight-step validation framework covering simulation-campaign design, baseline comparison, endpoint accuracy, trajectory fidelity, uncertainty calibration, distributional agreement, biological plausibility, and computational efficiency. The framework is illustrated through chimeric antigen receptor T cell (CAR-T) immunotherapy and hybrid neural ordinary differential equation (ODE) erythropoiesis examples and aligned with ICH M15 and ASME V&V40. Supplementary algorithms provide practical validation recipes.
    Keywords:  ASME V&V40; CAR-T; Gaussian process; ICH M15; context of use; erythropoiesis; machine learning; model-informed drug development; neural ODE; quantitative systems pharmacology; surrogate model; validation
    DOI:  https://doi.org/10.1016/j.drudis.2026.104729
  27. J Multidiscip Healthc. 2026 ;19 622340
    A Critical Review of PET/CT Assessment After CAR-T Cell Therapy in Large B-Cell Lymphoma, Limitations of Current Criteria, Emerging Biomarkers, and a Framework for Standardised Evaluation.
    Layal K Jambi, Saeed M Kabrah.
      Chimeric antigen receptor (CAR) T-cell therapy has fundamentally altered the management of relapsed or refractory Large B-Cell Lymphoma (LBCL). Despite remarkable clinical efficacy, the radiologic evaluation of therapeutic response remains highly problematic. Standard assessment frameworks, notably the Lugano classification and the Deauville Five-Point Scale (D5PS), were calibrated for cytotoxic chemoimmunotherapy and demonstrate profound inadequacies when applied to the unique biological kinetics of cellular immunotherapy. This review critically examines the limitations of standard 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) in the CAR-T setting through a multidisciplinary lens, incorporating perspectives from hematology, nuclear medicine, neuroradiology, and molecular pathology. Pre-infusion quantitative parameters, including total metabolic tumour volume and spatial dissemination, operate as robust biomarkers for risk stratification and predicting immune-mediated toxicities. Post-infusion, conventional visual grading yields unacceptable false-positive rates. Phenomena including pseudoprogression, delayed complete responses, and systemic inflammation secondary to Cytokine Release Syndrome (CRS) routinely mimic active malignancy. Furthermore, Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) necessitates specialized neuroradiological evaluation. To resolve these diagnostic ambiguities, circulating tumour DNA (ctDNA) provides a precise, tumour-specific molecular signal capable of differentiating therapy-induced inflammation from genuine refractory disease. This review supports a structural transition from static visual scoring to a dynamic, multi-modal paradigm. Accordingly, the CAR-T Response Assessment Framework (CART-RAF), is proposed as an algorithmic approach that integrates continuous metabolic kinetics with serial molecular surveillance. Adoption of this multidisciplinary framework may reduce false-positive progression classifications, limit the premature discontinuation of effective cellular therapy, and improve clinical outcomes.
    Keywords:  MTV; PET/CT; chimeric antigen receptor T-cell therapy; circulating tumour DNA; ctDNA; deauville score; large B-cell lymphoma; metabolic tumour volume; positron emission tomography computed tomography; prognostic biomarkers; radiomics
    DOI:  https://doi.org/10.2147/JMDH.S622340
  28. Transplant Cell Ther. 2026 Jul 10. pii: S2666-6367(26)00527-0. [Epub ahead of print]
    Impact of prior CAR T-cell treatment on graft-vs-host disease and non-relapse mortality after allogeneic transplantation.
    Tamer Othman, Dongyun Yang, Geoffrey Shouse, Hoda Pourhassan, Salman Otoukesh, Leonardo Farol, Leslie L Popplewell, Ahmed Aribi, Alex F Herrera, Joshua Mansour, Matthew Mei, Karamjeet S Sandhu, Tanya Siddiqi, Vaibhav Agrawal, Idoroenyi Amanam, Vinod Pullarkat, Tycel J Phillips, Haris Ali, Lihua E Budde, Ryotaro Nakamura, Stephen J Forman, Ibrahim Aldoss, Monzr M Al Malki.
       BACKGROUND: It remains unclear whether prior chimeric antigen receptor (CAR) T-cell therapy is associated with an increased risk of graft-versus-host disease (GVHD) or non-relapse mortality (NRM) following allogeneic hematopoietic cell transplantation (HCT).
    OBJECTIVE: We evaluated the incidence of NRM, acute GVHD, and chronic GVHD in patients who underwent HCT following CAR T-cell therapy compared with matched controls who did not receive CAR T-cell therapy prior to HCT.
    STUDY DESIGN: We conducted a retrospective propensity-score matched case (prior CAR T recipients)-control (no CAR T prior to HCT) study to describe the impact of prior CAR T treatment on HCT outcomes.
    RESULTS: Day-100 NRM in the case vs control groups were 6.2% vs 8.6% (p=0.82). Day-100 CI of grades II-IV and III-IV acute GVHD in the case vs control groups were 43.1% vs 44.8% (p=0.83) and 20.0% vs 12.1% (p=0.099), respectively. The 1-year CI of any and moderate/severe chronic GVHD in the case vs control groups were 43.8% vs 42.3% (p=0.87) and 28.1% vs 20.3% (p=0.23), respectively. Overall and GVHD/relapse-free survival were not statistically significantly different after adjusting for DRI, p=0.094 and p=0.14, respectively. The cumulative incidence of relapse and disease-free survival were not statistically significantly different. Patients who had less than 3 months between CAR T and HCT had improved graft-vs-host disease/relapse-free survival (GRFS), 40% vs 24.4% at 1-year (p=0.032), owing to reduced grade III-IV acute GVHD, 5% vs 26.7% at 100-days (p=0.030).
    CONCLUSION: . Prior CAR T-cell therapy was not associated with an increased risk of GVHD or NRM, suggesting that CAR T-cell therapy can be administered without adversely affecting subsequent HCT outcomes.
    Keywords:  CAR T; GVHD; NRM; allogeneic transplant; graft-vs-host disease
    DOI:  https://doi.org/10.1016/j.jtct.2026.06.052
  29. Digit Health. 2026 Jan-Dec;12:12 20552076261452583
    Smarter rules for digital health: How the digital omnibus can simplify without sacrificing patient rights.
    Michele Russo, Elena Giovanna Bignami.
      The European Commission's Digital Omnibus proposal aims to simplify the European Union's complex digital legislative framework, which includes the GDPR, Data Act, and AI Act. While streamlining regulatory compliance is an attractive objective for healthcare stakeholders, it must not compromise the foundational elements of patient rights, privacy, and data security. This policy-oriented perspective analyzes the proposed amendments and the subsequent European Data Protection Board (EDPB) and European Data Protection Supervisor (EDPS) Joint Opinion 2/2026. Through a thematic and doctrinal analysis of these regulatory documents, this article examines four critical areas impacting digital health: (1) definitions of personal and pseudonymised data; (2) data processing for scientific research and AI; (3) the balance between data subject rights and administrative burdens; and (4) emergency data access and ePrivacy. We argue that data security is a prerequisite for trustworthy digital health systems, and regulatory simplification must not inadvertently expand the attack surface for health data. We conclude that while the Digital Omnibus offers necessary relief from compliance fatigue, true digital health governance requires a 'security-by-design' roadmap. Policymakers must adopt targeted derogations for health data that facilitate EHDS cross-border interoperability and AI innovation, without dismantling the foundational pseudonymisation and transparency safeguards upon which patient trust relies.
    Keywords:  GDPR; artificial intelligence in healthcare; automated decision-making; data protection; data subject rights; digital health; health data governance; patient privacy; pseudonymisation; regulatory compliance
    DOI:  https://doi.org/10.1177/20552076261452583
  30. Bio Protoc. 2026 Jul 05. 16(13): e5715
    Construction and Functional Evaluation of Cyclic Peptide-Based CAR T Cells in Tumor Models.
    Xiaoting Meng, Qingmin Wu, Yu-Hsuan Tsai.
      Cyclic peptides are emerging as a promising class of recognition modules for chimeric antigen receptor (CAR) engineering. Compared with single-chain variable fragment (scFv)-based CARs, disulfide-directed multicyclic peptides (DDMPs) represent a novel alternative, offering a markedly smaller molecular size (<5 kDa), enhanced structural stability through disulfide-directed cyclization, and broad tolerance to sequence diversification that supports systematic affinity and specificity optimization. DDMP-based CAR T cells leverage these properties to mediate antigen-dependent cytotoxicity while exhibiting an attenuated cytokine secretion profile, supporting the development of potentially safer immunotherapies for solid tumors. Here, we present a comprehensive workflow spanning CAR construct design and generation through in vitro and in vivo functional evaluation. While DDMPs are used as the exemplar recognition module, sections A and C-L of the protocol are directly applicable to any CAR format, including scFv- and nanobody-based designs with minimal modifications, making the workflow accessible to the broader CAR T-cell research community. The protocol includes the generation of Jurkat NFAT reporter cell lines and luciferase-expressing tumor target lines, which are widely used in different assays. Together, these standardized readouts enable rigorous, objective comparison of CAR T-cell efficacy and safety across tumor models. Key features • DDMPs (<5 kDa) are compact, disulfide-cyclized antigen recognition modules that tolerate extensive sequence diversification, enabling affinity and specificity optimization beyond conventional scFv-based CARs. • An integrated pipeline normalizes all functional comparisons to CAR-positive cell numbers, eliminating transduction efficiency as a confounding variable across construct designs. • Complementary readouts cross-validate efficacy and specificity: NFAT activation, luminescence-based killing, flow cytometry-based cytolysis, and ELISA-based cytokine secretion. • Xenograft imaging via the in vivo imaging system (IVIS) validates DDMP-CAR T-cell antitumor activity, extending cross-validation to preclinical tumor models.
    Keywords:  Autologous CAR T; Chimeric antigen receptor; Cyclic peptide; DDMP; Disulfide-directed multicyclic peptide; HER2; NFAT reporter; Preclinical CAR T evaluation; Xenograft
    DOI:  https://doi.org/10.21769/BioProtoc.5715
  31. J Transl Med. 2026 Jul 06.
    AI-driven neoantigen identification: a comprehensive review from somatic variant calling to T cell recognition.
    Atefeh Bakhshian, Sajjad Ghorghanlu, Fereshteh Fallah Atanaki, Elham Erfani Ezadyar, Azadeh Ashkiyan, Ali Etemadi, Babak Negahdari, Kaveh Kavousi, Gholamali Kardar, Mohammadali Mazloomi.
       BACKGROUND: Neoantigens-tumor-specific peptides generated by somatic mutations-are central targets of effective anticancer T cell immunity and underpin the clinical success of immune checkpoint blockade and personalized cancer vaccines. Advances in high-throughput sequencing, immunopeptidomics, and artificial intelligence (AI) have transformed neoantigen discovery from tailored experimental workflows into scalable, computational pipelines. However, accurately identifying the small subset of tumor mutations that yield processed, presented, and immunogenic epitopes remains a major bottleneck.
    METHODS: This review summarizes how AI is reshaping neoantigen discovery, from somatic variant calling, HLA typing, and peptide processing to peptide-MHC binding, presentation, and T cell recognition. We first outline the immunobiological foundations of antigen presentation, emphasizing class I and II peptide-binding grooves and their allele-specific motifs, then describe AI workflows that integrate somatic mutation calling, HLA typing, transcriptomics, and immunopeptidomics to nominate candidate neoepitopes. We highlight recent AI-driven tools for presentation and immunogenicity prediction, integrative pipelines that support personal and shared neoantigen targeting, and early clinical applications in vaccination and T cell therapies.
    RESULTS: AI-driven models trained on eluted ligand datasets substantially outperform affinity-only predictors for peptide presentation across diverse HLA alleles and populations. Consortium-scale benchmarking demonstrates that integrating features of antigen processing, presentation, and TCR recognition can eliminate the majority of non-immunogenic candidates while retaining clinically relevant neoepitopes. Immunopeptidomics provides essential ground truth, revealing that only a small fraction of genomically predicted candidates are naturally presented and uncovering noncanonical antigen sources, including splice variants, post-translational modifications, and noncoding regions. Integrative pipelines now support both personal (private) and shared (public) neoantigen prioritization, enabling translational applications such as personalized vaccines and TCR-based therapies.
    CONCLUSIONS: AI-guided neoantigen discovery is now clinically actionable, enabled by immunopeptidomics and deep learning models. Despite significant progress, key challenges remain, including limited class II prediction accuracy, incomplete coverage of rare HLA alleles, tumor heterogeneity, and the need for standardized benchmarking and validation. Anchoring computational predictions to mass spectrometry-derived ligands and incorporating tumor evolution and immune escape mechanisms will be critical for improving target selection. Continued integration of AI, proteogenomics, and clinical data is poised to accelerate the development of effective, precision neoantigen-based cancer immunotherapies.
    Keywords:  Artificial intelligence; Cancer; Immunotherapy; MHC; Neoantigen
    DOI:  https://doi.org/10.1186/s12967-026-08535-x
  32. J Med Internet Res. 2026 Jul 10. 28 e88366
    An Ontology for the Adoption of Medical Devices in Health Care Organizations: Design and Development Study.
    Sara Vannelli, Daniele Spoladore, Filippo Visintin.
       Background: The health care industry is witnessing a rapid proliferation of medical devices. Health care organizations need effective tools to identify devices that best align with their needs, and ensure seamless integration into clinical processes. Existing conceptualizations of expert knowledge remain fragmented, and no comprehensive decision support systems exist to assist stakeholders in evaluating and introducing new medical devices. Ontology-based approaches offer a promising avenue to formalize such complex, multidisciplinary knowledge.
    Objective: This study aims to develop and validate an ontology designed as the backbone of a decision support system to facilitate the informed adoption of medical devices in health care organizations.
    Methods: The ontology was developed using a 5-phase methodology: (1) Elicitation of knowledge through a systematic literature review, a review of existing conceptualizations, and expert interviews; (2) Conceptualization of a preliminary conceptual map; (3) Co-design of a refined map through focus groups with experts; (4) Development of the ontology using the Protégé ontology editor; and (5) Validation of the ontology through interviews with experts. Forty experts from 13 companies across 3 European countries participated, ensuring multidisciplinary coverage.
    Results: The resulting ontology provides a modular and comprehensive conceptualization of medical devices that balances granularity, conciseness, and practical relevance. It explicitly models key dimensions required for informed adoption decisions, including medical conditions addressed by the device, health services enabled, roles and activities of health care professionals, manufacturer-related information, medical device applications, and structured evidence derived from Health Technology Assessment reports. The ontology's instantiability and practical applicability were validated by populating it with data from 4 Health Technology Assessment reports and by expert assessment, confirming its ability to address stakeholders' core decision-making needs.
    Conclusions: This study presents a validated ontology to support the informed adoption of medical devices in health care organizations. It addresses a literature gap by providing a comprehensive, structured conceptualization of medical devices that meets stakeholders' key information needs. By formalizing complex expert knowledge, the ontology lays a foundation for future research and the practical development of decision support systems that enable transparent, effective, and efficient medical device adoption.
    Keywords:  decision support system; health technology assessment; medical devices; ontology; service innovation; technology adoption
    DOI:  https://doi.org/10.2196/88366
  33. Front Digit Health. 2026 ;8 1827007
    Human digital twins in personalized and predictive healthcare: a comprehensive review of technologies, applications, and future directions.
    A Mohan Babu, E S Madhan.
      The role of real-time data, artificial intelligence, and computational modeling is discussed in this review analytics Human Digital Twins (HDTs) creation- virtual persons of personalities patients which advocate predictive simulation to forecast of physiological behavior, treatment responses, and disease tracks. A synthesis of existing knowledge is done up to the technologies is a foundation to HDTs, clinical application and implementation issues of interest to precision medicine. The conceptual basis of engineering of the digital twins is analyzed and production principles, and technologies, which allow to produce HDTs-machine. Are physiological modeling, learning and distributed cloud-based computing infrastructure identified and evaluated. Cards: cardiology, oncology, genomics and immunology are critically appraised. It is based on the comparative analysis of 35 peer-reviewed documents and technical as it was reported, HDTs have great potential in enhancing personalized prediction of side effects, optimization of clinical trial design using virtual, and scheduling of treatment cohort simulation. But, model standards, an important component of model validation, are not present interoperability, ethical governing mechanisms and regulatory avenues to clinical deployment. The main priority research directions are determined, such as the development of common-validation techniques; implementation of federated learning frameworks to support sharing of data with data privacy limitations; incorporation of multi-omics data into physiological models; and introducing open ethical review procedures. This review provides substantive evidence basis to researchers, clinicians and policy makers to market the. Knowledge about HDTs technology to population health and health care provision revolutionizes.
    Keywords:  artificial intelligence; computerized cardiology; digital twins; in silico medicine; personalized medicine; predictive healthcare
    DOI:  https://doi.org/10.3389/fdgth.2026.1827007
  34. J Transl Med. 2026 Jul 08.
    Bridging preclinical development and clinical manufacturing: a translational GMP-Platform for lentiviral vector production in academic CAR T-Cell therapy.
    Maribel Lara-Chica, Blanca Arribas-Arribas, Raquel Muñoz-García, María Dolores de la Rosa-Garrido, Miguel A Montiel-Aguilera, María Bermejo-González, Esteban Márquez-Pérez, Paola Hernández-Díaz, Beatriz Guijarro-Albaladejo, Belén Sierro-Martínez, José Antonio Pérez-Simón, Gloria Carmona-Sánchez, Estefanía García-Guerrero.
       BACKGROUND: The manufacturing of lentiviral vectors (LV) under Good Manufacturing Practices (GMP) remains a critical bottleneck limiting the clinical translation of academic CAR T-cell therapies. To address this challenge, we established and validated an integrated GMP facility (ViPro-IBiS-UPRC) for aseptic LV production within a public healthcare setting.
    METHODS: A stepwise optimization strategy was implemented to bridge preclinical development and GMP manufacturing, including refinement of transfection conditions, vector harvest timing, and scale-up surface transition. GMP-compliant production processes and quality control (QC) frameworks were subsequently developed and validated for HEK293T Lenti-X master and working cell banks (MCB/WCB) and for LV manufacturing.
    RESULTS: Cell banks demonstrated high viability (≥94%), robust expansion capacity, confirmed identity by DNA fingerprinting, and absence of microbial and viral contaminants, including adventitious and endogenous retroviruses. GMP-produced LV batches achieved functional titers ranging from 9.95 × 107 to 3.07 × 108 TU/mL and fulfilled all release criteria, including sterility, absence of mycoplasma, endotoxins, and replication-competent lentivirus. Residual host cell DNA and protein levels remained within international regulatory predefined acceptance thresholds. Stability studies demonstrated preservation of vector functionality up to 12 months under cryopreservation conditions. Following regulatory inspection, ViPro-IBiS-UPRC obtained GMP certification from the Spanish Agency of Medicines and Medical Devices (AEMPS) for LV production, supporting the manufacture of CARTemis-1, an anti-BCMA CAR T-cell product under clinical evaluation in relapsed multiple myeloma patients.
    CONCLUSIONS: Collectively, this work establishes a GMP-compliant academic platform for scalable LV manufacturing, enabling decentralized, cost-effective, and clinically compliant supply. This point-of-care manufacturing model strengthens the accessibility of academic CAR T-cell therapies within public healthcare systems.
    Keywords:  Academic CAR T-cell therapy; Aseptic manufacturing; Good manufacturing practices (GMP); Lentiviral vectors; Point-of-care production
    DOI:  https://doi.org/10.1186/s12967-026-08566-4
  35. Immunol Rev. 2026 Jul;340(1): e70140
    Modeling TCR-Epitope Recognition Specificity: What We Should Learn to Succeed.
    David Gfeller, Julien Racle, Rita Ann Roessner.
      T-cell recognition of infected or malignant cells is central to both spontaneous and therapy-induced cellular immune responses against pathogens and cancer. This recognition is elicited by the interaction between T-Cell Receptors (TCRs) and epitopes, which consist of antigenic peptides displayed on major histocompatibility complex molecules. TCR-epitope interactions are characterized by high diversity in TCR and epitope sequences and high structural flexibility in TCR loops. As a result, deciphering the rules of TCR-epitope recognition specificity and accurately predicting these interactions remains challenging. Here, we review the different strategies developed to predict TCR-epitope recognition, classify the principal computational frameworks, examine the data modalities on which they depend and discuss their current limitations. We then synthesize key conceptual insights that have emerged from recent research and outline how these lessons should inform the design of future experiments and next-generation computational tools.
    Keywords:  T‐cell epitope recognition; T‐cell receptor; computational immunology; machine learning
    DOI:  https://doi.org/10.1111/imr.70140
  36. Am J Clin Oncol. 2026 Jul 03.
    Single-Cell Transcriptomic Analysis Reveals γδ T-Cell Infiltration and Presence of Immune Regulatory Molecules in Biliary Tract Cancer Microenvironment.
    Saikat Mandal, Stuart Astbury, Jane I Grove, Judith M Ramage, Andrew M Jackson, Guruprasad P Aithal.
       OBJECTIVES: Biliary tract cancer (BTC) remains therapeutically challenging with poor survival outcomes; systemic therapies achieving complete responses in only 2% to 5% of patients. γδ T-cell-based adoptive cell therapy represents a promising strategy due to MHC-independent activation. γδ T cells are activated through direct engagement of butyrophilin (BTN) family molecules; conversely, nonclassical HLA class-I molecules, particularly HLA-E, function as inhibitory ligands for NKG2A expressed on γδ T cells, suppressing anti-tumor immunity. Characteristics of tumor-infiltrating γδ T cells, their activity, and inhibitory interactions in BTC remain unexplored.
    METHODS: Single-cell RNA-sequencing data from 19 BTC tumor samples in the Gene Expression Omnibus (GEO) were analyzed to characterize γδ T-cell infiltration and the expression of regulatory molecules. MHC-I molecules, butyrophilin (BTN) molecules, intercellular adhesion molecules (ICAM), and NKG2A checkpoint receptors were quantified.
    RESULTS: γδ T cells comprised 0% to 4.9% of all cells present in the BTC tumor samples. Expression of BTN2A1, BTN2A2, BTN3A1, BTN3A2, and ICAM1 was noted in all the tissue samples, supporting Vγ9Vδ2 T-cell activation potential. Classic HLA class-I expression was preserved (70% to 90% of cells). HLA-E was overexpressed (60% to 95.7% of cells expressing HLA-E). Around 30% of NK cells and γδ T cells exhibited NKG2A positivity (log2 expression >2).
    CONCLUSIONS: Given the presence of regulatory molecules such as BTN and ICAM, Vγ9Vδ2 T-cell-based adoptive cell therapy appears promising. A combination of elevated HLA-E expression with high γδ T-cell NKG2A positivity establishes a potent inhibitory checkpoint axis in BTC. These findings support the rationale of investigating anti-NKG2A blockade combined with γδ T-cell-based adoptive therapy as a novel therapeutic strategy.
    Keywords:  BTC; biliary tract cancer; cholangiocarcinoma; gallbladder cancer; γδ T cells
    DOI:  https://doi.org/10.1097/COC.0000000000001340
  37. Mol Ther. 2026 Jul 08. pii: S1525-0016(26)00573-3. [Epub ahead of print]
    Are the Current Preclinical Models Adequate to Evaluate CAR-T Cell Therapy in Paediatric High-Grade Gliomas?
    Ana Muñoz Grau, Fatima Hameedat, Bibi Sumayyah Hussein Sokeechand, Chitra Venugopal, Sheila Singh, Flávia Sousa.
      Paediatric high-grade gliomas (pHGGs) are aggressive childhood brain tumours with five-year survival rates below 20%. They are distinct from adult high-grade gliomas (aHGGs), driven by histone mutations, disrupted developmental programs, and an immunologically restrained tumour microenvironment (TME). While chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of haematological malignancies, its application to pHGGs faces significant challenges for clinical translation. This review aims to provide a comprehensive overview of pHGG biology, CAR-T cell therapy principles, and current preclinical models, highlighting translational gaps and strategies to bridge them. We first examined the molecular and cellular landscape of pHGGs, emphasizing the unique features that shape responsiveness to antigen-directed therapies, detailing the mechanisms of CAR-T therapy, successes in haematological malignancies, and specific challenges in central nervous system (CNS) tumours. Next, we critically discussed the preclinical platforms, ranging from traditional 2D cultures to advanced patient-derived 3D systems and in vivo mouse models. While these systems provide mechanistic insights and enable assessment of CAR-T efficacy, none fully replicate the paediatric TME or developmental context, contributing to the recurrent gap between preclinical efficacy and clinical outcomes. This review highlights current knowledge, translational limitations, and future strategies to enhance CAR-T research in paediatric neuro-oncology.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.06.043
  38. J Transl Med. 2026 Jul 07.
    CAR-Macrophage therapy for digestive system tumors: mechanisms, engineering and translational prospects.
    Wenzhang Wu, Daijun Wang, Yumin Li.
      Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable outcomes in the treatment of hematological malignancies, yet its efficacy is severely compromised in digestive system tumors. The inherent physical barriers and immunosuppressive tumor microenvironment (TME) of digestive tumors hinder the infiltration and effector function of antitumor immune cells, greatly limiting the efficacy of conventional immunotherapies and creating an urgent demand for novel targeted immunotherapeutic strategies. As pivotal resident immune cells in the TME, macrophages possess powerful phagocytic activity and antigen-presenting ability, making them ideal candidates for tumor immunotherapy. Chimeric antigen receptor macrophages (CAR-Ms) can penetrate and remodel the immunosuppressive TME and directly eliminate tumor cells, exhibiting unique advantages and great application potential for the treatment of digestive system tumors. Herein, we provide a comprehensive narrative review of the latest research advances in CAR-M therapy for digestive system tumors. This review mainly focuses on the cellular origins, innovative engineering and genetic modification strategies, and underlying antitumor mechanisms of CAR-Ms, as well as systematically discusses the current challenges and future prospects of CAR-M-based digestive tumor therapy. We aim to provide valuable theoretical references for the development and clinical translation of novel immunotherapies for digestive system tumors. With the rapid development of precision immunomedicine, CAR-M therapy is expected to become a promising alternative therapeutic strategy for clinical digestive system tumors treatment.
    Keywords:  Adoptive cell therapy; CAR-Ms; Digestive system tumors; Tumor immunotherapy
    DOI:  https://doi.org/10.1186/s12967-026-08543-x
  39. Blood Rev. 2026 Jul 01. pii: S0268-960X(26)00056-1. [Epub ahead of print] 101417
    What population-based databases reveal about equity in access to hematopoietic cell transplant and cellular therapy.
    American Society of Transplantation
       BACKGROUND: Large population-based databases are increasingly used to study access to hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy.
    METHODS: We conducted a systematic scoping review of studies using US databases (1/2008-2/2025) to examine access to HCT or CAR-T therapy for hematologic malignancies to identify limitations and explain differences in reported disparities.
    RESULTS: Thirty-five studies met inclusion criteria, and 46% used linked databases. Across data sources, older age, racial and ethnic minoritized status, lower neighborhood socioeconomic status, and non-private insurance were associated with lower likelihood of HCT and CAR-T receipt. However, disparities varied substantially by databases due to differences in eligible populations, data availability, and ability to identify treatment candidacy.
    CONCLUSION: No single database adequately characterizes disparities in access to cellular therapies. Equity-focused research requires deliberate alignment of research questions with database strengths and greater investment in data standardization and inclusion of social determinants of health.
    Keywords:  Access; Cellular therapy; Chimeric antigen receptor T-cell therapy; Database; Health equity; Healthcare disparity; Hematopoietic cell transplantation
    DOI:  https://doi.org/10.1016/j.blre.2026.101417
  40. Nat Commun. 2026 Jul 10.
    Engineering trispecific IL-2 receptor agonistic antibodies through geometry optimization for enhanced Treg targeting.
    Valentina Lykhopiy, Emilie Pollenus, Laurie Rangan, Michelle Stakenborg, Tugsan Tezil, Michiel Varheust, Giel Tanghe, Nina Lambrechts, Vanshika Malviya, Eva De Langhe, Gianluca Matteoli, Christophe Blanchetot, Luc Van Rompaey, Susan M Schlenner.
      Regulatory T cells (Tregs) are central to maintaining immune tolerance, and their selective activation via interleukin-2 (IL-2) signaling presents a promising therapeutic strategy for autoimmune diseases and transplant rejection. Here, we develop IL-2 receptor (IL-2R) agonists, employing trispecific antibodies that simultaneously engage all three IL-2R subunits. This design preferentially activates and expands Tregs over conventional T cells and natural killer cells that express the dimeric IL-2R (CD122 and CD132). Incorporation of a second CD25-targeting VHH domain confers further enhanced specificity and potency for CD25⁺ Tregs. Extensive engineering of antibody geometry was then critical to maximize Treg selectivity, highlighting the importance of spatial configuration in receptor engagement. This study reports the successful development of trispecific IL-2R-targeting antibodies and significantly expands the potential of antibody-based immunomodulation. By selectively activating the high-affinity trimeric IL-2R on Tregs, this versatile platform offers a differentiated and promising strategy for the treatment of autoimmune diseases and transplant rejection.
    DOI:  https://doi.org/10.1038/s41467-026-75024-6
  41. Clin Transl Sci. 2026 Jul;19(7): e70656
    MIDD Evidence to Support Drug Regulatory Decisions in China.
    Lili Gao, Yan Wang, Ruirui He, Chunmin Wei.
      The paper systematically reviews the technical guidelines for Model-Informed Drug Development (MIDD) issued by China's Center for Drug Evaluation (CDE), analyzing typical application cases of innovative drugs approved both in China and internationally to evaluate MIDD's critical role in supporting drug development and regulatory decision-making. As of December 2025, CDE has released seven specific guidelines focused on quantitative pharmacology models, covering the entire drug development lifecycle, including dose exploration and optimization, pediatric extrapolation, rare disease drug development, and exposure-response (E-R) relationship research. MIDD have been successfully applied across multiple domains in innovative drug development, optimizing dosing regimens through E-R analysis for dose selection; constructing comprehensive evidence chains via modeling and simulation for pediatric and rare disease drug development; supporting dosage rationality through population PK andPBPK models for dose adjustments in special populations; and characterizing complex in vivo processes in advanced therapeutic products through mechanistic models. While MIDD enhances R&D efficiency and reduces clinical trial burdens, the field in China currently faces three major challenges: data quality, prospective design, and validation standards. It is necessary to strengthen data collection, model validation, and full lifecycle management to promote the paradigm shift from "model-assisted" to "model-driven" drug development, thereby accelerating the global market entry of Chinese innovative drugs.
    Keywords:  China; MIDD; innovative drugs
    DOI:  https://doi.org/10.1111/cts.70656
  42. Pharm Stat. 2026 Jul-Aug;25(4):25(4): e70108
    A Bayesian Optimal Interval Design Considering Efficacy and Toxicity in Early Phase Basket Trials.
    Tomoyuki Kakizume, Kentaro Takeda, Masataka Taguri, Satoshi Morita.
      Oncology drug development has increasingly shifted toward determining optimal biological doses rather than maximum tolerated doses (MTDs), particularly for targeted therapies and immunotherapies that exhibit complex dose-efficacy relationships. Concurrently, basket trials have emerged as an efficient approach for evaluating investigational treatments across multiple cancer types sharing common molecular targets. We propose the BOIN-ETB design, a model-assisted dose-finding design that addresses optimal dose (OD) identification in phase I/II basket trials by incorporating both toxicity and efficacy endpoints. The proposed approach employs common toxicity boundaries across cancer types while implementing cancer-specific efficacy boundaries to account for differential efficacy responses between baskets. OD selection utilizes utility functions that quantify efficacy-toxicity trade-offs. Through comprehensive simulation studies across Fourteen realistic scenarios, the BOIN-ETB design demonstrates robust performance in identifying true ODs while maintaining acceptable safety profiles across diverse cancer populations. The design provides superior consistency compared to alternative approaches, particularly in scenarios with heterogeneous dose-efficacy relationships between cancer types, making it well-suited for contemporary oncology dose-finding basket trials.
    Keywords:  Bayesian adaptive dose‐finding design; basket trial; model‐assisted design; optimal dose; phase I‐II clinical trial design
    DOI:  https://doi.org/10.1002/pst.70108
  43. PLoS Med. 2026 Jul 06. 23(7): e1004861
    Discordance in orphan drug approvals between the U.S. Food and Drug Administration and the European Medicines Agency: A retrospective observational analysis.
    Jin Ding, Michael M Hopkins, Paul A Martin.
       BACKGROUND: The United States (US) and European Union (EU) have long-established orphan drug regulations to incentivise the development of medicines for rare diseases. While the numbers of orphan approvals have risen rapidly, there is increasing discordance in regulatory outcomes between the US and EU. This discordance primarily stems from two sets of cases: US Food and Drug Administration (FDA) orphan approvals not authorised by the European Medicines Agency (EMA), and FDA orphan approvals with EMA authorisation but without orphan designation. We examined factors associated with these two sets of cases to understand the growing gap in orphan approvals between the US and EU.
    METHODS AND FINDINGS: We collected data on FDA orphan drug approvals between 2011 and 2023 from the FDA Orphan Drug Designations and Approvals Database and their corresponding EMA regulatory status from EMA medicines database. We used descriptive statistical analysis to examine trends and identify discordance in outcomes between agencies. Univariable logistic regression assessed pre-specified factors associated with discordance, including therapeutic area (cancer/non-cancer), company size (large/medium/small), company headquarters location (US/EU/others) and approval period (2011-2016/2017-2023). The main methodological limitations are that the study identified associations but does not establish causality, with unmeasured factors potentially contributing to the observed discordance. Of 814 FDA orphan approvals, only 29% received corresponding EMA marketing authorisation with orphan designation. A further 38% were authorised by the EMA but without orphan status, while the remaining 33% were not authorised by the EMA. Compared with the 2011-2016 period, cases in the 2017-2023 period were associated with lower odds (OR 0.66 (95% CI [0.48,0.92]; p = 0.013)) of EMA marketing authorisation. Compared with cancer approvals, non-cancer approvals were associated with lower odds (OR 0.53 (95% CI [0.38, 0.75]; p < 0.001)) of having EMA marketing authorisation, but when authorised, were associated with higher odds (OR 2.36 (95% CI [1.50, 3.70]; p < 0.001)) of receiving orphan designation. Compared with large companies, orphan approvals from small and medium-sized companies were associated with lower odds (OR 0.45 (95% CI [0.28, 0.74]; p = 0.001) and (OR 0.29 (95% CI [0.20, 0.43]; p < 0.001)) of EMA marketing authorisation, but among authorised products they were associated with higher odds (OR 2.95 (95% CI [1.75, 4.99]; p < 0.001) and (OR 2.14 (95% CI [1.17, 3.90]; p = 0.014)) of orphan-designated marketing authorisation, respectively. EU companies were associated with higher odds (OR 1.69 (95% CI [1.17-2.43]; p = 0.005)) of receiving EMA orphan approvals compared with US companies.
    CONCLUSIONS: Between 2011 and 2023, regulatory outcomes for orphan drug approvals increasingly diverged between the FDA and the EMA, particularly for cancer indications and approvals sponsored by small US sponsors. Among FDA orphan drugs authorised by the EMA, many were not designated as orphan products because of regulatory differences, particularly regarding requirements around significant benefit and biomarker-defined sub-populations in oncology. FDA-approved orphan drugs that lack EU marketing authorisation may be withheld by companies not because of regulatory barriers but due to insufficient commercial incentives to launch in Europe, resulting in fewer treatment options for European rare disease patients. Our findings suggest that orphan incentives are not the primary driver of commercial EU-launch decisions and that recent EU regulatory reform of these incentives may not achieve their goal of improving access to therapy for rare diseases.
    DOI:  https://doi.org/10.1371/journal.pmed.1004861
  44. ACS Nano. 2026 Jul 07.
    A Lung-Targeted γδ T Cell Nanovaccine Couples Pulmonary Immune Priming to Systemic Antitumor Immunity in Non-Small-Cell Lung Cancer.
    Zeyu Yang, Liyan Li, Zepeng He, Haolin Chen, Zhenfu Wen, Zhihui Zhang, Hong Liu, Lixin Liu, Yongming Chen.
      Non-Small-Cell Lung Cancer (NSCLC) often responds poorly to immune checkpoint blockade due to its immunosuppressive, "cold" tumor microenvironment. Activating alternative immune effectors may overcome this limitation. Here we identified lung-enriched γδ T cells as a key compartment in NSCLC and developed a lung-targeted lipid nanovaccine to activate them in situ. Analysis of patient transcriptomic data sets reveals that γδ T cell and CD1d signatures are associated with improved patient survival in NSCLC. Using this insight, we engineered α-galactosylceramide (α-GalCer) and poly(I:C)-loaded lipid nanoparticles that preferentially accumulated in the lung after intravenous administration. In orthotopic NSCLC models, the nanovaccine activated γδ T cells, enhanced functional CD8+ T cell infiltration, remodeled the immunosuppressive tumor microenvironment, and significantly prolonged survival. Depletion of γδ T cells abolished therapeutic benefit, demonstrating that γδ T cells represented the important effector population for this strategy. Furthermore, splenectomy attenuated vaccine efficacy, suggesting a contribution of systemic immune crosstalk to vaccine efficacy. Together, these findings establish a γδ T cell-centered lung-targeted immunotherapy strategy for treating immune-resistant NSCLC.
    Keywords:  NSCLC; lipid nanoparticle; lung-target delivery; nanovaccine; γδ T cell
    DOI:  https://doi.org/10.1021/acsnano.6c06272
  45. Immunotherapy. 2026 Jul 09. 1-17
    CD137 in cancer therapy - bench to bedside.
    Kathrine S Rallis, Jessica J Liegel, Alexandra Pommier, M Felicia Ciuculescu, José A Cancelas, John G Gribben, David E Avigan.
      CD137 (4-1BB; TNFRSF9) is an inducible costimulatory receptor of the tumor necrosis factor receptor (TNFR) superfamily expressed on activated CD8+ and CD4+ T-cells, natural killer cells, and dendritic cells. By reinforcing T-cell survival, expansion, and memory formation, CD137 has become an attractive target in cancer immunotherapy. Therapeutic strategies include agonistic monoclonal antibodies, bispecific molecules, and adoptive cell therapies enriched for tumor-reactive lymphocytes. Clinical-grade closed bioreactor systems feature a CD137-based enrichment platform utilizing antigen-induced CD137 upregulation to isolate and expand clinically relevant T-cell subsets. Additional innovations such as dendritic cell co-culture systems expressing CD137L and single-cell technologies that characterize highly reactive CD137+ T-cells further enhance precision and potency. Clinical trials of CD137 agonists have shown promising anti-tumor activity; however, hepatotoxicity and variable patient responses remain challenges. Recent work in non-human primate models has clarified the role of CD137 signaling in modulating alloreactivity, with implications for graft-versus-host disease. Despite ongoing barriers - including toxicity, therapeutic resistance, and limited biomarkers - CD137 remains a compelling immunologic target. Future efforts will emphasize context-specific agonism, refined cellular engineering, and multi-omic integration to improve patient selection and therapeutic design. This review summarizes CD137 biology, emerging therapeutic strategies, and translational and clinical directions.
    Keywords:  CD137; bispecifics; cancer; immunotherapy; monoclonal antibodies
    DOI:  https://doi.org/10.1080/1750743X.2026.2700925
  46. Front Immunol. 2026 ;17 1850600
    Immune regulation in mitochondrial transfer: knowledge structure and emerging trends from a bibliometric perspective.
    Qiyu He, Zhimin Tan, Juan Xu, Tianhong Wang, Qian Li, Xiaoqiang Li.
       Background: Mitochondrial transfer has emerged as an important form of intercellular communication with growing relevance to immune regulation, inflammation, tissue repair, and tumor immunity. However, the knowledge structure, developmental trajectory, and emerging hotspots of this field remain unclear.
    Methods: We conducted a bibliometric analysis of studies on mitochondrial transfer and immune regulation published between 2016 and 2025. Publications were retrieved from PubMed, Embase, the Cochrane Library, Scopus, and Web of Science, and analyzed using bibliometrix in R and CiteSpace. Annual publication trends, contributions of countries, institutions, authors, and journals, as well as keyword co-occurrence, clustering, burst detection, and co-citation patterns were evaluated.
    Results: A total of 967 publications were included. Annual publication output increased steadily, with faster growth after 2020. China and the United States were the leading contributors and occupied central positions in international collaboration networks. Keyword and co-citation analyses showed that early studies mainly focused on mitochondrial DNA-associated inflammatory sensing, innate immunity, and inflammatory injury, whereas recent studies increasingly emphasized intercellular mitochondrial transfer, mitochondrial transplantation, T-cell function, tumor-associated macrophages, cancer immunotherapy, metabolic rewiring, and autophagy-associated mitochondrial quality control. Mitochondrial transplantation and tunneling nanotube were among the most prominent burst terms. Co-citation analysis identified major knowledge domains related to mitochondrial danger signaling, intercellular transfer mechanisms, mesenchymal stem cell-mediated immune regulation, tumor immunity, and translational applications.
    Conclusion: Bibliometric mapping shows a clear shift from mitochondrial danger signaling toward intercellular transfer and immune-cell metabolic remodeling. Current evidence suggests that immune outcomes are shaped by mitochondrial source, transfer route, recipient-cell state, and disease context. More source-defined and context-specific studies are needed to clarify the therapeutic potential of mitochondrial transfer.
    Keywords:  bibliometric analysis; immune regulation; immunometabolism; mitochondrial transfer; mitochondrial transplantation
    DOI:  https://doi.org/10.3389/fimmu.2026.1850600
  47. J Med Internet Res. 2026 Jul 06. 28 e86878
    Health Data Quality Skill Gaps and Training Needs Among European Health Data Stakeholders: Cross-Sectional Survey.
    Jens Declerck, Niina Eklund, Carlos Sáez, Peter Rijnbeek, Enrique Bernal-Delgado, Erik van Mulligen, Dipak Kalra.
       BACKGROUND: The secondary use of health data is accelerating across Europe driven by growing demand for data-enabled research, innovation, and policymaking. The European Health Data Space (EHDS) establishes a regulatory framework to support this ecosystem, including Article 78, which mandates a data quality and utility labeling mechanism for datasets intended for reuse. Implementing this framework requires that data holders, data users, and health data access bodies possess sufficient skills, training, and organizational capacity to assess, document, and communicate data quality. However, little empirical evidence exists on whether European health data stakeholders currently possess these capabilities or how their needs differ across the 3 EHDS-defined roles.
    OBJECTIVE: This study aimed to identify current skill gaps, training needs, and organizational readiness related to health data quality among European health data stakeholders within the context of the EHDS.
    METHODS: A cross-sectional online survey was conducted between March 2024 and April 2024 using convenience sampling through the QUANTUM (Quality, Utility, and Maturity Measured; Developing a Data Quality and Utility Label for the European Health Data Space) consortium network, professional mailing lists, and health data communities. The survey targeted individuals involved in the secondary use of health data who identified as data holders, data users, or health data access bodies. The survey assessed 5 domains: stakeholder roles and data interaction, individual skills and experience, perceived challenges and skill gaps, organizational support and tools, and learning needs and preferences. Overall, 64 responses were collected from participants representing 44 institutions across 18 European countries.
    RESULTS: Overall, 82.8% (53/64; 95% CI 71.8%-90.1%) of respondents interacted with health data at least weekly, and 84.4% (54/64; 95% CI 73.6%-91.3%) rated data quality as moderately to absolutely critical for their work. Despite this, 87.5% (56/64; 95% CI 77.2%-93.8%) reported that poor data quality limited their effectiveness, with missing or inconsistent data identified as the most prevalent challenge. While 79.7% (51/64; 95% CI 67.4%-88.3%) reported prior experience with data quality tasks, key skill gaps were identified in applying data quality metrics, auditing and reporting, and metadata management. At the organizational level, only 15.6% (10/64; 95% CI 8.7%-26.6%) reported clearly defined data quality roles, and 68.8% (44/64; 95% CI 56.6%-78.8%) lacked a dedicated data quality manager or team.
    CONCLUSIONS: This study provides an empirical assessment of data quality skills and organizational readiness across the 3 EHDS-defined stakeholder groups. The findings highlight that practical experience alone does not ensure data quality competence and that structural deficits, particularly unclear roles and limited governance, constrain effective data quality management. The results offer a role-specific, evidence-based road map for capacity-building efforts essential to the successful implementation of the EHDS Article 78 data quality and utility labeling framework. This evidence underscores the urgent need for coordinated capacity building to ensure successful EHDS data quality implementation.
    Keywords:  European Health Data Space; QUANTUM project; capacity building; data holders; data quality; data quality labeling; data secondary use; data users; health data; health data access bodies
    DOI:  https://doi.org/10.2196/86878
  48. Drug Discov Today. 2026 Jul 04. pii: S1359-6446(26)00137-6. [Epub ahead of print] 104732
    Organoid-AI platforms need integrated governance in drug discovery.
    Johnny Sakr.
      Organoid-AI platforms are becoming decision systems in drug discovery, not just combined tools. They shape compound prioritisation, toxicity assessment, and programme progression. Yet governance often validates the biological model and the computational model separately, even when the evidential claim depends on their interaction. But separate validation can create false assurance: donor imbalance, batch effects, and culture drift can become algorithmic shortcuts, while confident model outputs can obscure weak biological transportability. This Feature proposes proportionate, platform-level governance built around a single context of use, linked provenance, transportability testing, and predefined fallback rules, scaled to decision stakes. The aim is not to slow adoption, but to make these platforms credible enough to act as preclinical gatekeepers.
    Keywords:  artificial intelligence; drug discovery; model qualification; new approach methodologies; organoid-AI platforms; platform validation; regulatory science; transportability
    DOI:  https://doi.org/10.1016/j.drudis.2026.104732
  49. Nat Rev Drug Discov. 2026 Jul 08.
    FDA approves novel cell therapy made with haematopoietic stem cells, Tregs and T cells.
    Asher Mullard.
      
    DOI:  https://doi.org/10.1038/d41573-026-00119-0
  50. Adv Sci (Weinh). 2026 Jul 06. e76382
    Autoantigen mRNA-LNP Vaccination Drives Therapeutic Efficacy in Preclinical Models for Autoimmunity.
    Paulien Baeten, Karen Beets, Tessa Schalley, Janne Verreycken, Gayel Duran, Daphne Lintsen, Lisa Schuetz, Xue Zhong, Rinke Nieuwschepen, Melissa Schepers, Brecht Moonen, Jeroen Bogie, Jana Van Broeckhoven, Carlo Heirman, Jurgen Van den Heuvel, Bart Vanderborght, Ismael Varela, Roxanne Nouille, Lotte Jacobs, Jessica Filtjens, Sabah Kasmi, Elise Seynaeve, Veronica Mavrovouna, Jana De Vrieze, Michael A Brehm, Sandra Maréchal, Sophie Janssens, Florence Lambolez, Niels Hellings, Stefaan De Koker, Bieke Broux.
      Autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes (T1D) lack therapies that induce durable, antigen-specific immune tolerance. We investigated whether mRNA lipid nanoparticles (LNPs) encoding disease-relevant autoantigens could re-establish immune homeostasis in preclinical models. While mRNA-LNP microbial vaccines evoke strong effector immune responses, we show that both systemic and intramuscular delivery of MOG27-63 mRNA-loaded LNPs attenuated disease severity in experimental autoimmune encephalomyelitis (EAE). Antigen-specific protection was similarly observed in a T1D adoptive transfer model. Therapeutic efficacy achieved using immunostimulatory LNPs challenges the current assumption that tolerogenic mRNA vaccines require immune-silent LNPs. Furthermore, divergent outcomes between autoantigens and irrelevant antigens suggest that antigen identity determines whether mRNA-LNPs promote immune tolerance or activation. Mechanistically, optimized LNPs efficiently targeted antigen-presenting cells (APCs) in the liver and spleen. This promoted a homeostatic APC phenotype and a hyporesponsive CD4+ T cell phenotype without inducing regulatory T cells (Tregs). Therefore, autoantigen mRNA was co-delivered with "immunoregulatory" mRNAs encoding cytokines (IL-2 mutein) or chemokines (CCL1) known to enhance Treg expansion and recruitment. This co-delivery further improved clinical outcomes in EAE. Together, these findings demonstrate that systemic and intramuscular treatment with mRNA-LNPs encoding autoantigens alongside immunoregulatory molecules represents a promising strategy for antigen-specific immunotherapy in autoimmune diseases.
    Keywords:  autoimmune diseases; lipid nanoparticles; mRNA therapeutics; tolerizing vaccines
    DOI:  https://doi.org/10.1002/advs.76382
  51. Cell Metab. 2026 Jul 07. pii: S1550-4131(26)00233-0. [Epub ahead of print]38(7): 1269-1272
    Microbiota and immunotherapy: The birth of a new paradigm?
    Rachel C Newsome, Christian Jobin.
      Emerging data suggest fecal microbiota transplantation (FMT) may improve cancer patients' responses to immune checkpoint blockade not only by enriching beneficial bacteria but also by depleting harmful taxa. Here, we discuss the "supplementation" and new "depletion" FMT paradigms in cancer management and highlight key knowledge gaps to be addressed to move this field forward.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.007
  52. Lancet. 2026 Jul 10. pii: S0140-6736(26)00905-0. [Epub ahead of print]
    Advancing the relevance of clinical trials for older patients.
    Hans Wildiers, Marije Hamaker, Simon Mooijaart, Supriya Mohile, Florence Canoui-Poitrine, Luigina Guasti, Nienke de Glas.
      Older patients represent the fastest growing patient group in clinical care. They are a heterogeneous group, for whom evidence for making treatment decisions is often scarce. Important domains for advancing the relevance of clinical trials for older patients are selection and inclusion of representative patients, choosing appropriate therapeutic interventions, and studying relevant outcomes. In the last decade, a myriad of publications has recommended multiple solutions that improve the relevance of trials for older people. Although uptake of these recommendations has been slow, there are now some excellent and successful implementation approaches that show that it is possible to design and execute trials that are inclusive of older patients, address relevant outcomes, and allow for real-world comparisons of intervention effectiveness. Observational studies based on different data sources add useful complementary information. This narrative review aims to synthesise best practices and successful strategies to improve the relevance of clinical trials for older patients.
    DOI:  https://doi.org/10.1016/S0140-6736(26)00905-0
  53. AAPS PharmSciTech. 2026 Jul 09. pii: 255. [Epub ahead of print]27(5):
    The Role of Contract Manufacturing in Antibody-Drug Conjugate (ADC) Drug Substance Development - Strategies for Successful Engagement.
    Conor S Barry.
      Antibody-Drug Conjugates (ADCs) represent a rapidly evolving, and increasingly important frontier in targeted therapeutics, demanding specialised approaches to development and manufacturing. With a highly complex supply chain, specialist Contract Development and Manufacturing Organisations (CDMOs) play a critical role in ADC development. Increasingly, positive CDMO partnerships with sponsor companies can build competitive advantage in an increasingly innovative and competitive clinical development environment for ADCs. Carefully considered CDMO engagement strategies can be employed to deliver successful outcomes for ADC development and manufacture across the full spectrum of the development life-cycle. This commentary considers early and late-stage ADC development, focusing on the systematic optimisation, technology transfer, and gap analysis essential for robust scale-up and manufacture. Facility design requirements and process modifications are discussed in the context of scalable, cGMP-compliant manufacturing, highlighting the engineering and environmental controls necessary for the safe and efficient handling of ADCs. The discussion will offers insights into the requirements for successful ADC development and manufacture with CDMO partners, while ensuring, regulatory compliance.
    Keywords:  antibody–drug conjugate (ADC); clinical bioconjugate development; contract manufacturing; late-phase bioconjugate development; technology transfer
    DOI:  https://doi.org/10.1208/s12249-026-03466-8
  54. Transfus Med Hemother. 2026 May 21.
    From Donation to Innovation: New Blood-Derived Products.
    Kerstin Wendland, Kathleen Selleng, Konstanze Aurich.
       Background: Recent advances in transfusion medicine are transforming donated blood into a versatile source for a new generation of therapeutic products. This narrative review summarizes emerging innovations across plasma, red blood cells (RBCs), platelets, donor stem cells, and cord blood.
    Summary: Developments in plasma technology, including dried plasma, isoagglutinin-depleted universal plasma, and protein-derived products aim to enhance safety, stability, and clinical applicability. RBC innovations focus on improved preservation, engineered or artificial oxygen carriers, extracellular vesicle-based products, and strategies for producing universal blood cells. Platelet-derived products such as platelet-rich plasma, platelet lysates, and platelet extracellular vesicles are expanding applications beyond hemostasis into regenerative medicine. Advances in donor stem cell technologies offer new pathways for scalable, donor-independent production of blood cells. Additionally, cord blood (CB)-derived red cells represent a promising new product with unique biological properties.
    Key Message: Together, these developments illustrate a shift toward more engineered, customizable, and sustainable blood-derived therapeutics, with the potential to address clinical needs unmet by traditional transfusion components.
    Keywords:  Blood product storage; Cord blood; Platelet-based products; Universal blood products
    DOI:  https://doi.org/10.1159/000552492
  55. J Recept Signal Transduct Res. 2026 Jul 10. 1-7
    Effects of diffusion, affinity, and permeation rate on drug cell therapy.
    Terry Kenakin.
      A mathematical model is described that enables calculation of drug concentration gradients within structured tissues for high affinity molecules that are taken up by cells. Access of drugs to the complete tissue mass may be prevented by high affinity binding, receptor re-binding, avid permeation into the cell and restricted diffusion (high tissue tortuosity). Varying parameters such as affinity and kinetic constants (association and dissociation rate constants) may be a strategy to manipulate affinity and penetration into structured tissues.
    Keywords:  Drug diffusion; drug binding; tissue penetration
    DOI:  https://doi.org/10.1080/10799893.2026.2699292
  56. Blood Adv. 2026 Jul 08. pii: bloodadvances.2026019856. [Epub ahead of print]
    Alternative Conditioning Regimens for Hemoglobinopathy Gene Therapy: Balancing Efficacy, Toxicity, and the Next Frontier.
    Akshay Sharma, Selim Corbacioglu.
      Gene therapy for sickle cell disease and transfusion-dependent thalassemia is now widely available, yet its broader application is constrained by the need for effective and tolerable conditioning. This review examines the central role of conditioning in enabling durable engraftment of gene-modified hematopoietic stem cells, emphasizing the narrow therapeutic window between insufficient niche clearance and excessive toxicity. Busulfan remains the standard, supported by consistent engraftment and clinical efficacy, but is limited by acute and long-term toxicities, including infertility and potential genotoxicity. Emerging strategies aim to mitigate these risks. Reduced-intensity melphalan shows early promise but raises concerns regarding durability, while treosulfan offers a potentially safer profile, though data in the autologous setting are lacking. Antibody-based, nongenotoxic approaches represent a transformative direction but remain investigational. Refining conditioning through comparative trials and long-term follow-up will be critical to fully realizing the curative potential of gene therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2026019856
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