bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–01–11
fifty-five papers selected by
Luca Bolliger, lxBio
  1. [Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies and Coping Strategies--Review].
  2. Redefining cell therapy: CAR-engineered innate immune cells to conquer solid and hematologic malignancies.
  3. From CAR-T Cells to Exosome-Based Immunotherapy: Exploring the Frontiers of Cell-Free Targeted Cancer Therapeutics.
  4. Advancing Cancer Immunotherapy: Chimeric Antigen Receptor (CAR)-T Cell Engineering through Novel Screening Methods.
  5. Engineering immunity with CAR-NK cells: advancing the frontiers of cancer immunotherapy.
  6. Current status and perspective of off-the-shelf CAR-T cells in cancer immunotherapy.
  7. Emerging strategies to reduce the side effects of CAR-T cell therapy: focusing on gene editing and nanotechnology.
  8. NK Cell-Based Immunotherapy: Pioneering a New Era in Cancer Treatment.
  9. Chimeric antigen receptor natural killer cell therapy for solid tumors: mechanisms, clinical progress, and strategies to overcome the tumor microenvironment.
  10. CAR-γδ T cells: a new paradigm of programmable innate immune sentinels and their systemic applications in cancer and beyond.
  11. Chimeric Antigen Receptor T-Cell Therapy: More Than an Anti-Cancer Drug.
  12. Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside.
  13. CAR-NK Engineering to Overcome TME Barriers.
  14. Operationalizing Access for Chimeric Antigen Receptor T cell Therapies: A Cross-functional Perspective.
  15. CD47/SIRPα Immune Checkpoint Modulation: A Synergistic Strategy for Next-Generation CAR Therapies.
  16. From Vision to Viability: Developing Infrastructure for Cell and Gene Therapy Programs.
  17. Optimizing In Vivo CAR-T Cell Engineering for Cancer Immunotherapy.
  18. Next steps in regulatory T cells: Biology and clinical application.
  19. CAR-T cell exhaustion in B cell lymphoma: Current status, mechanisms, and potential solutions.
  20. Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms.
  21. Engineering single-vector logic-gated CAR T cells with transgene sizes beyond current limitations.
  22. CAR-T-drug conjugate against solid tumor.
  23. Putting the Horse Before the CAR T Cells: Persistent Sepsis Risks Despite Improved Tolerance of Chimeric Antigen Receptor T-Cell Therapy.
  24. The efficacy and safety of CAR-T therapy in relapsed or refractory multiple myeloma patients: a systematic review and meta-analysis.
  25. CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
  26. Circadian Timing Optimizes Allo-HSCT to Prevent aGVHD: A Breakthrough in Chrono-Immunotherapy.
  27. Combining conventional and adapter CAR T cells: An elegant solution to erase current CAR T cell limitations.
  28. Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.
  29. Factors influencing pharmaceutical companies' decisions to pursue compassionate use programs in the EU: a qualitative study in The Netherlands.
  30. CAR-NK cell therapy: a new frontier in the treatment of pediatric autoimmune diseases.
  31. 2025 White Paper on Recent Issues in Bioanalysis: Redosing Patients with AAV Gene Therapy; CRS Immunogenicity Risk; Shedding Assays; NHP Studies Immunogenicity; CMC vs Bioanalytical Assays; Artificial Intelligence-Powered Genomic Pipelines for NGS (PART 3A - Recommendations on Gene, Cell, and Vaccine Therapies Immunogenicity & Technologies; Biotherapeutics & Biosimilars Immunogenicity Assessment & Clinical Relevance PART 3B - Regulatory Agencies' Input on Immunogenicity/Technologies of Biotherapeutics, Gene, Cell & Vaccine Therapies).
  32. Admixture Compatibility Studies in Parenteral Formulations: Packaging, Device, and Regulatory Perspectives.
  33. Leveraging PCORnet® to Advance Clinical Genetics and the Genomic Learning Health System.
  34. Epstein-barr virus and multiple sclerosis: from pathogenesis and diagnosis to EBV-specific T cell therapy and gene-targeted therapeutics.
  35. Immunotherapies for Central Nervous System Tumors and their Neurologic Complications.
  36. Toward precision immunotherapy in nephrology: 1 step forward.
  37. CD30+ T-cell lymphoma following Chimeric Antigen Receptor T-cell therapy (CART-cell therapy): Diagnostic uncertainty in a postimmunotherapy setting.
  38. Hypoxia promotes BCMA loss and a suppressive secretome thereby hindering CAR T cell therapy in multiple myeloma.
  39. CAR-T cells in the treatment of neurological autoimmune diseases.
  40. Recharging cellular immunotherapy - targeting immunometabolic aging.
  41. Hybrid Nanocarriers for Cancer Therapy: Advancements in Co-Delivery of Gene Therapy and Immunotherapy.
  42. Microbiome modulation of tumorigenesis and immune responses.
  43. Gaining regulatory acceptance for novel technologies in nonclinical drug development: A scoping review of its conceptualization in scientific literature.
  44. Towards an Integrated Framework for Health Surveillance Systems: A Systematic Literature Review of Design Components and Implementation Challenges.
  45. Hybrid exosomes: a rising horizon for precision cancer therapy.
  46. Is There a Future for CAR-T Therapy in Acute Myeloid Leukemia?
  47. Generation of thymus-reconstituting T cell progenitors from human pluripotent stem cells.
  48. Efficacy and safety of chimeric antigen receptor T-cell therapy in relapsed/refractory large B-cell lymphoma: a systematic review and meta-analysis.
  49. Probiotic Development Strategy Centered on Stability and Regulatory Considerations.
  50. Health technology assessment of an automated unit-dose drug distribution system in a high-specialization national referral hospital of the Italian National Health Service.
  51. Bridging discovery and therapy in precision medicine-Phage display as a catalyst for nanobody innovation: A review.
  52. Autoimmunity and Periodontitis.
  53. In Vivo Generation and Manipulation of CAR-T-mimicking Cells via Magnetic Bispecific Nano-antibody for Solid Tumor Therapy.
  54. CAR-T therapy in non-small cell lung cancer: Clinical prospects, potential, and strategies for cardiotoxicity management.
  55. Bidirectional Regulation in the Tumour Microenvironment: The Interaction Between Tumour-Associated Macrophages and T Cells Reshapes the Paradigm of Cancer Immunotherapy.
  1. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2025 Dec;33(6): 1820-1824
    [Mechanisms of Resistance to Chimeric Antigen Receptor T Cell Therapy in Hematological Malignancies and Coping Strategies--Review].
    Jun-Xia He, Ya-Ming Xi.
      Chimeric antigen receptor (CAR) T cell therapy has made a major breakthrough in the treatment of hematological malignancies. However, more and more studies have shown that factors such as T-cell exhaustion, tumor antigen modulation, immunosuppressive tumor microenvironment, and CAR-T cell dysfunction can lead to relapse and CAR-T cell resistence in hematologic malignancies. Developing dual-targeted CAR-T cells, exploring new immune targets, blocking CAR-T cell exhaustion, combining CAR-T cells with other therapies, implementing bridging therapies, and designing novel immunotherapies may be strategies to address CAR-T cell resistance. This article reviews the mechanisms of resistance to CAR-T cell therapy in hematological malignancies and the corresponding coping strategies.
    Keywords:  chimeric antigen receptor T cells; hematological malignancies; mechanisms of resistance; coping strategies
    DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2025.06.042
  2. Mol Biol Rep. 2026 Jan 06. 53(1): 254
    Redefining cell therapy: CAR-engineered innate immune cells to conquer solid and hematologic malignancies.
    Ashik Anil Mathew, Ronak Raheja, Kannan Ramalingam.
      Chimeric antigen receptor (CAR) technology has revolutionized cancer therapy, yet its full potential remains untapped within the innate immune system. Beyond CAR-T cells, a growing cadre of MHC-independent effectors, including NK cells, macrophages, γδ T cells and the emerging innate-like T cells such as invariant NKT (iNKT) and mucosal-associated invariant T (MAIT) cells, offer complementary mechanisms for tumor recognition and elimination. These platforms combine facile, off-the-shelf manufacture from healthy donors with low graft-versus-host disease risk and a reduced propensity for severe cytokine release syndromes. Mechanistically, they span missing-self and antibody-dependent cytotoxicity (NK), phagocytosis and cross-presentation (macrophages), stress-ligand recognition (γδ T cells), and rapid, tissue-tropic, TCR-mediated responses to conserved lipid and metabolite antigens (iNKT via CD1d; MAIT via MR1). CAR engineering of these cells leverages their innate rapidity, innate/adaptive cross-talk, and distinctive homing to confront heterogeneous and immune-evasive tumors. Here, we synthesize recent advances in cell design, dual/split CARs, switchable control systems, armored payloads and synthetic-biology circuits, and evaluate translational progress, manufacturing bottlenecks, and regulatory considerations. We argue that integrating innate and innate-like programs with precision CAR architectures will yield a new generation of universal, resilient cellular therapeutics with broadened antigen reach, improved safety profiles, and enhanced capacity to overcome the suppressive tumor microenvironment.
    Keywords:  CAR-Innate cells; CAR-NK; CAR-macrophage; CAR-γδ t cells; Chimeric antigen receptor; Solid tumors
    DOI:  https://doi.org/10.1007/s11033-025-11407-0
  3. Cells. 2025 Dec 31. pii: 70. [Epub ahead of print]15(1):
    From CAR-T Cells to Exosome-Based Immunotherapy: Exploring the Frontiers of Cell-Free Targeted Cancer Therapeutics.
    Alexandru Tîrziu, Florina Maria Bojin, Oana Isabella Gavriliuc, Cosmin Ioan Faur, Virgil Păunescu.
      Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering "off-the-shelf" applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy.
    Keywords:  CAR-NK cells; CAR-T cell therapy; cancer immunotherapy; cell-free therapeutics; exosome-based immunotherapy; extracellular vesicles; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15010070
  4. Biomol Ther (Seoul). 2026 Jan 01. 34(1): 30-44
    Advancing Cancer Immunotherapy: Chimeric Antigen Receptor (CAR)-T Cell Engineering through Novel Screening Methods.
    Junyoung Ha, Jihye Seong.
      Cancer immunotherapy represents a paradigm-shifting achievement in oncology. Particularly, chimeric antigen receptor (CAR)-T cell therapy utilizing genetically engineered T cells has produced remarkable clinical responses in hematological malignancies. However, significant challenges still remain including limited efficacy in solid tumors and critical safety concerns. The functionality of CAR-T cells depends on their synthetic receptor, CAR, which redirects T cell specificity and enhances effector functions. Therefore, optimal CAR engineering is crucial for successful development of CAR-T cell therapy. In this review, we discuss the limitations of current CAR screening methods, which primarily assess antigen binding affinity in vitro and often fail to predict T cell function and in vivo therapeutic performance. Advanced cell-based screening platforms have been developed to overcome these limitations. We overview the principles of these CAR screening systems utilizing reporter cell lines. While most are based on the detection of antigen binding properties or CAR-T cell activation markers, we emphasize a FRET-based immunological synapse biosensor as a powerful system that directly assesses CAR activation upon antigen binding. This platform offers significant advantages in speed and scalability for predicting CAR-T cell functionality. We also discuss recent advances in CAR library screening directly in primary T cells, which provides more physiologically relevant data. Such advanced platforms are essential to accelerate the development of safe and effective CAR-T therapy for solid tumors, ultimately expanding the therapeutic potential of this transformative cancer treatment.
    Keywords:  Biosensor; CAR-T cell therapy; Cancer immunotherapy; Chimeric antigen receptor; Fluorescence resonance energy transfer
    DOI:  https://doi.org/10.4062/biomolther.2025.204
  5. Front Pharmacol. 2025 ;16 1738558
    Engineering immunity with CAR-NK cells: advancing the frontiers of cancer immunotherapy.
    Vlad Andrei Cianga, Ion Antohe, Cosmin Minciună, Angela Dăscălescu.
      Chimeric antigen receptor-modified natural killer (CAR-NK) cells are emerging as a promising alternative to CAR-T therapies, offering advantages such as reduced toxicity, allogeneic feasibility, and flexible manufacturing. Current reviews cover NK biology and CAR engineering progress, yet lack a unified perspective that connects these advances. This review provides a novel synthesis by mapping specific tumor immune evasion mechanisms, including antigen loss, lineage plasticity, impaired antigen processing, epitope masking, and trogocytosis to corresponding next-generation CAR-NK engineering solutions. This "evasion-to-solution" framework highlights how innovations such as dual-antigen CARs, low-affinity designs, NK-specific signaling, iPSC-derived NK platforms, and multiplex gene editing directly mitigate known mechanisms that lead to therapeutic failure. By linking tumor biology to engineering strategy, this review offers a translational roadmap for the rational design of more adaptable and resilient CAR-NK therapies.
    Keywords:  CAR engineering; CAR-NK cell therapy; CRS; ICANS; adoptive cell immunotherapy (APC); cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; immunotherapy
    DOI:  https://doi.org/10.3389/fphar.2025.1738558
  6. Biomed Pharmacother. 2026 Jan 08. pii: S0753-3322(26)00018-1. [Epub ahead of print]195 118986
    Current status and perspective of off-the-shelf CAR-T cells in cancer immunotherapy.
    Shiva Fallahianshafiei, Ali Babaeizad, Piao Yang, Anita S La'ah, Mohsen Sheykhhasan.
      Recent advances in cancer immunotherapy have highlighted the promise of off-the-shelf chimeric antigen receptor (CAR)-T cell therapy. This has offered solutions to key limitations of conventional autologous approaches, such as patient-specific cell collection and lengthy production times. This review summarizes the development, clinical application, and challenges of CAR-T cell technology. We reviewed CAR design and function, cancer-targeting mechanisms, and approaches to developing universal donor platforms that could replace the need for patient-specific cell harvesting. We discussed key challenges of CAR-T technology and its potential solutions. This review also summarizes CAR-T cell therapies recently approved by the FDA. Finally, we explored future directions, regulatory challenges and the potential of personalized medicine, emphasizing how off-the-shelf CAR-T therapies could revolutionize cancer treatment by making it more scalable and accessible.
    Keywords:  Allogeneic CAR-T cells; Cancer immunotherapy; FDA-approved CAR-T cells; Immune rejection; Personalized cancer treatment; Regulatory landscape; Tumor heterogeneity; Universal CAR-T cells
    DOI:  https://doi.org/10.1016/j.biopha.2026.118986
  7. Clin Transl Oncol. 2026 Jan 04.
    Emerging strategies to reduce the side effects of CAR-T cell therapy: focusing on gene editing and nanotechnology.
    Jinxin Dong, Denis Andreevich Nikolenko, Shuxrat Boymuradov, Lilya Garifulina, Elnaz Khodabandehloo.
      CAR-T cell therapy has been transformative in treating certain blood malignancies and is also being adopted for treating other malignancies, including solid tumors. Despite its undeniable successes, CAR-T cell therapy is frequently associated with severe and potentially life-threatening side effects and toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), graft-versus-host disease (GvHD) in allogeneic settings, secondary CAR-T-derived malignancies, and long-term immunosuppression-induced risk of infections. Recent advances in integrating gene-editing technology and nanomedicine into CAR-T cell therapy have opened new avenues to enhance the safety profile of CAR-T cell therapy and broaden its clinical applications. Gene-editing tools enable targeted modulation of the CAR-T cells' genome, thereby improving their safety profile by preventing related side effects. In parallel, nanomedicine can be used at various stages, including manufacturing and post-treatment, to prevent their occurrence or manage them. This review highlights the current preclinical and clinical landscape, explores the emerging combinatorial strategies, and discusses future directions to achieve a safe and more controllable CAR-T cell therapy.
    Keywords:  CAR-T cell therapy; CRISPR/Cas9; Chimeric antigen receptor (CAR); Gene editing; Nanomedicine; Nanoparticles
    DOI:  https://doi.org/10.1007/s12094-025-04185-5
  8. Curr Pharm Biotechnol. 2026 Jan 05.
    NK Cell-Based Immunotherapy: Pioneering a New Era in Cancer Treatment.
    Chengyao Ma, Shiming Zhang, Yan Ding, Xiaofei Wang.
      Natural killer (NK) cells are essential cytotoxic effectors of the innate immune system with significant therapeutic advantages in cancer immunotherapy, primarily due to their intrinsic MHC-unrestricted cytotoxicity and capacity for antigen-independent tumor recognition. Compared to T cell-based immunotherapies, NK cell-centered strategies facilitate precision immunotherapy through chimeric antigen receptor (CAR) engineering while demonstrating superior allogeneic compatibility. This inherent resistance to graft-versus-host disease (GVHD) circumvents the limitations of autologous cell sourcing and enables "off-the-shelf" therapeutic availability. This review systematically outlines the developmental biology and functional characteristics of NK cells, their diverse cellular origins, and the dynamic regulatory mechanisms governed by the balance of activating and inhibitory receptors. Furthermore, it highlights recent advances in the clinical translation of engineered NK cell therapies, including CAR-NK cells, and discusses their therapeutic applications in cancer treatment.
    Keywords:  CAR-NK; NK cells; cancer treatment; clinical trials; immunotherapy; sources of NK cells.
    DOI:  https://doi.org/10.2174/0113892010434344251122040856
  9. Exp Biol Med (Maywood). 2025 ;250 10841
    Chimeric antigen receptor natural killer cell therapy for solid tumors: mechanisms, clinical progress, and strategies to overcome the tumor microenvironment.
    Yu Xiang, Jiayi Dong, Lijuan Shao, Size Chen.
      Natural killer (NK) cells represent a fundamental component of the innate immune system, endowed with the ability to identify and eradicate virus-infected and malignant cells. The advent of chimeric antigen receptor (CAR) technology has introduced innovative strategies for augmenting the antitumor potential of natural killer (NK) cells. Chimeric antigen receptor natural killer (CAR-NK) cells exert dual cytotoxic effects against tumor cells through CAR-mediated antigen-specific recognition in concert with the nonspecific cytolytic activity mediated by intrinsic NK receptors. This review critically evaluates the clinical progression of CAR-NK cells specifically against solid tumors, focusing on mechanisms to overcome the immunosuppressive tumor microenvironment (TME), the complexity of allogeneic manufacturing, and the latest engineering strategies for enhanced homing and persistence. Specifically, we emphasize the urgent need for robust Phase II/III clinical data and standardized Good Manufacturing Practice (GMP) protocols to realize the full potential of off-the-shelf allogeneic CAR-NK therapies. Additionally, we examine technological advancements and emerging directions addressing persistent challenges in this domain to offer theoretical underpinnings and research perspectives for the clinical deployment of CAR-NK cell therapy in solid tumor management.
    Keywords:  chimeric antigen receptor natural killer cells; gene editing; immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.3389/ebm.2025.10841
  10. Front Immunol. 2025 ;16 1735763
    CAR-γδ T cells: a new paradigm of programmable innate immune sentinels and their systemic applications in cancer and beyond.
    Xiang Fang, Shixuan Yan, Long He, Changwen Deng.
      This review systematically introduces the concept of CAR-γδ T cells as programmable innate immune sentinels, innovatively proposing to overcome multiple limitations of conventional CAR-αβ T cells in both solid tumor therapy and non-malignant disease contexts. The core innovation lies in the deep integration of γδ T cells' natural immune features - including MHC-independent, anti-exhaustion phenotypic plasticity, and tissue-homing capability - with CAR engineering, potentially yielding synergistic effects between precise targeting, innate immune activation, and microenvironment modulation. We highlight recent advances in cutting-edge technologies such as multi-signal integration, genome editing, and the development of off-the-shelf CAR-γδ T cell platforms. Unlike previous reviews that focus narrowly on a single disease or signaling pathway, this work not only summarizes the biological characteristics of γδ T cells but also proposes a "δT-centric" engineering design principle and constructs a multi-disease application framework. In solid tumors, this approach may enable the remodeling of the immunosuppressive microenvironment and addresses tumor heterogeneity, whereas in non-malignant diseases-including fibrosis, autoimmune disorders, and chronic infections-it supports tissue homeostasis restoration. We propose that this paradigm could shift the perception of CAR-γδ T cells from conventional effector tools to dynamic immune hubs capable of responding adaptively to disease microenvironments. It proposes a novel conceptual and technological framework for both basic research and clinical translation across a broad spectrum of diseases.
    Keywords:  CAR-γδ T cells; innate-like T cell engineering; programmable immune sentinels; universal CAR platforms; δT-centric engineering
    DOI:  https://doi.org/10.3389/fimmu.2025.1735763
  11. HLA. 2026 Jan;107(1): e70550
    Chimeric Antigen Receptor T-Cell Therapy: More Than an Anti-Cancer Drug.
    Hannah C M Schenk, Ilse Gille, Carolt Arana, Jordi Rovira, Eduard Palou, Fritz Diekmann, Dave L Roelen, Mirjam H M Heemskerk, Sebastiaan Heidt.
      Initially, chimeric antigen receptor (CAR) T-cell therapy was developed to eliminate malignant B cells in haematological B-cell malignancies by targeting CD19 and B-cell maturation antigen. This approach achieved notable success, resulting in (malignant) B-cell depletion and inducing clinical remission in cancer patients. The scope of CAR T-cell therapy has since expanded to various other applications. Recently, CD19-directed CAR T cells have shown promising results in treating B-cell-mediated autoimmune diseases, with patients experiencing long-lasting symptom cessation. Despite these advancements, the unselective targeting of both pathogenic and protective B cells calls for precise immunotherapies capable of selectively removing pathogenic B cells. Therefore, antigen-specific CARs were designed to specifically interact with and deplete subpopulations of target cells expressing the target antigens. Subsequently, modified CARs were introduced by incorporating autoantigens into the sequence, which allowed antigen-specific B cells to bind to CAR T cells. Additionally, antigen-specific CAR T cells have been exploited to treat viral infections. Moreover, CAR technology was expanded to regulatory T cells (Tregs), where CARs can be adopted to induce a tolerogenic environment in target tissues, offering new possibilities in autoimmune diseases, as well as prevention of graft-versus-host disease in haematopoietic stem cell transplantation and transplant rejection in the setting of solid organ transplantation. Although CAR T cells and CAR Tregs are promising and broadly explored, safety issues must be addressed and possible solutions thoroughly investigated. This review outlines the broad potential of CAR-based therapies in autoimmunity, virology and transplantation while addressing the need for solutions to current safety issues.
    Keywords:  CAR (chimeric antigen receptor); autoimmunity; cellular therapy; infection; transplantation
    DOI:  https://doi.org/10.1111/tan.70550
  12. Research (Wash D C). 2026 ;9 1068
    Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside.
    Yuhe Wang, Wenxia Shao, Jianhua Mao, Qing Ye.
      As pioneering immunotherapy approaches, chimeric antigen receptor T cell (CAR-T) and natural killer cell (CAR-NK) therapies have shown notable clinical effectiveness when addressing different kinds of hematologic malignancies. For example, the application and efficacy of CAR-T cell therapy in acute lymphocytic leukemia, large B cell lymphoma, mantle cell lymphoma, and multiple myeloma have been widely recognized. In addition, the safety and feasibility of CAR-NK therapy when used to treat refractory/recurrent large B cell lymphoma have been verified. In particular, CD19-targeted CAR-T cell therapy has achieved marked efficacy and breakthrough progress in treating relapsed and refractory B cell leukemia and lymphoma. Although CAR-T cell therapy has achieved significant effectiveness in treating these diseases, patients still face challenges, including primary resistance and secondary recurrence after treatment. The complex mechanisms of resistance and recurrence involve multiple factors, such as target cells, CAR cell characteristics, and immune suppression conditions. This review examines resistance and recurrence mechanisms in CAR-T and CAR-NK therapies while exploring current therapeutic strategies and future research directions.
    DOI:  https://doi.org/10.34133/research.1068
  13. Cells. 2025 Dec 22. pii: 21. [Epub ahead of print]15(1):
    CAR-NK Engineering to Overcome TME Barriers.
    Fahmida Islam, Aleta Pupovac, Richard L Boyd, Alan O Trounson.
      Chimeric antigen receptor (CAR)-based immunotherapy has shown considerable promise in cancer treatment by redirecting immune effector cells to recognize and eliminate tumor cells in an antigen-specific manner. While CAR-T cells bearing tumor-specific CARs have shown remarkable success in treating some hematological malignancies, their clinical application is limited by cytokine release syndrome, neurotoxicity, and graft-versus-host disease. In contrast, CAR-natural killer (NK) cells retain their multiple forms of natural anti-tumor capabilities without the pathological side effects and are compatible with allogeneic "off-the-shelf" application by not requiring prior activation signaling. Despite CAR-NK therapies showing promising results in hematological malignancies, they remain limited as effector cells against solid tumors. This is primarily due to the complex, immunosuppressive tumor microenvironment (TME), characterized by hypoxia, nutrient depletion, lactate-induced acidosis, and inhibitory soluble factors. Collectively, these significantly impair NK cell functionality. This review examines challenges faced by CAR-NK therapy in combating solid tumors and outlines strategies to reduce them. Barriers include tumor antigen heterogeneity, immune escape, trogocytosis-mediated fratricide, rigid structural and metabolic barriers in the TME, immunosuppressive factors, and defective homing and cell persistence of CAR-NK cells. We also emphasize the impact of combining other complementary immunotherapies (e.g., multi-specific immune engagers and immunomodulatory agents) that further strengthen CAR-NK efficacy. Finally, we highlight critical research gaps in CAR-NK therapy and propose that cutting-edge technologies are required for successful clinical translation in solid tumor treatment.
    Keywords:  CAR-NK cells; TME; antigen heterogeneity; immune escape
    DOI:  https://doi.org/10.3390/cells15010021
  14. Mayo Clin Proc Innov Qual Outcomes. 2026 Feb;10(1): 100682
    Operationalizing Access for Chimeric Antigen Receptor T cell Therapies: A Cross-functional Perspective.
    Surya Singh, Carol Greulich, Ariel Perez, Kelly Terrell, Julie Walz-Jensen, Michael D Dalzell.
      Chimeric antigen receptor T cell (CAR T) treatment efficacy has been shown to be greater in those who receive timely infusions, while mortality rates increase with each month's delay in treatment. Yet health care infrastructure constraints, an intricate treatment process, and reimbursement complexities present challenges that affect timely patient access to CAR T therapy. Best practices for decreasing time to treatment are not well established. Autolus Inc convened an expert panel of 3 advisors from established hematopoietic stem-cell transplant centers and 3 advisors with extensive national or regional payer experience to identify operational barriers that contribute to treatment delays as well as potential means for addressing them. Opportunities exist to expand treatment capacity by reducing redundant prerequisites for treatment center certification and through collaboration between established centers and newer centers that need critical expertise to gain accreditation. Aligning clinical criteria are important for improving clinician understanding of the treatment process, facilitating timely referral to treatment centers, and streamlining payer authorization processes. Negotiating financial arrangements is the most time-consuming step of the process before CAR T manufacturing can begin; contracts between treatment centers and payers can help to facilitate timely care, but single-case agreements are necessary for treatment centers and payers without extensive CAR T experience. Single-case agreements should consider each side's experience and financial exposure. In identifying obstacles to timely care and working through potential solutions, participants developed a genuine appreciation for the interdependence among stakeholders. Recognition of mutual interest is a starting point for cross-functional cooperation.
    DOI:  https://doi.org/10.1016/j.mayocpiqo.2025.100682
  15. Mol Cancer Ther. 2026 Jan 10.
    CD47/SIRPα Immune Checkpoint Modulation: A Synergistic Strategy for Next-Generation CAR Therapies.
    Mohammad Javad Yousefi-Hashemabad, Amirhossein Kamroo, Ali Rezvanimehr, Kiarash Saleki, Erfan Barootchi, Aida Mehrani, Alireza Kordi, Andia Saleki, Pardis Zamani, Amirhossein Bazdar, Abdolrahman S Nateri, Shayan Barootchi, Nima Rezaei.
      Cancer immunotherapy has been revolutionized through the implementation of the state-of-the-art "chimeric antigen receptor" (CAR)-mediated therapies. CAR-based technologies, which encompass CAR T cells, CAR macrophages, and CAR-NK cells, show great promise in the treatment of various cancers. Despite the success of CAR-based therapies in treating malignancies, they face numerous challenges, including dysfunction of effector innate and adaptive immune cells, immunosuppressive tumor microenvironment (TME), antigen heterogeneity, and on-target/off-tumor bio-toxicity. The CD47/SIRPα axis is recognized as a critical innate immune checkpoint and is important in regulating myeloid-derived clearance of tumor cells and the innate-adaptive cells' cross-talk in cancer immunity. This signaling axis has risen as a promising target to boost the CAR-based immunotherapies by overcoming phagocytic inhibition and modulating immune evasion. This narrative review explores the integration of CD47/SIRPα modulation as an adjunct to CAR therapies. CD47/SIRPα immune-modulation revealed its potential to boost infiltration, persistence, and phagocytic activity of the immune cells. However, its blockade also poses challenges, including hematologic toxicities, CAR T cell clearance, and compensatory escape pathways. Future work will depend on selective targeting, combinatorial checkpoint modulation, and engineered CAR designs that preserve safety while unlocking durable responses. Herein, we discuss pre-clinical and clinical advancements, safety considerations, and cutting-edge advancements.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-0531
  16. Transplant Cell Ther. 2026 Jan 07. pii: S2666-6367(26)00004-7. [Epub ahead of print]
    From Vision to Viability: Developing Infrastructure for Cell and Gene Therapy Programs.
    Zahra Mahmoudjafari, Joseph McGuirk, Nausheen Ahmed.
       BACKGROUND: Cell and gene therapies (CGTs), including CAR T-cell therapy, tumor-infiltrating lymphocytes, and gene therapies, represent a transformative advancement in oncology and other disease states. Their delivery is complex, requiring multidisciplinary coordination, specialized infrastructure, and adherence to evolving regulatory standards. Institutions lacking robust frameworks risk inefficiencies, safety events, and non-compliance. Despite growing adoption, there is limited literature detailing operational strategies for implementing CGT programs.
    OBJECTIVE(S): To provide a comprehensive, practice-oriented framework for developing institutional infrastructure that supports safe, efficient, and sustainable delivery of CGTs. This manuscript aims to outline actionable strategies for health systems to operationalize CGT programs across clinical, operational, and financial domains.
    STUDY DESIGN: This work is a descriptive analysis and synthesis of best practices derived from early adopters, accreditation standards, and institutional experience. It presents a structured roadmap encompassing strategic planning, governance, operational readiness, pharmacy integration, financial modeling, technology infrastructure, quality management, and outreach strategies. No statistical analysis was performed, as this is a conceptual and operational framework rather than an empirical study.
    RESULTS: The proposed framework emphasizes eight interdependent domains that collectively enable successful CGT program implementation. Strategic planning establishes vision alignment, readiness assessments, and governance structures to guide resource allocation and sustainability. Operational readiness focuses on developing standard operating procedures, multidisciplinary education, and escalation pathways to ensure seamless patient care. Product access requires early engagement with manufacturers and qualification processes for both commercial and investigational therapies. Pharmacy plays a pivotal role in protocol development, toxicity management, and biosafety handling, while financial and payer strategies address reimbursement complexities and long-term sustainability. Technology and data integration within electronic health records and dashboards support real-time coordination and compliance reporting. Quality management ensures adherence to accreditation standards and continuous improvement. Finally, outreach and referral strategies streamline patient access and foster collaboration with community providers. Together, these domains form a comprehensive blueprint for mitigating risk, optimizing patient safety, and ensuring timely access to therapy.
    CONCLUSION(S): CGTs offer unprecedented therapeutic potential but require deliberate infrastructure development to translate innovation into clinical practice. Institutions that invest in coordinated multidimensional readiness, spanning strategic, operational, and financial domains, will be best positioned to deliver high-quality, equitable care. This framework serves as a blueprint for centers seeking to implement CGT programs and adapt to the rapidly evolving therapeutic landscape.
    DOI:  https://doi.org/10.1016/j.jtct.2026.01.002
  17. Cancer Res. 2026 Jan 05.
    Optimizing In Vivo CAR-T Cell Engineering for Cancer Immunotherapy.
    Ruiheng Wang, Jianhua Yu, Michael A Caligiuri, Shoubao Ma.
      Chimeric antigen receptor (CAR)-T cell therapy enables potent, antigen-specific immune responses and has demonstrated success in treating hematologic malignancies. However, conventional ex vivo CAR-T manufacturing remains costly, individualized, and logistically complex, posing significant barriers to accessibility and scalability. In vivo CAR-T cell engineering offers a transformative alternative by reprogramming endogenous T cells within the patient, bypassing the need for cell harvesting and expansion. This review focuses on current in vivo CAR-T delivery strategies, including viral vectors (such as lentiviruses, γ-retroviruses, adeno-associated viruses, and viral-like particles) and non-viral systems (such as lipid nanoparticles and polymer-based carriers), with a focus on how these platforms are engineered to achieve efficient, specific, and safe CAR transgene transfer. We also discuss the design principles of vector tropism, membrane modifications, and targeting ligands, as well as translational studies in both preclinical and clinical settings. Finally, the review explores delivery-related challenges and future perspectives for optimizing vector stability, enhancing T cell targeting, and reducing immunogenicity to advance in vivo CAR-T therapy toward broader clinical applications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3748
  18. Cell. 2026 Jan 08. pii: S0092-8674(25)01370-4. [Epub ahead of print]189(1): 6-22
    Next steps in regulatory T cells: Biology and clinical application.
    Chengyu Zou, Peiying Li, Bin Li, Tim Sparwasser, Junying Yuan.
      Recent advances in regulatory T cell (Treg) biology and clinical application of Treg-based treatments show promise as a new generation of transforming therapeutics for immune-related disorders, positioning Tregs as a "living drug" to rebuild immune tolerance and repair damaged tissues simultaneously. This perspective summarizes the key knowledge on Treg biology and highlights the recent important discoveries in the development of clinical applications based on Treg biology, from low-dose interleukin-2 therapy showing promising results in trials for ALS and adoptive Treg transfer demonstrating efficacy in preventing GVHD to early pilot studies of CAR Tregs. Drawing on these advances, we provide perspectives on key research priorities and translational challenges and set forth a roadmap that integrates basic and clinical insights into developing next-generation therapies focusing on precision tolerance strategies.
    Keywords:  AD; ALS; FOXP3; GVHD; Treg; autoimmune disease
    DOI:  https://doi.org/10.1016/j.cell.2025.11.035
  19. Mol Ther Oncol. 2026 Mar 19. 34(1): 201099
    CAR-T cell exhaustion in B cell lymphoma: Current status, mechanisms, and potential solutions.
    Ruocong Zhao, Jianglong Xia, Yuanyuan Zheng, Wenfa Huang, Li Yu, Lixin Wang.
      Chimeric antigen receptor T cell (CAR-T) therapy represents a revolutionary approach in the treatment of refractory or relapsed hematological malignancies including lymphoma. Despite its efficacy, a significant subset of patients experiences disease progression or relapse after initial response, and CAR-T cell exhaustion in the tumor microenvironment (TME) is a critical cause for the unsatisfactory responses. This review discusses the current situation of CAR-T therapies in the clinical treatment of lymphoma patients, the mechanisms of CAR-T cell exhaustion, and potential strategies to overcome CAR-T cell exhaustion, thereby bringing hope to improve therapeutic outcomes for lymphoma patients.
    Keywords:  MT: Regular Issue; cell therapy; chimeric antigen receptor; exhaustion; lymphoma
    DOI:  https://doi.org/10.1016/j.omton.2025.201099
  20. J Immunother Cancer. 2026 Jan 09. pii: e013285. [Epub ahead of print]14(1):
    Advancing adoptive T cell therapy in ovarian cancer: barriers, innovations, and emerging platforms.
    Gabriel Nascimento De Souza Santos, Celia DeJohn, Suzanne M Hess, Emese Zsiros, A J Robert McGray.
      Adoptive cell therapy (ACT) has demonstrated curative potential in select cancers, but its translation to solid tumors such as ovarian cancer (OC) has been hindered by multiple factors, including tumor heterogeneity, immune exclusion, and a profoundly immunosuppressive tumor microenvironment. This review provides a comprehensive analysis of current ACT modalities, including tumor-infiltrating lymphocytes, T cell receptor-engineered, and chimeric antigen receptor-T cell therapies, as well as emerging approaches such as bispecific T cell engager (BiTE)-secreting T cells, dual-targeting platforms, and synthetic antigen receptors. We examine their application in OC and contextualize relevant findings using insights from other solid tumors. Key barriers, including limited T cell persistence, antigen escape, and T cell exhaustion, are explored alongside strategies to enhance efficacy through cytokine armoring, checkpoint modulation, metabolic reprogramming, and gene editing. We further highlight innovations in safety engineering, including logic-gated and self-regulating synthetic circuits, to mitigate toxicity and improve precision. Additional attention is given to the evolving role of allogeneic products and in vivo engineering as scalable solutions. Finally, we emphasize the critical value of integrating high-dimensional tools such as spatial transcriptomics, single-cell profiling, and machine learning to refine ACT design, identify biomarkers of response, and support patient selection and stratification. Collectively, these advances offer a roadmap for overcoming the unique immunologic barriers to ACT in OC and accelerating the development of more potent, durable, and personalized T cell-based strategies.
    Keywords:  Adoptive cell therapy - ACT; Bispecific T cell engager - BiTE; Chimeric antigen receptor - CAR; Ovarian Cancer; Tumor infiltrating lymphocyte - TIL
    DOI:  https://doi.org/10.1136/jitc-2025-013285
  21. J Immunother Cancer. 2026 Jan 09. pii: e012318. [Epub ahead of print]14(1):
    Engineering single-vector logic-gated CAR T cells with transgene sizes beyond current limitations.
    Philipp C Rommel, Nils W Engel, Julia K Malachowski, Divanshu Shukla, Isabella R Hodson, Donna Gonzales, Johannes C M van der Loo, Regina M Young, James L Riley, Bruce L Levine, Carl H June.
       BACKGROUND: Engineering chimeric antigen receptor (CAR) T cells with logic-gated synthetic Notch (synNotch) receptor circuits can enhance specificity and mitigate on-target/off-tumor toxicity. However, the conventional synNotch system uses two lentiviral vectors encoding the synNotch receptor and inducible CAR, requiring dual transduction and cell sorting, which limits clinical translation. Integrating the synNotch-CAR circuit into a single lentiviral vector could overcome this limitation, yet manufacturing CAR T cells with large transgenes remains challenging, as increasing transgene size drastically reduces lentiviral titers and T cell transduction efficiency. Current production workflows compensate for low transduction efficiency by sorting transduced cells, further impeding clinical translation. Consequently, these constraints have limited the broader development of synNotch-CAR T cell therapies.
    METHODS: We engineered a single-vector synNotch (svsNotch) system that integrates all components of the conventional dual-vector circuit into one lentiviral vector to facilitate clinical translation. To overcome the low lentiviral titers and T cell transduction efficiency caused by the large svsNotch transgene, we established an optimized CAR T cell production workflow for effector T cells with large lentiviral transgenes.
    RESULTS: Our optimized workflow increased T cell transduction rates by up to 14.8-fold and enabled the production of effector T cells with lentiviral transgenes exceeding the effective packaging capacity limit of 9.2 kb. As a proof of concept, we engineered human epidermal growth factor receptor 2 (HER2)-mesothelin (MSLN) svsNotch (9.2 kb), in which a synNotch receptor targeting HER2 regulates the expression of a second-generation 4-1BBζ CAR against MSLN to enable selective targeting of double-positive HER2+MSLN+ ovarian tumors. In vitro, HER2-MSLN svsNotch T cells demonstrated superior specificity to conventional dual-vector synNotch-CAR T cells, with selective cytotoxicity against HER2+MSLN+ but not HER2koMSLN+ tumor cells. To enable in vivo monitoring, we engineered HER2-MSLN-click beetle green (CBG) svsNotch (10.1 kb) incorporating CBG luciferase. In mouse models using constitutive CAR T cells as controls, HER2-MSLN-CBG svsNotch T cells exhibited minimal cytotoxicity in the absence of HER2 and superior efficacy against HER2lowMSLNhigh and HER2highMSLNhigh tumors.
    CONCLUSION: These data establish a framework for engineering logic-gated single-vector immunotherapies and provide an optimized workflow for generating CAR T cells with transgenes that exceed current size limitations.
    Keywords:  T-lymphocytes; chimeric antigen receptor - CAR; immune modulatory; immunotherapy; ovarian cancer
    DOI:  https://doi.org/10.1136/jitc-2025-012318
  22. bioRxiv. 2026 Jan 02. pii: 2026.01.02.696502. [Epub ahead of print]
    CAR-T-drug conjugate against solid tumor.
    Shan Xin, Yanzhi Feng, Feifei Zhang, Jiang Yu, Chuanpeng Dong, Bo Tao, Kaiyuan Tang, Qihao Wu, Binfan Chen, Ping Ren, Nipun Verma, Chuan Liu, Kazushi Suzuki, Xinyu Ling, Daniel Park, Harriet Kluger, Jason M Crawford, Rong Fan, Jiangbing Zhou, Sidi Chen.
      Chimeric antigen receptor (CAR)-T cell therapy has been clinically successful in hematologic cancers but faces challenges in solid tumors, primarily due to limited tumor infiltration, immunosuppressive tumor microenvironments (TME), and antigen heterogeneity. While combining CAR-T cell therapy with chemotherapy can enhance antitumor activity, this often leads to substantial systemic toxicity. In this study, we introduce CAR-T-drug conjugate (CAR-T-D-C), a new class of dual-functional therapeutics that effectively addresses these obstacles by integrating click chemistry for precise conjugation of cytotoxic agents onto antigen-specific CAR-T cells. By transforming the hostile TME into an ally, this approach facilitates localized delivery of cytotoxic payload directly to the tumor site, enhancing the overall effectiveness of CAR-T therapy in solid tumors. CAR-T-D-Cs with different CAR-T cell binders exhibit robust antitumor activity across diverse solid tumor models, including both human tumor xenografts and syngeneic models. Spatial transcriptomic studies reveals that CAR-T-D-C achieves improved CAR-T tumor infiltration and functional activation within the TME. Compared to conventional CAR-T therapy, CAR-T-D-C markedly enhances immune cell infiltration, augments effector functions, promotes antigen spreading, amplifies systemic immune responses, and improves overall anti-tumor immunity. CAR-T-D-C represents a versatile therapeutic concept that combines the potency of small molecule drugs and the specificity of CAR-T cells as a 2-in-1 immunochemotherapy for treatment of solid tumors.
    DOI:  https://doi.org/10.64898/2026.01.02.696502
  23. Crit Care Med. 2026 Jan 07.
    Putting the Horse Before the CAR T Cells: Persistent Sepsis Risks Despite Improved Tolerance of Chimeric Antigen Receptor T-Cell Therapy.
    Daniel A Sweeney, Andre C Kalil.
      
    Keywords:  chimeric antigen receptor T cell; complications; critical care; infection; sepsis
    DOI:  https://doi.org/10.1097/CCM.0000000000007047
  24. Hematology. 2026 Dec;31(1): 2613505
    The efficacy and safety of CAR-T therapy in relapsed or refractory multiple myeloma patients: a systematic review and meta-analysis.
    Yiwei Zhou, Xueqi Xie, Kai Feng, Weijie Cao, Danfeng Zhang.
      Objectives: The introduction of novel therapies has markedly improved the prognosis of multiple myeloma (MM), yet relapse remains common. For patients with relapsed or refractory multiple myeloma (RRMM), immunotherapy - particularly chimeric antigen receptor T-cell (CAR-T) therapy - shows significant promise. This review summarizes current evidence on CAR-T efficacy and safety.Methods: We performed a systematic review of studies published between 1 January 2021 and 1 August 2024 in PubMed, Web of Science, and Embase. Of 4,301 articles identified, 29 met inclusion criteria.Results: Our findings demonstrate that CAR-T therapy is highly effective in the treatment of RRMM, with an overall response rate (ORR) of 86%. Among responders, the minimal residual disease (MRD) negativity rate was 78%. The median progression-free survival (mPFS) was 9.88 months, and the median duration of response (mDOR) was 12.17 months. In terms of safety, cytokine release syndrome (CRS) occurred in 83% of patients (any grade), with 5% experiencing grade ≥3 CRS. The incidence of grade ≥3 neurotoxicity (NT) was 2%. Infections were reported in 50% of patients (any grade), with 21% experiencing grade ≥3 infections.Conclusion: This meta-analysis provides robust evidence supporting the clinical application of CAR-T therapy in the management of relapsed or refractory multiple myeloma.
    Keywords:  CAR-T cell therapy; immunotherapy; multiple myeloma; systematic review
    DOI:  https://doi.org/10.1080/16078454.2026.2613505
  25. Cancer Lett. 2026 Jan 02. pii: S0304-3835(26)00003-0. [Epub ahead of print]639 218240
    CAR-T Cell Exhaustion in Cancer over the Past Decade: Mitochondrial Metabolism as a Target for Counteraction.
    Lingling Si, Di Wei, Jinghao Pan, Renato B Baleeiro, Louisa S Chard Dunmall, Yaohe Wang.
      Chimeric antigen receptor T (CAR-T) cell therapy has emerged as a transformative advancement in cancer immunotherapy, but remains limited by multiple challenges. The exhaustion of T cells represents a critical obstacle limiting the success of immunotherapeutic interventions. Targeting mitochondrial metabolism offers a promising approach to mitigate exhaustion and enhance CAR-T persistence. Mechanistically, mitochondrial dysfunction within the tumor microenvironment disrupts energy metabolism, reactive oxygen species (ROS) homeostasis, and cell survival, impairing CAR-T function. Here, we review the current challenges facing the clinical application of CAR-T therapy in cancers and summarize mitochondrial-centered approaches to overcome some of these obstacles by optimizing mitochondrial metabolic pathways. We emphasize the essential role of mitochondrial metabolism in augmenting therapeutic efficacy and persistence of CAR-T cells. Future breakthroughs will depend on robust clinical evidence and precise metabolic modulation to enhance CAR-T therapies.
    Keywords:  CAR-T therapy; Combination therapy; Metabolic reprogramming; Mitochondrial metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2026.218240
  26. Stem Cells. 2026 Jan 07. pii: sxaf084. [Epub ahead of print]
    Circadian Timing Optimizes Allo-HSCT to Prevent aGVHD: A Breakthrough in Chrono-Immunotherapy.
    Xiaguang Huang, Hening Xu, Yanru Xia, Zeshan Lu, Shiwei Duan, Yongming Xia.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely regarded as the most potent curative cell therapy for a range of malignancies, particularly hematologic cancers. However, its clinical application remains significantly constrained by acute graft-versus-host disease (aGVHD), a severe and potentially fatal complication. As such, developing more effective strategies to prevent and manage aGVHD has become an urgent priority in the field. In a groundbreaking study, the team led by Zhan Cheng and Zhu Xiaoyu introduced a novel time-based approach, revealing that the biological rhythm regulating the immune microenvironment can be harnessed to optimize the timing of hematopoietic stem cell infusion. Their findings demonstrate that this chronotherapeutic strategy can significantly reduce the incidence of aGVHD, offering a simple, drug-free, and cost-free innovation to improve outcomes in allo-HSCT.
    Keywords:  acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; chronotherapy; circadian rhythm; immune microenvironment
    DOI:  https://doi.org/10.1093/stmcls/sxaf084
  27. Mol Ther. 2026 Jan 06. pii: S1525-0016(25)01075-5. [Epub ahead of print]
    Combining conventional and adapter CAR T cells: An elegant solution to erase current CAR T cell limitations.
    Chiara Martinello, Els Verhoeyen.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.052
  28. Signal Transduct Target Ther. 2026 Jan 01. 11(1): 2
    Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.
    Yiran Wu, Yuchen Wu, Zhengyu Gao, Weixing Yu, Long Zhang, Fangfang Zhou.
      T cell exhaustion is a prevalent phenomenon in chronic infections and tumor microenvironments, severely compromising the effectiveness of antitumor and antiviral immunity. In recent years, there has been significant progress in understanding the underlying mechanisms of T cell exhaustion, including external factors and intrinsic cellular changes that drive this dysfunctional state. Key external factors such as persistent antigen exposure, immune checkpoint signaling, and the cytokine milieu, as well as intrinsic changes such as altered metabolic processes, epigenetic modifications, and transcriptional reprogramming, contribute to T cell dysfunction. Emerging therapies targeting T cell exhaustion aim to restore immune function and enhance antitumor and antiviral immunity. These therapeutic strategies include immune checkpoint inhibition, cytokine therapies, metabolic reprogramming, and cell-based therapies. Despite these advancements, reversing T cell exhaustion presents several challenges, such as individual variability, resistance, and potential side effects. Furthermore, accurately assessing markers of T cell functional recovery and the long-term impacts of these therapeutic approaches remain challenging research areas. This review provides an overview of the history and milestones in T cell exhaustion research; summarizes the mechanisms of T cell exhaustion and its implications in cancer, chronic infections, and autoimmune diseases; discusses advancements and challenges in emerging therapies; and explores future research directions aimed at improving T cell function and enhancing immune responses.
    DOI:  https://doi.org/10.1038/s41392-025-02327-3
  29. J Pharm Policy Pract. 2026 ;19(1): 2605391
    Factors influencing pharmaceutical companies' decisions to pursue compassionate use programs in the EU: a qualitative study in The Netherlands.
    Aimée Timmerman, Nienke Rodenhuis, Lucia Marie Albertine Crane-van Opstal, Anthonius de Boer, Leon Bongers, Anna Maria Gerdina Pasmooij.
       Background: Access to unauthorized medicines in the EU is legally restricted, except in certain cases such as clinical trials, magistral preparations, hospital exemptions, and early access programs, including compassionate use programs (CUPs) and named patient use (NPU). CUPs, regulated under Article 83 of Regulation (EC) No 726/2004, are intended for a group of patients with an unmet medical need. Despite this EU-wide regulation, the implementation of CUPs varies among member states, and the factors driving pharmaceutical companies to pursue them are poorly understood.
    Methods: This study conducted semi-structured interviews with pharmaceutical companies that had applied for CUPs in the Netherlands, as well as those with potentially eligible medicines that had not pursued CUPs. The interviews explored the decision-making processes and factors influencing CUP applications. Transcripts were analyzed using Atlas.ti software, with coding categories derived from the interview guide and emerging themes.
    Results: Ten interviews were conducted. Factors influencing CUP applications were classified into four categories: regulatory, medical, operational, and financial. Regulatory factors included recommendations from the Health and Youth Care Inspectorate (IGJ) and European Medicines Agency (EMA), concerns about post-marketing authorization uncertainties, and timelines for CUP approval. Medical factors involved unmet medical needs, patient numbers, and the alignment of CUP indications with authorized indications. Operational factors included prior experience with CUPs, supply availability, and the appeal of NPU due to faster approval times. Financial factors centered on reimbursement expectations and decisions by company headquarters on the free provision of medicines.
    Conclusion: The decision to pursue CUPs is influenced by multiple factors, with regulatory uncertainties and operational complexities playing significant roles. Improving clarity concerning CUP regulations, particularly data collection and the post-marketing phase, could encourage more pharmaceutical companies to apply for CUPs, which would provide patients with earlier access to potentially promising treatments.
    Keywords:  Compassionate use; early access; medicines; named patient; unmet need
    DOI:  https://doi.org/10.1080/20523211.2025.2605391
  30. World J Pediatr. 2026 Jan 06.
    CAR-NK cell therapy: a new frontier in the treatment of pediatric autoimmune diseases.
    Qing Ye, Han-Yan Meng, Jian-Hua Mao.
      
    DOI:  https://doi.org/10.1007/s12519-025-01010-5
  31. Bioanalysis. 2025 Nov;17(22): 1365-1409
    2025 White Paper on Recent Issues in Bioanalysis: Redosing Patients with AAV Gene Therapy; CRS Immunogenicity Risk; Shedding Assays; NHP Studies Immunogenicity; CMC vs Bioanalytical Assays; Artificial Intelligence-Powered Genomic Pipelines for NGS (PART 3A - Recommendations on Gene, Cell, and Vaccine Therapies Immunogenicity & Technologies; Biotherapeutics & Biosimilars Immunogenicity Assessment & Clinical Relevance PART 3B - Regulatory Agencies' Input on Immunogenicity/Technologies of Biotherapeutics, Gene, Cell & Vaccine Therapies).
    Omar Tounekti, Sophie Shubow, Sarah Wassmer, Andrea Van Tuyl, Lin Yang, Binsheng Gong, Mohsen Rajabi Abhari, Warren Kalina, Heather Myler, Jason DelCarpini, David Escobar, Michele Fiscella, Boris Gorovits, Swati Gupta, Susan C Irvin, Chad Irwin, Wojciech Jankowski, Vibha Jawa, Hatice Karauzum, Claire Kerridge, Yanmei Lu, Christian Mayer, Jessica McGregor, Andrew Melton, Rocio Murphy, Jasdeep Nanra, Anna Nowocin, Michael A Partridge, Sandra Prior, Zuben Sauna, Bradley Scott, Jessica Seitzer, Mark Stern, Hiroshi Sugimoto, Melissa Taylor, Adrian Wong, Wenming Xiao, Yuanxin Xu, Tong-Yuan Yang, Daisy Yuill, Robert J Kubiak, Theingi Thway, George Gunn, Ryan Pelto, Giane Sumner, Daniel Baltrukonis, Sanjay L Dholakiya, Shannon Dogmanits, Fabio Garofolo, Maria Jadhav, Daniel Kramer, Erik Meyer, Susovan Mohapatra, Reza Mozaffari, Kun Peng, Samuel Pine, Johann Poetzl, Michele Rasamoelisolo, Weiping Shao, Roland F Staack, Steven Swanson, Atiya Taqui, Stephanie Vauleon, Yun Wang, Yi Wen.
      The 19th Workshop on Recent Issues in Bioanalysis (19th WRIB) took place in New Orleans, LA, USA on April 7-11, 2025. Over 1200 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 19th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "Implementation Practice for the Newest ELN/LIMS Systems" and on "Vaccine Cell-Based/Functional & Molecular Assays as part of the harmonization of vaccine clinical assays global initiative" were the special features of the 19th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and Regulatory Agency experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2025 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2025 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication (Part 3) covers in the Part 3A the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity and in Part 3B the Regulatory Inputs on these topics. Part 1 (Mass Spectrometry Assays and Regulated Bioanalysis/BMV) and Part 2 (Biomarkers/BAV, IVD/CDx, LBA and Cell-Based Assays) are published in volume 18 of Bioanalysis, issues 3 and 2, respectively.
    Keywords:  Bioanalysis; WRIB; biomarkers; cell therapy; gene therapy; immunogenicity; vaccine
    DOI:  https://doi.org/10.1080/17576180.2025.2586976
  32. AAPS PharmSciTech. 2026 Jan 09. 27(1): 70
    Admixture Compatibility Studies in Parenteral Formulations: Packaging, Device, and Regulatory Perspectives.
    Chetana Eknure, Vishvesh Joshi, Yogeshwar Bachhav.
      Parenteral therapies are vital in critical care, oncology, and nutrition, offering rapid onset, precise dosing, and high bioavailability. However, their safety is often compromised by admixture incompatibilities and drug-device interactions that threaten stability, efficacy, and patient outcomes. This review synthesizes the current scientific understanding of physicochemical and material-based incompatibilities in reconstituted formulations, intravenous drug admixtures, and parenteral nutrition, highlighting their implications for safety and efficacy. Key risks include precipitation, pH shifts, phase separation, leachables, particulates, and adsorption, with documented links to treatment failure, infusion reactions, and product recalls. Interactions with packaging systems-glass, plastics, elastomers, and siliconized components-are critically examined, alongside regulatory requirements for extractables, leachables, and container-closure integrity. Emerging strategies, such as advanced packaging materials, fluoropolymer-coated elastomers, and real-time monitoring technologies, are highlighted as pathways to safer parenteral therapy. By uniting clinical insights with regulatory requirements and emerging technologies, this review highlights admixture compatibility studies as essential to ensuring the safety, efficacy, and reliability of parenteral drug delivery.
    Keywords:  Admixture compatibility; Container-closure system; Drug-device interactions; Parenteral formulations; Regulatory Compliance
    DOI:  https://doi.org/10.1208/s12249-025-03315-0
  33. Med Care. 2026 Feb 01. 64(2S Suppl 3): S314-S319
    Leveraging PCORnet® to Advance Clinical Genetics and the Genomic Learning Health System.
    Russell L Rothman, Josh Peterson, Sunil Kripalani, Jennifer B Barrett, Lisa Bastarache, Les Lenert, Bradley Taylor, Ryan Carnahan, Lemuel R Waitman.
       BACKGROUND: Scientific advances and cost efficiencies in genetics and genomics are expanding clinical application for prevention, diagnosis, and treatment.
    OBJECTIVE: PCORnet®, a research network that includes participation from 78 health systems nationally and is linked to more than 47 million unique patients with at least one encounter annually, can help (1) understand the ability of genetics/genomics to predict health outcomes, (2) identify diseases impacted by genetic/genomic factors, (3) evaluate pharmacogenomics' role in medication optimization, (4) evaluate emerging gene therapies, and (5) compare clinical genetic or genomic strategies within learning health systems to improve outcomes, while (6) facilitating patient and other partner engagement across these areas.
    MAIN ARGUMENTS: The breadth of data accessible via PCORnet represents a unique opportunity to study relationships among genetic markers and clinical and exposome-based disease risk factors, particularly as more genomic data become available. The network's experience developing computable phenotypes for identifying specific diseases can be leveraged to evaluate the role of genetics/genomics in health. The PCORnet infrastructure can be used to identify patients with particular conditions for predictive modeling or comparative clinical effectiveness research using electronic health record data. The network can also recruit patients for observational cohorts or pragmatic clinical trials on pharmacogenomics or the return of genetic results, evaluation of emerging gene therapies, or embedded research into learning health systems to compare clinical genetics/genomics implementation approaches in health care. The partner engagement focus of the PCORnet® Network Partners can enrich research and improve health care delivery and outcomes. The rise of clinical genetics and genomics will profoundly impact health care in the next decade, and the PCORnet® Network Partners are primed to make a leading contribution in this area.
    Keywords:  PCORnet; comparative clinical effectiveness research; genetics; genomics; real-world evidence research
    DOI:  https://doi.org/10.1097/MLR.0000000000002247
  34. J Appl Genet. 2026 Jan 08.
    Epstein-barr virus and multiple sclerosis: from pathogenesis and diagnosis to EBV-specific T cell therapy and gene-targeted therapeutics.
    Mukesh Pushkarna, Ahmed Zwamel, Seema Verma, H Malathi, Mukhlisa Mustafayeva, Harpreet Kaur, Ali M Ali Al-Nuaimi, Beneen Husseen, Mohammad Dahghani.
      Multiple sclerosis (MS) is a central nervous system (CNS) disorder defined by inflammation, demyelination, and neuronal damage. Several independent studies have confirmed the prevalence of EBV infection in MS and the presence of elevated anti-EBV antibody titers in serum prior to and throughout the clinical period of MS. EBV stands out from other human-infecting viruses in that it can activate, infect, and clone the B cells and remain a latent infection inside them. The prevalence of EBV-positive B cell lymphoproliferative diseases in immunocompromised individuals demonstrates the critical significance of immune surveillance in managing EBV infection. It has also been postulated that a deficiency in EBV-specific CD8+ T cell regulation predisposes to MS by allowing EBV-infected autoreactive B cells and plasma cells to concentrate in the CNS. Thus, EBV-specific T-cell therapy might have the potential to eradicate B lymphocytes infected by EBV in the CNS, preventing disease development and leading to enhanced clinical outcomes. One of the effective approaches for treating MS patients is application of EBV-specific T cells. In this method, peripheral blood mononuclear cells (PBMCs) are isolated from patients and expanded with EBV-specific antigens, resulting in antiviral cytotoxic response. This review discusses the significance of EBV in the pathogenesis of MS, the impact of disease-modifying T-cell treatments targeting EBV, therapeutic implications to target EBV in MS pathogenesis, and several novel EBV-targeting gene therapies.
    Keywords:  Anti-EBV immunity; EBNA1; EBV-specific t-cell therapy; Multiple sclerosis
    DOI:  https://doi.org/10.1007/s13353-025-01041-8
  35. Curr Neurol Neurosci Rep. 2026 Jan 03. 26(1): 7
    Immunotherapies for Central Nervous System Tumors and their Neurologic Complications.
    Kun-Wei Song, Brian J Scott.
       PURPOSE OF REVIEW: To discuss the landscape of immunotherapy trials for central nervous system (CNS) tumors including immune checkpoint inhibitors, vaccine therapies, oncolytic viruses, and chimeric antigen receptor T-cell therapy as well as explore the corresponding spectrum of neurologic toxicities.
    RECENT FINDINGS: As more clinical trials are underway in CNS tumors, we are starting to appreciate both the promise of immunotherapy and current limitations. While a subset of patients demonstrate benefit, immunotherapy trials have not transformed CNS tumor outcomes, which prompts the field to consider next generation therapies and combinatorial approaches. In addition, novel toxicities of CNS immunotherapy are being described such as tumor-inflammation associated neurotoxicity. Immunotherapy in CNS tumor is still in its nascent stages and shows early signs of promise. However, immunotherapeutic approaches in CNS tumors need to account for the unique physiology of the CNS and the corresponding neurologic toxicities that are associated with therapies targeting the CNS. Elucidating both will set the stage for advancement of safe and effective immunotherapy for CNS tumors.
    Keywords:  Immune-oncology; Immunotherapy; Neurotoxicity; Pseudoprogression; Tumor-inflammation associated neurotoxicity
    DOI:  https://doi.org/10.1007/s11910-025-01477-9
  36. Kidney Int. 2026 Jan;pii: S0085-2538(25)00865-8. [Epub ahead of print]109(1): 31-33
    Toward precision immunotherapy in nephrology: 1 step forward.
    Nicola M Tomas.
      Membranous nephropathy is an autoimmune disease most commonly caused by autoantibodies against the phospholipase A2 receptor 1. The pathogenicity of these autoantibodies offers the chance to develop highly specific therapies by targeting their cellular source (i.e., the autoreactive B cells). In this issue, Altun et al. provide further evidence for the feasibility of chimeric autoantibody receptor T cells to selectively eliminate these cells in phospholipase A2 receptor 1-associated membranous nephropathy, offering unprecedented specificity. Future studies need to address important open questions to evaluate the translational potential of this approach.
    DOI:  https://doi.org/10.1016/j.kint.2025.10.007
  37. JAAD Case Rep. 2026 Jan;67 226-229
    CD30+ T-cell lymphoma following Chimeric Antigen Receptor T-cell therapy (CART-cell therapy): Diagnostic uncertainty in a postimmunotherapy setting.
    Madison McClanahan, Madison Stokes.
      
    Keywords:  CAR-T cell therapy; CD30+ lymphoma; CD30-positive lymphoma; cutaneous T-cell lymphoma; dermatology; immune reconstitution; lymphoproliferative disorders; multiple myeloma; oncology; secondary malignancy; solitary cutaneous lesion; spontaneous regression
    DOI:  https://doi.org/10.1016/j.jdcr.2025.11.005
  38. Exp Hematol Oncol. 2026 Jan 08. 15(1): 1
    Hypoxia promotes BCMA loss and a suppressive secretome thereby hindering CAR T cell therapy in multiple myeloma.
    Chenggong Tu, Arne Van der Vreken, Fien Meeus, Lauren van den Broecke, Jack Brons, Kim De Veirman, Karin Vanderkerken, Elke De Bruyne, Karine Breckpot, Eline Menu.
       INTRODUCTION: Multiple myeloma (MM) develops in the hypoxic bone marrow (BM) microenvironment, which alters tumor behavior and immune responses. While hypoxia is known to directly suppress immune function, its effect on immunotherapy-relevant antigen expression and the MM secretome remains underexplored. Here, we investigated how hypoxia affects BCMA expression and BCMA-targeted CAR T cell responses.
    METHODS: MM cells were cultured under normoxia (21% O₂) or hypoxia (1% O₂). BCMA surface and total expression were analyzed. Anti-BCMA CAR T cells were co-cultured with normoxic or hypoxic MM cells to assess cytotoxicity and cytokine release. Conditioned media and small extracellular vesicles (sEVs) were isolated, quantified, and RNA-profiled.
    RESULTS: MM cells cultured in hypoxia showed reduced BCMA surface and total protein expression, resulting in reduced CAR-mediated signaling. Importantly, the hypoxic tumor secretome further reduced BCMA levels and significantly impaired CAR T cell killing and cytokine production, which was partially reversible by γ-secretase inhibition. To dissect the suppressive nature of the hypoxic secretome, we identified an increase in small extracellular vesicle (sEV) release under hypoxia. RNA profiling of sEVs revealed a hypoxia-induced RNA signature with potential immunomodulatory roles.
    CONCLUSION: This study shows that hypoxia diminishes BCMA expression and enhances secretion of immunosuppressive factors, including sEVs, thereby limiting the efficacy of BCMA CAR T cell therapy in MM.
    DOI:  https://doi.org/10.1186/s40164-025-00732-6
  39. Pract Neurol. 2026 Jan 06. pii: pn-2025-004890. [Epub ahead of print]
    CAR-T cells in the treatment of neurological autoimmune diseases.
    New and Emerging Oncotherapeutic Neurotoxicity (NEON) Network
      Chimeric antigen receptor T cells (CAR-T cells) have revolutionised cancer treatment by offering personalised therapy of unprecedented efficacy to patients with relapsed B-cell malignancies and myeloma. CAR-T cells are designed selectively to target CD19 or other B-cell antigens with high affinity, leading to a potent immune response and effective killing of malignant B cells. More recently, CAR-T treatment has been shown to be safe and effective in a very limited number of patients with severe, refractory autoimmune conditions such as systemic lupus erythematosus, systemic sclerosis and myositis. This paper describes the early use and feasibility of CAR-T therapies in the treatment of refractory autoimmune neurological diseases.
    Keywords:  NEUROIMMUNOLOGY
    DOI:  https://doi.org/10.1136/pn-2025-004890
  40. Immunotherapy. 2026 Jan 07. 1-2
    Recharging cellular immunotherapy - targeting immunometabolic aging.
    Kathrine Rallis, Alexandra Pommier, Abhishek Singh, José Cancelas.
      
    Keywords:  CAR T cells; Immunotherapy; aging; cancer; cellular therapy; metabolism
    DOI:  https://doi.org/10.1080/1750743X.2025.2607468
  41. Int J Mol Sci. 2025 Dec 25. pii: 248. [Epub ahead of print]27(1):
    Hybrid Nanocarriers for Cancer Therapy: Advancements in Co-Delivery of Gene Therapy and Immunotherapy.
    Kulzhan Berikkhanova, Isah Inuwa, Abdulrahman Garba Jibo, Nurzhan Berikkhanov, Nurzhan Bikhanov, Yessenkhan Sultan, Ardak Omarbekov.
      Over the years, cancer has continued to be a leading global health threat, prompting researchers to explore advanced therapies that go beyond traditional treatments like chemotherapy and radiotherapy. Among these advanced therapies, gene therapy and immunotherapy have shown significant promise in treating cancer by either altering genetic makeup or stimulating the immune system. However, their clinical applications face significant obstacles such as poor drug delivery, rapid degradation, and immune system clearance. Hybrid nanocarriers have emerged as a transformative development in modern precision oncology, enabling the co-delivery of gene therapy and immunotherapy agents in a highly targeted manner to address the persistent limitations of traditional cancer treatments. This review focuses on hybrid nanocarrier systems specifically engineered for co-delivery applications and critically evaluates when and how these multifunctional platforms outperform conventional single-modality or non-hybrid formulations. We compare key hybrid architectures in terms of payload compatibility, pharmacokinetics, immune modulation, and translational readiness, and examine the influence of tumor microenvironmental characteristics on their therapeutic performance. Particular emphasis is placed on stimuli-responsive designs, biomimetic surface engineering, and artificial intelligence-assisted optimization as emerging strategies to enhance co-delivery efficacy. By synthesizing current evidence and identifying key scientific and manufacturing gaps, this review aims to provide a practical foundation for advancing hybrid nanocarriers from laboratory development to clinically meaningful, personalized cancer therapies.
    Keywords:  cancer; gene therapy; hybrid nanocarriers; immunotherapy; precision oncology
    DOI:  https://doi.org/10.3390/ijms27010248
  42. J Biomed Sci. 2026 Jan 05. 33(1): 4
    Microbiome modulation of tumorigenesis and immune responses.
    Yuning Chen, Ying Fang, Zibai Lyu, Yanxin Tian, Siyue Niu, Yan-Ruide Li, Lili Yang.
      The microbiome has emerged as a critical, context-dependent regulator of tumorigenesis and anticancer immunity, capable of either promoting cancer progression or protecting against malignancy. This dual role is mediated by multiple interconnected mechanisms-including chronic inflammation, modulation of immune responses, and alterations in host metabolic signaling. These microbiome-cancer interactions vary across organs, influencing malignancies in the colon, breast, lung, and beyond. Clinically, the microbiome significantly affects patient responses to cancer therapies, particularly immunotherapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR)-T cell therapy. Although emerging therapeutic strategies aimed at modulating the microbiome have shown promising early results, challenges remain, including individual microbiome variability and the dynamic interplay between the immune system and microbial communities. Nevertheless, harnessing the microbiome holds significant potential to transform precision oncology, offering personalized cancer prevention and treatment strategies tailored to each patient's unique microbial ecosystem.
    Keywords:  Cancer immunotherapy; Dysbiosis; Immune modulation; Microbial metabolites; Microbiome; Microbiome-targeted therapies; Tumorigenesis
    DOI:  https://doi.org/10.1186/s12929-025-01208-9
  43. Drug Discov Today. 2026 Jan 06. pii: S1359-6446(26)00002-4. [Epub ahead of print] 104597
    Gaining regulatory acceptance for novel technologies in nonclinical drug development: A scoping review of its conceptualization in scientific literature.
    Ivar T van der Zee, Joyce M Hoek, Jarno Hoekman, Marie L De Bruin.
      Although integrating novel technologies into nonclinical drug development can counteract declining R&D success, their path to regulatory acceptance is often unclear and uncertain as they are not subject to a single, predictable regulatory approval framework like medicinal products. Existing literature on regulatory acceptance is mostly confined to specific technologies or regulatory pathways, hindering cross-domain learning. Therefore this scoping review develops a more context-agnostic understanding of regulatory acceptance by characterizing its commonalities across a range of technological and regulatory contexts. Our analysis of 54 articles found that regulatory acceptance can take on multiple forms, shaped by a particular scope (technological, contextual, and geographical) and formation process involving a driving need, gaining regulatory confidence, and interaction between actor groups. As technological specificity increases, the nature of the aforementioned elements shifts from broad discussions of potential to formal, evidence-based procedures. Understanding acceptance as a diverse process unified by core conceptual elements, rather than a single hurdle, provides a common language that cuts across technological domains and helps contextualize future research, thereby enabling regulators and developers to better integrate novel technologies in nonclinical drug development.
    Keywords:  drug development; innovation; nonclinical; regulatory; regulatory acceptance; regulatory readiness
    DOI:  https://doi.org/10.1016/j.drudis.2026.104597
  44. Health Sci Rep. 2026 Jan;9(1): e71652
    Towards an Integrated Framework for Health Surveillance Systems: A Systematic Literature Review of Design Components and Implementation Challenges.
    Maryam Mollabagher, Alireza Hassanzadeh, Mohammad Mahdi Sepehri, Abbas Habibelahi, Abolghasem Sarabadani.
       Background and Aims: Health surveillance systems play a critical role in early detection, timely response, and evidence-based policymaking. Despite significant technological progress, challenges such as data fragmentation, limited interoperability, and inconsistent governance continue to undermine system effectiveness. This study aims to advance the understanding of surveillance design by developing an integrated framework that consolidates technical, organizational, and ethical dimensions.
    Methods: A systematic literature review (SLR) was conducted following PRISMA 2020 guidelines, covering studies indexed in Scopus and Web of Science up to April 2025. From 191 initially retrieved records, 36 studies met the inclusion criteria and were thematically analyzed.
    Results: Through thematic analysis, ten key design components were identified. These findings offer actionable insights for policymakers, healthcare administrators, and system developers. Based on these findings, an integrated, evidence-based framework is proposed to support effective system implementation. These key components are: leadership and management, stakeholder engagement, education and awareness, workforce competence, finance and insurance, data privacy and security, patient comfort, risk assessment, infrastructure readiness, and cultural/ethical considerations.
    Conclusion: The synthesis revealed recurring implementation challenges, including fragmented data systems, inadequate stakeholder participation, and limited financial or technical capacity. Based on the findings, this study proposes an evidence-based integrated framework to guide the design and implementation of adaptive, efficient, and ethically grounded surveillance systems. The proposed framework provides actionable insights for policymakers, healthcare administrators, and digital health architects seeking to strengthen surveillance infrastructures across diverse health settings and promote sustainable, data-driven decision-making.
    Keywords:  artificial intelligence; digital health; medical informatics; public health surveillance; surveillance systems; systematic literature review (SLR)
    DOI:  https://doi.org/10.1002/hsr2.71652
  45. RSC Adv. 2026 Jan 02. 16(2): 1292-1309
    Hybrid exosomes: a rising horizon for precision cancer therapy.
    Swarup Sonar, Asmit Das, Sidhanti Nyahatkar, Rajib Dhar, Ketki Kalele, Vinod R M T Balasubramaniam, Ling Shing Wong, Vinoth Kumarasamy, Vetriselvan Subramaniyan.
      Extracellular vesicles (EVs) are nanoscale vesicles, which show significant promise as biomarkers for cancer diagnosis and prognosis, by providing valuable information about cancer progression and treatment response. Their therapeutic potential (including their popular subset: exosomes) is significant, but challenges remain. These limitations with natural exosomes, necessitate innovative engineering strategies. However, current methods for engineering exosomes, such as chimeric and surface modifications, still need to be improved. A prominent issue is drug off-targeting, leading to ineffective treatment and side effects. To address these challenges, "hybrid exosomes" have been engineered by combining the inherent biocompatibility of natural exosomes with the versatility of synthetic nanoparticles. Cutting-edge design strategies for hybrid exosomes, such as bio-hybrid approaches, emphasize their superior drug loading capacity, and targeted delivery to tumor sites, resulting in minimized toxicity profiles. Furthermore, we showcase recent breakthroughs in leveraging hybrid exosomes for the effective delivery and cellular uptake of chemotherapeutic agents and immunotherapies, which offer significantly enhanced therapeutic outcomes in preclinical cancer models, with emerging clinical relevance. This review explores the evolving field of hybrid exosomes, a novel approach to cancer therapeutics and highlights their potential to overcome existing limitations in cancer treatment. Hybrid exosomes offer a transformative approach to cancer treatment, promising affordable and effective precision therapy with a significant impact on cancer therapeutics.
    DOI:  https://doi.org/10.1039/d5ra04927j
  46. Cancers (Basel). 2025 Dec 29. pii: 107. [Epub ahead of print]18(1):
    Is There a Future for CAR-T Therapy in Acute Myeloid Leukemia?
    Caterina Alati, Martina Pitea, Matteo Molica, Marco Rossi, Maria Eugenia Alvaro, Gaetana Porto, Erica Bilardi, Giovanna Utano, Giorgia Policastro, Maria Caterina Micò, Violetta Marafioti, Massimo Martino.
      Acute myeloid leukemia (AML) is an aggressive cancer with rapid progression and a high relapse rate, highlighting the urgent need for effective treatments. While recent advances in drug therapies and combination regimens have improved outcomes, relapsed and refractory (R/R) AML still shows low response rates, poor prognosis, and limited survival. The lack of effective immunotherapies further complicates the management of R/R AML. The bone marrow tumor microenvironment (TME) poses a significant barrier, requiring multifaceted, combined therapeutic strategies for clinical success. This TME creates an immunosuppressive and metabolically challenging environment that limits the expansion, persistence, cytotoxicity, and survival of chimeric antigen receptor (CAR) T cells. Unlike CD19 in B-cell acute lymphoblastic leukemia (B-ALL), AML lacks a truly leukemia-specific antigen. Although clinical trials are ongoing, no CAR-T therapies have received FDA approval for AML. This paper explores the reasons behind these ongoing challenges.
    Keywords:  AML; CAR-T therapy; acute myeloid leukemia; leukemia-specific antigen; treatment; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers18010107
  47. Cell Rep Methods. 2026 Jan 08. pii: S2667-2375(25)00308-X. [Epub ahead of print] 101272
    Generation of thymus-reconstituting T cell progenitors from human pluripotent stem cells.
    Elena S Philonenko, Baoyun Zhang, Eugene Albert, Zahir Shah, Denis Maksimov, Yahai Shu, Peng Li, Pavel Volchkov, Igor M Samokhvalov.
      Generating a large number of progenitors that can repopulate the immune system of a recipient is one of the key steps toward efficient cancer immunotherapy. Here, we describe the engineering of T cell progenitors capable of direct and long-term reconstitution of the thymus. In the thymus, human pluripotent stem cell (hPSC)-derived progenitor T cells (pro-T cells) developed into single-positive human T cells that entered circulation and settled in the spleen. Single-cell transcriptome analysis of differentiating hPSCs attested to the emergence of cells that displayed the transcription signature of the early T cell progenitors. Comparative transcription profiling revealed the similarity of the hPSC-pro-T cells with the early T cell precursors of the human thymus. The in vitro generation of T cell progenitors provides a powerful model for studying the molecular mechanisms of human T cell development and improves the perspectives for T cell regenerative medicine, including chimeric antigen receptor T (CAR-T) cell therapies.
    Keywords:  CP: stem cell; T cell progenitors; cell transplantation; differentiation; human pluripotent stem cells; thymus
    DOI:  https://doi.org/10.1016/j.crmeth.2025.101272
  48. Ther Adv Hematol. 2026 ;17 20406207251407511
    Efficacy and safety of chimeric antigen receptor T-cell therapy in relapsed/refractory large B-cell lymphoma: a systematic review and meta-analysis.
    Qiang Li, Shenghua Xu, Yun Zhong, Peng Rao, Hui Huang, Yan Huang.
       Background: Individuals diagnosed with relapsed or refractory large B-cell lymphoma (R/R LBCL) typically exhibit a dismal prognosis when treated with conventional therapeutic modalities. CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has brought about a paradigm shift in the treatment paradigm of this disease. Nevertheless, a comprehensive assessment of the efficacy and safety profiles of diverse CAR-T products (e.g., axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel)) is imperative.
    Objective: This systematic review aims to systematically summarize and evaluate the efficacy and safety of CAR T-cell therapies for R/R LBCL through systematic review and meta-analytic approaches.
    Design: This is a systematic review and meta-analysis.
    Data sources and methods: Relevant studies were identified by systematically searching PubMed and Web of Science until November 29, 2023. Cohort studies and clinical trials were incorporated, with the inclusion of single-arm studies. CAR T-cell therapies are involved in tisa-cel, axi-cel, and liso-cel. Proportions and their 95% confidence intervals were calculated using standard meta-analytic approaches.
    Results: Thirty-seven studies were included in meta-analyses, liso-cel demonstrated equivalent overall survival rates (70.3%) to axi-cel (65.6%) at 12 months post-treatment, whereas tisa-cel was 48.0%. Objective response rate for liso-cel was comparable to axi-cel (79.0% vs 76.8%, p meta-regression = 0.74), both of which were notably higher than those observed for tisa-cel (58.3%, both p meta-regression < 0.05). Regarding safety assessments, liso-cel exhibited the lowest cytokine release syndrome rate at 43.0%, followed by tisa-cel at 70.9%, and axi-cel at 87.9%. However, tisa-cel had the lowest incidence of neurologic events (14.9%), in contrast to liso-cel (21.1%) and axi-cel (52.3%).
    Conclusion: Based on the available evidence, liso-cel has shown promising efficacy and a manageable safety profile in patients with R/R LBCL, when compared to axi-cel and tisa-cel. However, real-world data on liso-cel are limited.
    Keywords:  axicabtagene ciloleucel (axi-cel); lisocabtagene maraleucel (liso-cel); meta-analysis; relapsed or refractory large B-cell lymphoma (R/R LBCL); systematic review; tisagenlecleucel (tisa-cel)
    DOI:  https://doi.org/10.1177/20406207251407511
  49. Compr Rev Food Sci Food Saf. 2026 Jan;25(1): e70320
    Probiotic Development Strategy Centered on Stability and Regulatory Considerations.
    Hye Kim, Ariful Haque, Abdur Razzak, Min Ji Jang, Sehyeon Song, Seockmo Ku.
      The development of probiotic strains has become a major focus in both academic and industrial research, driven by their health benefits and growing consumer demand. However, functional outcomes demonstrated under laboratory conditions often fail to align with the stability and large-scale performance required for industrial applications, creating a major obstacle to commercialization. This gap underscores the need for standardized evaluation frameworks that integrate scientific validation with industrial performance metrics. This review critically examines the probiotic development pipeline, encompassing strain screening, resilience-enhancing strategies, and global regulatory frameworks. Particular attention is given to the effects of production stressors such as heat, oxygen, and digestion on strain viability. Studies reporting up to a 31-fold increase in survival after heat shock and up to a 100-fold improvement through microencapsulation during drying are highlighted to illustrate both the potential and limitations of adaptive strategies. These findings reveal the strong strain specificity and inconsistent reproducibility of current approaches, offering important insights for strategic development. Furthermore, regulatory systems in the United States, European Union, Japan, Korea, and China are compared to emphasize how heterogeneity in classification, safety assessment, and functional substantiation complicates global market entry. This review delves into how harmonized evaluation frameworks and sustained collaboration between academia, industry, and regulatory authorities help to develop next-generation probiotics by integrating functionality, safety, stability, industrial application, and regulation parameters to achieve balanced progress in efficacy, safety, scalability, and economic feasibility.
    Keywords:  microencapsulation; probiotics; regulatory frameworks; stability; strain development
    DOI:  https://doi.org/10.1111/1541-4337.70320
  50. Glob Reg Health Technol Assess. 2026 Jan-Dec;13:13 1-6
    Health technology assessment of an automated unit-dose drug distribution system in a high-specialization national referral hospital of the Italian National Health Service.
    Davide Croce, Francesco De Nardo, Francesca Convenga, Debjani Mueller, Michela Franzin.
       Introduction: Automated unit-dose (UD) medication distribution systems are increasingly recognized as enabling technologies for safer, more efficient, and traceable drug administration in hospitals. Closed-loop UD systems integrate electronic prescribing, automated dispensing, and bedside barcode scanning to ensure full traceability throughout the medication process. This study evaluated the clinical effectiveness, organizational impact, and cost-effectiveness of a closed-loop UD system implemented at a 930-bed national referral hospital in Northern Italy, compared with the previous ward-stock system.
    Methods: A convergent mixed-methods mini-Health Technology Assessment combined administrative, clinical, and financial data (2018-2021) with literature evidence and 18 semi-structured staff interviews. Outcomes included medication administration errors (MAEs), adverse drug reactions (ADRs), and preventable hospitalizations. Cost-effectiveness was assessed from the Italian National Health Service perspective, and qualitative findings were analyzed using framework analysis.
    Results: Based on literature-derived parameters, the model suggests a reduction in MAE rate from 10.6% to 5.0%, preventing an estimated 57,247 errors, 4,294 ADRs, and 42 hospitalizations per year. These outcomes were associated with net annual savings of €1.32 million and an ICER of €48.67 per error avoided. The model also indicated that around 34,000 nursing hours could be reallocated to direct patient care, while qualitative evidence highlighted improved staff satisfaction and medication traceability. Sensitivity analyses confirmed economic robustness in 95% of simulations.
    Conclusions: Implementation of a closed-loop UD system enhances medication safety, workflow efficiency, and cost-effectiveness, supporting its scalability as a strategic innovation aligned with institutional goals for quality and sustainability.
    Keywords:  Automation hospital pharmacy; Cost-effectiveness; Drug administration errors; Drug distribution systems; Health technology assessment; Unit-dose distribution
    DOI:  https://doi.org/10.33393/grhta.2026.3615
  51. Int J Biol Macromol. 2026 Jan 02. pii: S0141-8130(26)00009-7. [Epub ahead of print]340(Pt 1): 150083
    Bridging discovery and therapy in precision medicine-Phage display as a catalyst for nanobody innovation: A review.
    Hee Eon Lee, Jae Hyeon Hwang, Michael Lim, Sukmook Lee.
      Monoclonal antibodies, particularly immunoglobulin G (IgG)-based formats, have shown significant efficacy in targeted therapies; however, they face limitations such as poor tissue penetration, complex manufacturing, and antigen escape. These limitations have driven the development of alternative therapeutic strategies, such as bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells, each with their own technical and translational challenges. Nanobodies (Nbs), derived from camelid heavy-chain-only antibodies, are the smallest functional antibody fragments and are gaining attention as next-generation therapeutics. Their small size, high stability, superior solubility, efficient tissue penetration, and ease of genetic manipulation make them well-suited for addressing limitations of conventional antibodies. The FDA approval of caplacizumab and ciltacabtagene autoleucel validates the clinical potential of Nb therapeutics. However, continued innovation in their discovery and development remains essential. This review focuses specifically on the role of phage display in the advancement of FDA-approved and clinical-stage Nb therapeutics as of April 2025. It highlights how the Nb format design affects their mechanism of action and therapeutic potential across various diseases. By summarizing recent developments and outlining future directions, this review highlights the transformative role of phage display-derived Nb therapeutics in precision medicine and the management of complex diseases.
    Keywords:  Drug discovery; Nanobody therapeutics; Phage display technology; Precision medicine; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150083
  52. J Periodontal Res. 2026 Jan 07.
    Autoimmunity and Periodontitis.
    Massimo Costalonga, Vivek Thumbigere-Math, Mark C Herzberg.
      Autoimmunity arises when central and peripheral immune tolerance fails, allowing self-reactive T and B cells to attack host tissues. Immune attack on host tissues gives rise to a spectrum of autoimmune diseases. This narrative review explains the basic immune mechanisms that may contribute to systemic autoimmunity and exacerbate periodontitis. Current evidence suggests that during T cell development in the thymus, the risk of overt self-reactivity is reduced by the elimination of thymocytes that recognize self-epitopes with high affinity. Despite this stringent editing, some T cells specific for self-peptides escape deletion and persist as dormant cells in the circulation. Dormant cells can remain functionally inactive or anergic due to insufficient co-stimulatory signals, maintaining peripheral self-tolerance. During infection or tissue injury, neutrophil activation, microbial enzymes, and host peptidyl-arginine deiminases (PADs) can catalyze citrullination of self-proteins, generating structurally altered epitopes (neoantigens). In periodontitis, the neoantigen pool is expanded during NETosis, inflammation-driven post-translational modifications of proteins. Modifications are made collectively by peptidyl-arginine deiminases (PADs) produced by Porphyromonas gingivalis and the host. Hence, dormant autoreactive T cells are activated by antigen-presenting cells (APCs) displaying these modified self-antigens or cross-reactive microbial peptides on MHC molecules in the presence of microbial- or danger-associated molecular pattern molecules (MAMPs/DAMPs). Once activated, these autoreactive CD4+ T cells differentiate into effector cells. These effector T cells can break tolerance, providing cognate help to B cells to promote autoantibody production. Autoreactive B cells arise stochastically during early B cell development through random somatic recombination of immunoglobulin genes. Affinity maturation and epitope spreading broaden the B cell receptor (BCR) repertoire generating autoreactive B cells. Normally restrained, these B cells become activated when their BCRs engage self-antigens in the presence of strong proinflammatory cues (MAMPs/DAMPs). With cognate help from autoreactive T helper cells, B cells undergo class-switching and sustained autoantibody production. Together, autoreactive T cells and B cell-derived autoantibodies drive cellular and humoral autoimmunity, respectively. Compelling mechanistic and clinical evidence support a model in which periodontal pathobionts like P. gingivalis and A. actinomycetemcomitans contribute to systemic autoimmunity via processes including protein citrullination, epitope spreading and molecular mimicry between microbial and host antigens, which further amplify cross-reactivity. These interactions are most clearly illustrated in RA but increasingly implicated in other diseases such as IBD and AD. Thus, periodontitis not only causes local immune-mediated tissue destruction but also facilitates systemic dissemination of autoreactive T and B cells, thereby contributing to the initiation and/or exacerbation of autoimmune diseases.
    DOI:  https://doi.org/10.1111/jre.70058
  53. Adv Mater. 2026 Jan 06. e20493
    In Vivo Generation and Manipulation of CAR-T-mimicking Cells via Magnetic Bispecific Nano-antibody for Solid Tumor Therapy.
    Yueqiang Zhu, Chaoran Chen, Junbin Chen, Miao Su, Wanling Huang, Sichen Liu, Mingda Yang, Chengqiong Mao, Song Shen, Xianzhu Yang, Jun Wang.
      The therapeutic efficacy of chimeric antigen receptor (CAR)-T cell therapy in combating solid tumors remains constrained, primarily due to inadequate tumor infiltration and the immunosuppressive tumor microenvironment. Herein, we present a simple yet effective strategy for generating activated CAR-T-mimicking cells and enabling their magnetically guided migration into tumor tissues, thereby enabling a more potent and precise treatment of solid tumors. By functionalizing magnetic nanoparticles with anti-CD3 antibodies (aCD3) and anti-PDL1 antibodies (aPDL1), we have developed a magnetic bispecific nano-antibody (M-BiNanoAb), which effectively engages circulating T cells following intravenous administration and reprograms them into CAR-T-mimicking effector cells. Within this design, the aPDL1 and aCD3 moieties emulate the antigen-recognition domain and signaling domain of traditional CAR structures, respectively. Remarkably, the strategic application of an external magnetic field enables the precise navigation of these bioengineered T cells toward solid tumor regions, thereby facilitating the eradication of PDL1-overexpressing cancer cells. In preclinical models of solid tumors, this magnetically guided strategy for generating and manipulating CAR-T-mimicking cells demonstrated extraordinary antitumor activity, underscoring its transformative potential in advancing CAR-T-based therapies against solid malignancies.
    Keywords:  CAR‐T cell therapy; T cell infiltration; magnetic bispecific nano‐antibody; nanomedicine
    DOI:  https://doi.org/10.1002/adma.202520493
  54. Transl Oncol. 2026 Jan 06. pii: S1936-5233(25)00393-6. [Epub ahead of print]64 102662
    CAR-T therapy in non-small cell lung cancer: Clinical prospects, potential, and strategies for cardiotoxicity management.
    Yihao Liu, Yizhu Gao, Chenyu Huo, Tao Zeng, Wenjun Meng, Haoling Zhang, Qinqin He.
      Lung cancer ranks first among all malignancies in incidence, with current treatment strategies including surgery, chemotherapy, immunotherapy, and targeted therapy. Despite these advances, drug resistance in advanced non-small cell lung cancer (NSCLC) remains a major obstacle and innovative therapeutic approaches are imperative to address it. Chimeric antigen receptor T-cell (CAR-T) therapy has shown impressive and long-lasting results in blood cancers, but its success in solid tumors such as lung cancer remains limited. This review summarizes recent advances and future directions of CAR-T therapy in NSCLC, focusing on major therapeutic targets such as EGFR, MSLN, PD-L1, MUC1, CEA, and ROR1, as well as on the efficacy and potential of combining CAR-T therapy with other treatment modalities. Additionally, we discuss adverse events in NSCLC patients undergoing CAR-T therapy, emphasizing cytokine release syndrome (CRS) and cardiovascular complications-their incidence, pathophysiology, interrelation, and management strategies.
    Keywords:  CAR-T; Cancer immunology; Cardio-Immunology; Cardiotoxicity; Cytokine release syndrome (CRS); Immune evasion; Immunotherapy; NSCLC
    DOI:  https://doi.org/10.1016/j.tranon.2025.102662
  55. Immunology. 2026 Jan 07.
    Bidirectional Regulation in the Tumour Microenvironment: The Interaction Between Tumour-Associated Macrophages and T Cells Reshapes the Paradigm of Cancer Immunotherapy.
    Yuting Li, Lufang Wang.
      This review provides an in-depth analysis of the complex bidirectional interaction mechanisms between tumour-associated macrophages (TAMs) and T cells in the tumour microenvironment (TME). It elaborates on how TAMs, especially M2-type TAMs, suppress the anti-tumour function of T cells and induce their exhaustion through multiple pathways, such as secreting immunosuppressive cytokines (e.g., IL-10, TGF-β), highly expressing immune checkpoint ligands (e.g., PD-L1), recruiting other immunosuppressive cells (e.g., Treg cells), depleting key metabolites (e.g., arginine), and remodelling the extracellular matrix (ECM), thereby promoting tumour immune escape and disease progression. Meanwhile, the review also explores how T cells reverse-regulate the polarization state of TAMs through the activation of the CD40-CD40L axis and the secretion of specific cytokines (e.g., IFN-γ or IL-4). Based on this, the review systematically proposes innovative immunotherapy strategies targeting this key bidirectional interaction, including blocking the recruitment of TAMs (e.g., CCL2/CCR2, CXCL12/CXCR4 inhibitors), directly eliminating TAMs (e.g., CSF1R inhibitors, bisphosphonates, trabectedin), or reprogramming them into anti-tumour M1-type (e.g., CD40 agonists, TLR agonists, CD47-SIRPα axis blockers), and emphasises the great potential of combining these TAM-targeting strategies with immune checkpoint inhibitors (e.g., anti-PD-1/PD-L1 antibodies). These combined therapies aim to synergistically enhance efficacy and overcome the current challenges of drug resistance in immunotherapy, offering new hope for more durable and effective treatment for cancer patients. Additionally, the review looks forward to the application prospects of advanced cell therapies such as nanoparticle delivery systems and chimeric antigen receptor macrophages (CAR-M) in reshaping the TME and enhancing anti-tumour immune responses, providing multi-dimensional and in-depth theoretical basis and practical directions for future cancer immunotherapy.
    Keywords:  T cells; combined immunotherapy; immune checkpoint inhibitors; immune microenvironment; tumour‐associated macrophages
    DOI:  https://doi.org/10.1111/imm.70103
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒12 at 4:40.