bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–05–17
fifty-one papers selected by
Luca Bolliger, lxBio
  1. Allogenic Memory-Like Natural Killer Cell Therapy.
  2. Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation.
  3. Determinants of Chimeric Antigen Receptor (CAR) T Cell Success: In Vitro and In Vivo Preclinical Assessment.
  4. Advancing health technology assessment in Taiwan: over 15 years of evidence-based reform, innovation, and patient partnership.
  5. CD19 CAR T cell therapy in systemic sclerosis: A case study that reaffirms the promise of cell therapy to treat autoimmune disease.
  6. Chimeric antigen receptor T-cell therapy in neurological disorders: Emerging applications, evidence, and challenges.
  7. Evaluating Multimodal Functionality of Chimeric Antigen Receptor T Cells at Single-Cell Resolution through Optofluidics Analysis.
  8. [Strategies to overcome CAR-T cell exhaustion and terminal differentiation].
  9. Impact of physical and chemical parameters on spinoculation for chimeric antigen receptor T cell manufacturing using a quality-by-design approach.
  10. Paving the road for CARs in pediatric autoimmune diseases.
  11. Exploring current evidence on bispecific CAR-T cell therapy for acute leukemias: a systematic review.
  12. A new era of natural killer cell immunotherapy in tumor treatment: latest advances and cutting-edge perspectives from basic research to clinical practice.
  13. Advances in adoptive cell therapy for ovarian cancer.
  14. [Biomarkers for enhancing efficacy of CAR-T cell therapy].
  15. Clinical Development of T-Cell Bispecific Antibodies: Review, Challenges, and Prospective Solutions in Solid Tumor.
  16. A comprehensive evaluation of CAR-T cell gene therapy, tracing its revolutionary clinical breakthroughs and advancements toward next-generation engineering.
  17. Circadian engineering of in vivo CAR T cell therapy for precision oncology.
  18. IL-12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.
  19. Increased mRNA-lipid nanoparticle transfection per ng mRNA by concentrating cells.
  20. Time Frame Analysis of Medical Device Approval, New Health Technology Assessment, and Reimbursement Decision-Making in Korea.
  21. Experiences and expert panel consensus on bridging therapy before anti-BCMA CAR-T cell therapy in multiple myeloma.
  22. Rapid identification of antigen-specific TCRs for cancer immunotherapy.
  23. Engineered artificial antigen-presenting cells for tumor immunotherapy: Design strategies, clinical applications, and translational challenges.
  24. Environmental Aspects in Price and Reimbursement Decisions of Medicines-A Scoping Review.
  25. In Vivo Generation of CAR-T Cells: Current Obstacles, Strategic Solutions, and Clinical Translation.
  26. Reprogramming CAR with cytokine signaling increases the efficacy of CAR-T cell therapy in solid tumour treatment and confers sustained immune memory.
  27. Chimeric Antigen Receptor T‑Cell Therapy Targeting Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30) for Relapsed or Refractory Anaplastic Large Cell Lymphoma: Rationale, Strategies, and Emerging Clinical Evidence.
  28. Epigenetic editing balances TCR suppression and persistence in CAR T cells.
  29. T cell Engineer: An interactive website to track CAR T cell negative regulators.
  30. Preclinical evaluation of a novel CD4 specific CAR NK cell therapy for T-cell malignancies.
  31. Oxidized mannan-MOG35-55 conjugate as a platform for antigen-specific immune modulation in multiple sclerosis.
  32. HHV-6 reactivation in the era of CAR T-cell therapy: A systematic review of emerging challenges.
  33. Chimeric Antigen Receptor T-Cell Therapy in Autoimmune Disorders: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.
  34. Chimeric antigen receptor-natural killer cell therapy in first-relapse epithelial ovarian cancer: an early health-economic evaluation in the Netherlands.
  35. A roadmap for supporting the development of advanced therapy medicinal products in a European framework.
  36. ImmTAC: A Novel Platform of T-Cell Receptor-Based Soluble Bispecifics.
  37. The Gut Microbiota in Hematologic Malignancies: Mechanisms, Clinical Associations, and Translational Opportunities.
  38. Development of CAR NK Cell Lines Selectively Targeting Cancer Cells Expressing Membrane Hsp70.
  39. Dynamic, single-cell monitoring of CAR T cell identity and activation with Raman spectroscopy.
  40. Special issue: cell and gene causal inference in the design and analysis of gene therapy clinical trials.
  41. Antiangiogenic therapy enhances CAR-T cell efficacy in solid tumors: Insights from a hybrid multiscale model.
  42. Next-generation CAR-NK cell therapy for glioblastoma: strategies to overcome antigen escape and the immunosuppressive tumor microenvironment.
  43. Protocol for a multi-modal performance-profiling workflow of CAR T cell products.
  44. Foundation models in healthcare: a comprehensive review from technical advances to clinical translation.
  45. Clinical Development of Bispecific Antibodies: Review, Advances, and Challenges in Hematological Malignancies.
  46. Pseudo-autologous Stem Cell Transplant for the Treatment of Secondary Central Nervous System Lymphoma.
  47. Natural killer cells in pediatric HIV cure strategies: from viral control to immunotherapeutics.
  48. Immunotherapy for Senescent Cell Clearance: Hallmarks, Strategies and Translational Challenges.
  49. mRNA therapeutics: Molecular mechanisms, delivery platforms, regulatory frameworks, and equitable global access.
  50. Mania and psychosis following chimeric antigen receptor T-cell therapy: A report of two cases and mechanistic discussion.
  51. Orphan drug regulation: a global comparison of the United States Food and Drug Administration, European Medicines Agency, and Japanese pharmaceuticals and medical devices agency approaches.
  1. Mo Med. 2026 Mar-Apr;123(2):123(2): 136-141
    Allogenic Memory-Like Natural Killer Cell Therapy.
    Alaa M Khalifa, Melissa M Berrien-Elliott.
      Adoptive cell therapy has witnessed significant progress with the success of chimeric antigen receptor (CAR) T cells for treating cancer. However, their autologous nature limits scalability, and increases production time and manufacturing costs. Additionally, CAR-T cell administration can result in severe toxicities, including cytokine release syndrome (CRS) and neurotoxicity. To address these issues, allogeneic, natural killer (NK) cells are being explored as an alternative. NK cells are cytotoxic lymphocytes that play a pivotal role in tumor surveillance and eradication. Unlike T cells, NK cells can identify and eliminate targets without MHC restriction or prior sensitization. Furthermore, NK cells exhibit enhanced responses after exposure to virus infections or cytokine activation (cytokine induced memory-like). Allogeneic NK cell therapies offer a promising alternative to autologous cell therapies, with reduced risk of graft-versus-host disease and rapid availability. This review summarizes the current landscape of allogeneic memory-like NK cell therapies, including clinical applications and challenges.
    Keywords:  Transplantation; adoptive transfer; cancer immunotherapy; natural killer cells
  2. Front Immunol. 2026 ;17 1775981
    Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation.
    Xiaokuan Zhou, Mengqi Zhai, Zhe Zhang, Guojun Zhang.
      Hematologic disorders, including malignant and autoimmune conditions, present persistent clinical challenges characterized by relapse, treatment resistance, and profound immune dysregulation. While conventional immunotherapies have advanced, their efficacy is frequently limited by HLA downregulation and effector T cell exhaustion. In this context, γδ T cells offer a promising therapeutic alternative. Recognizing antigens independently of MHC restriction, γδ T cells possess intrinsic tissue-homing capabilities and exhibit dual cytotoxic and immunoregulatory functions. These properties make them highly suitable candidates for allogeneic, "off-the-shelf" cellular therapies where αβ T cells face alloreactive limitations. This review systematically synthesizes the immunobiology of γδ T cells, exploring the functional heterogeneity of specific subsets and their regulation within the tumor microenvironment (TME). We critically evaluate recent preclinical and clinical evidence supporting adoptive transfer, CAR-γδ T strategies, and combination regimens across acute leukemias, lymphomas, multiple myeloma, and immune cytopenias. Furthermore, we address critical translational barriers-including in vivo persistence, subset exhaustion, and manufacturing variability-and discuss rational engineering strategies, metabolic preconditioning, and epigenetic modulation as solutions. Ultimately, advancing γδ T cell therapies requires overcoming these hurdles to transition them effectively from the bench to mainstream clinical practice.
    Keywords:  CAR-γδ T cell therapy; cytokine plasticity; hematologic malignancies; translational barriers; γδ T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1775981
  3. Cancers (Basel). 2026 Apr 29. pii: 1412. [Epub ahead of print]18(9):
    Determinants of Chimeric Antigen Receptor (CAR) T Cell Success: In Vitro and In Vivo Preclinical Assessment.
    Michael K Sheng, William J Murphy.
       BACKGROUND/OBJECTIVES: Chimeric antigen receptor (CAR) T cell therapy has profoundly transformed the cancer treatment landscape, achieving unprecedented clinical success in patients with hematological malignancies. However, challenges such as cytokine release syndrome, neurotoxicity, antigen escape, and limited efficacy in solid tumors remain, underscoring the need for robust preclinical modeling to evaluate novel CAR T cell products.
    METHODS: This review provides a comprehensive overview of in vitro and in vivo preclinical modeling for CAR T cell functionality and toxicity assessment. We examine traditional experimental approaches and their limitations, discuss emerging technologies, and highlight how these strategies can be integrated to advance future CAR T cell therapies.
    RESULTS: In vitro assays provide insights into efficacy but fail to model trafficking, dynamic immune cell interactions, and complex tumor microenvironments. In vivo mouse models allow for more complex physiological evaluation but are limited by species differences. Next generation platforms, such as patient-derived tumor organoids and organ- or multi-organ-on-a-chip microfluidics are emerging as potential tools to model CAR T cell therapy in physiologically relevant contexts and computational approaches are being increasingly used to develop novel CAR designs and predict patient responses.
    CONCLUSIONS: By integrating traditional experimental approaches with innovative technologies, the CAR T cell field is poised to generate more clinically relevant and predictive data thereby accelerating the development of safer, more effective, and personalized CAR T cell therapies.
    Keywords:  CAR T cells; immunotherapy; in vitro; in vivo; preclinical modeling; translational research
    DOI:  https://doi.org/10.3390/cancers18091412
  4. Int J Technol Assess Health Care. 2026 May 11. 42(1): e50
    Advancing health technology assessment in Taiwan: over 15 years of evidence-based reform, innovation, and patient partnership.
    Li-Ying Huang, Shou-Yu Lin, Ming-Hsun Liu.
       OBJECTIVE: Since 2007, the Taiwan Health Technology Assessment (HTA) system has developed from a review process for new drug reimbursement into a core element of National Health Insurance (NHI) decision-making. This study examines Taiwan's development of a sustainable, learning-oriented HTA ecosystem.
    METHODS: This article synthesizes more than 15 years of HTA development in Taiwan, highlighting recent advancements, including parallel reviews, temporary reimbursement pathways, managed entry agreements (MEAs), real-world evidence (RWE) guidelines, precision medicine frameworks, and structured health technology reassessment. Drawing on national policy sources, administrative datasets, and published evaluations, four interrelated domains were analyzed: institutional development and governance; access pathways for high cost and high clinical impact; infrastructure for evidence generation; and mechanisms to strengthen patient and patient organization involvement (PPI).
    RESULTS: In 2024, 196 rapid HTA assessments were completed, reflecting increased system capacity and methodological sophistication. This evolution builds on earlier HTA-driven policy experiences, including immune checkpoint inhibitors supported by HTA, MEA design, and national RWD collection. These developments formed the groundwork for managing uncertainty, assessing high-cost therapies, and supporting life cycle evidence. Parallel review improved timely access to novel medicines without compromising assessment rigor. The Taiwan Cancer Drugs Fund provided a structured model for temporary reimbursement and RWD collection. Formal PPI processes expanded the integration of patient voices.
    CONCLUSIONS: Taiwan's HTA system is transitioning into a learning health system that supports adaptive coverage, continuous reassessment, and sustainable access to new medical technologies. Developments offer guidance to health systems seeking to balance access, evidence development, and financial sustainability.
    Keywords:  health technology assessment (HTA); managed entry agreements (MEAs); patient and patient organization involvement (PPI); real-world evidence (RWE)
    DOI:  https://doi.org/10.1017/S0266462326103766
  5. Mol Ther Adv. 2026 Mar 12. 34(1): 201684
    CD19 CAR T cell therapy in systemic sclerosis: A case study that reaffirms the promise of cell therapy to treat autoimmune disease.
    James L Riley.
      
    DOI:  https://doi.org/10.1016/j.omta.2026.201684
  6. J Neurol Sci. 2026 May 07. pii: S0022-510X(26)00264-9. [Epub ahead of print]487 125982
    Chimeric antigen receptor T-cell therapy in neurological disorders: Emerging applications, evidence, and challenges.
    Jin Jun Luo, Shaun Wang, Xiaohong Si.
      Chimeric antigen receptor (CAR) T-cell therapy, initially developed for hematologic malignancies, engineers autologous T cells to eliminate pathogenic immune populations and aims to induce durable immune remodeling. Advancing understanding of the immunopathogenesis of several neurological disorders, particularly antibody-mediated diseases, has prompted investigation of CAR T-cell therapy beyond oncology. Early clinical studies suggest that CAR T-cell therapy may induce sustained remission in selected antibody-mediated neurological disorders, including myasthenia gravis, multiple sclerosis, and neuromyelitis optica spectrum disorder. However, evidence for immune-mediated neuropathies remains limited and largely theoretical, whereas genetic and metabolic neuromuscular disorders are biologically unsuitable targets. Neurological toxicities, particularly immune effector cell-associated neurotoxicity syndrome, remain a concern for broader adoption. Ultimately, CAR T-cell therapy represents a paradigm shift from chronic immunosuppression toward immune reconstitution in neurology. Its future role will depend on careful patient selection, strategies to mitigate neurotoxicity, and rigorous neurologist-led clinical trials. This work reviews the biological rationale, emerging clinical evidence, and neurological considerations for CAR T-cell therapy across central and peripheral nervous system disorders. We summarize clinical studies evaluating CAR T-cell therapy in neuroimmunology with an emphasis on feasibility, safety, neurological efficacy, and management of its complications.
    Keywords:  CAR T-cell therapy; Chimeric antigen receptor; Cytokine release syndrome; Immune effector cell–associated neurotoxicity syndrome; Neurological autoimmune disorders
    DOI:  https://doi.org/10.1016/j.jns.2026.125982
  7. J Vis Exp. 2026 Apr 21.
    Evaluating Multimodal Functionality of Chimeric Antigen Receptor T Cells at Single-Cell Resolution through Optofluidics Analysis.
    Julia Franz, Fabian Freitag, Patrick Ho, Theodor Bormann, Michael Hudecek, Maik Luu.
      Adoptive T-cell therapy is a novel treatment paradigm in which autologous T cells are genetically modified to express a tumor-targeting chimeric antigen receptor (CAR) prior to ex vivo expansion and re-infusion into the patient. Despite remarkable demonstrations of anti-tumor potency in patients with advanced hematological malignancies, long-lasting responses fail to manifest in a substantial fraction of cases. Although several idiosyncratic factors may contribute to the variability in clinical outcomes, there is mounting evidence that the percentage of polyfunctional T cells in the pre-infusion CAR-T cell product strongly correlates with the durability of cancer remission. Unfortunately, standard evaluations of CAR-T cell products currently rely on bulk population measurements or terminal assays, limiting the ability to isolate and study sub-populations with heightened functional properties. Here, we demonstrate a workflow that leverages an optofluidics platform to evaluate both the cytokine secretion profile and activation via CD137 expression of individual CAR-T cells, which can be optionally combined with cytotoxic activity assessment. Cells exhibiting the greatest degree of multimodal functionality can be isolated for further analyses to inform the design of next-generation CAR-T cell therapies.
    DOI:  https://doi.org/10.3791/69702
  8. Rinsho Ketsueki. 2026 ;67(4): 335-341
    [Strategies to overcome CAR-T cell exhaustion and terminal differentiation].
    Yuki Kagoya.
      Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has been successfully established in B-cell malignancies and multiple myeloma. The fitness of infused CAR-T cells is closely associated with durable clinical responses. Terminal differentiation, which compromises long-term persistence, and exhaustion, which dampens effector function, are major drivers of T-cell dysfunction. Recent studies have demonstrated that genetic engineering approaches that modulate gene expression and epigenetic programs can counteract these mechanisms and enhance T-cell function. In addition, strategies to augment T-cell function through artificial cytokine signaling have been extensively investigated. This review discusses these recent advancements.
    Keywords:  Chimeric antigen receptor; Cytokine signaling; Epigenetics; T-cell fitness
    DOI:  https://doi.org/10.11406/rinketsu.67.335
  9. Mol Ther Adv. 2026 Mar 12. 34(1): 201691
    Impact of physical and chemical parameters on spinoculation for chimeric antigen receptor T cell manufacturing using a quality-by-design approach.
    Pedro Silva Couto, Dale J Stibbs, Braulio Carrillo Sanchez, Pierre Springuel, Syd McLean, Ursula Schultz, Manuel Effenberger, Yasuhiro Takeuchi, Qasim A Rafiq.
      Chimeric antigen receptor (CAR) T cell therapies represent a significant advancement for treating hematological malignancies, particularly in relapsed/refractory cases. Despite their clinical success, the high cost of CAR T cell therapies remains a major barrier to broader implementation. A significant proportion of these costs stems from the dependency on viral vectors and the limited understanding of transduction mechanisms. This work evaluates the impact of physical and chemical parameters during transduction using a spinoculation process. Physical parameters, such as spinoculation duration and speed, were identified as key drivers of transduction efficiency, contributing to a 20%-30% increase in transduction. Similarly, the addition of LentiBOOST and polybrene enhanced transduction efficiency by approximately 1-2-fold compared with control conditions without these supplements. Given that both physical and chemical parameters influence transduction efficiency, a quality-by-design approach was used to systematically investigate their potential synergistic or antagonistic interactions. This systematic approach highlighted the cytotoxic impact of polybrene and demonstrated that LentiBOOST is critical to drive transduction, particularly in CD4 subsets. The optimized process led to a 2-3-fold improvement in transduction without compromising CAR T cell growth or functionality and was shown to be compatible with serum- and xeno-free medium, supporting its translational potential.
    Keywords:  CAR T; cell therapy; lentiviral vector; manufacturing; transduction
    DOI:  https://doi.org/10.1016/j.omta.2026.201691
  10. Immunity. 2026 May 12. pii: S1074-7613(26)00174-3. [Epub ahead of print]59(5): 1180-1183
    Paving the road for CARs in pediatric autoimmune diseases.
    Mohamad Hamieh, Virginia Pascual.
      Severe pediatric autoimmune diseases (AD) have limited therapeutic options. In a recent issue of Nature Medicine, Becilli et al.1 report a case series where CD19 CAR T cell treatment of pediatric AD patients induced rapid and durable remissions with manageable toxicity. Notably, patients discontinued standard therapies, and benefits persisted even after B cell reconstitution, highlighting the potential of a reset of the immune system that warrants further exploration.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.012
  11. Front Oncol. 2026 ;16 1720483
    Exploring current evidence on bispecific CAR-T cell therapy for acute leukemias: a systematic review.
    Gabriela Valencia Putri Husodho, Anatalya Diah Ayu Kumalasari, Agyta Hanifa Faiza, Edward Kurnia Setiawan Limijadi, Meita Hendrianingtyas.
       Introduction: Chimeric antigen receptor T cell (CAR-T cell) therapy is an immunotherapy for acute leukemias utilizing recombinant receptors specific to antigens involved in T-cell function to direct tumor cell recognition and elimination. However, major limitations include relapse due to antigen escape and tumor heterogeneity, as well as on-target off-tumor effects. Bispecific CAR-T cells are developed to overcome these issues.
    Method: A literature search was conducted to identify relevant articles using three databases (PubMed, Scopus, ProQuest) between 2016 and 2025. Studies written in English and in vivo, in vitro, and clinical trial research designs were included. Articles without complete data and case reports were excluded. The systematic review followed PRISMA guidelines.
    Results: Nine studies were included in the final synthesis. Bispecific CAR-T cell therapy was superior in tumor eradication and limiting adverse effects in both AML and ALL. CARs used in AML often targeted CD123 and CD33; development of more diverse targets, including cell signaling of tumor growth (FLT3, NKG2D, TIM3, FRβ), addressed heterogeneity. CD19 was the most common CAR in ALL, additionally targeting CD22, CD20, and BAFF-R; addressing CD19-negative relapse was quite common. Phase I clinical trials were done for CD19/CD22 bispecific CAR-T cells, proving effective with low incidence of cytokine release syndrome, neurotoxicity, or other adverse effects. Preclinical trials showed that bispecific CAR-T cells had longer in vivo persistence.
    Conclusion: Bispecific CAR-T cell therapy is more effective in managing acute leukemias than conventional CAR-T cells. Future research should focus on developing diverse targets and advancing into clinical trials.
    Systematic Review Registration: Open Science Framework (OSF) Registries https://osf.io/, registration DOI: https://doi.org/10.17605.
    Keywords:  bispecific CAR-T cell; chimeric antigen receptor; dual-targeting; immunotherapy; leukemia
    DOI:  https://doi.org/10.3389/fonc.2026.1720483
  12. Front Immunol. 2026 ;17 1795143
    A new era of natural killer cell immunotherapy in tumor treatment: latest advances and cutting-edge perspectives from basic research to clinical practice.
    Xin Du, Shixin Shi, Haiyan Liu.
      As early as 1863, Virchow observed that cancer often arises at sites of chronic inflammation. Modern epidemiological and clinical studies have confirmed the link between inflammation and cancer. Natural Killer (NK) cells actively participate in and regulate inflammatory processes; however, they are not strictly classified as classic 'inflammatory cells' in cellular taxonomy. NK cells rapidly identify and eliminate malignantly transformed cells in a non-major histocompatibility complex (MHC)-restricted manner, a characteristic that distinguishes them from other immune cells. Furthermore, their use in allogeneic settings carries a very low risk of graft-versus-host disease (GvHD), making them ideal candidates for developing 'off-the-shelf' cellular immunotherapies. Although early clinical attempts using unmodified NK cells showed limited efficacy, the past decade has witnessed rapid advancements in genetic engineering, cell expansion and differentiation, and synthetic biology, propelling NK cell therapy into a new era of development. This article aims to provide a systematic and multi-dimensional review of the latest research progress in NK cell therapy. We begin by revisiting the core biological basis of NK cell anti-tumor activity, focusing on design strategies, clinical breakthroughs, and bottlenecks of Chimeric Antigen Receptor NK (CAR-NK) cell therapy in hematological malignancies and solid tumors. We delve into antibody-based NK cell recruitment strategies (such as BiKEs/TriKEs) and techniques to enhance antibody-dependent cellular cytotoxicity (ADCC), and analyze cytokine-induced memory-like NK (CIML-NK) cells as a non-gene editing enhancement strategy. Simultaneously, we focus on the core challenges currently faced by NK cell therapies, particularly in solid tumors, including poor tumor infiltration, potent suppression by the tumor microenvironment (TME), and limited in vivo persistence. We summarize diversified synergistic strategies, such as combination with immune checkpoint inhibitors, radiotherapy, chemotherapy, targeted drugs, and direct modifications of the TME. Finally, this article discusses contentious points within the field and provides a forward-looking perspective on future directions, striving to offer a comprehensive and insightful reference for the translation of NK cell therapy from the laboratory to widespread clinical application.
    Keywords:  CAR NK cell therapy; NK cell; cancer; cancer immunotherapy; chimeric antigen receptor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1795143
  13. Front Immunol. 2026 ;17 1794716
    Advances in adoptive cell therapy for ovarian cancer.
    Na Zhao, Yujiao An, Shanwei Guo, Zhen Xu, Hongtang Shi, Zhentao Zhang.
      Ovarian cancer remains the most lethal gynecological malignancy worldwide, with late-stage diagnosis, high recurrence rates, and chemoresistance posing persistent clinical challenges. Adoptive cell therapy (ACT), a rapidly advancing immunotherapeutic strategy, offers promising efficacy with low systemic toxicity and has emerged as a compelling option to address these limitations. This review provides a comprehensive overview of ACT modalities-including tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor T cells (CAR-T), natural killer (NK) cells, and other emerging cellular therapies such as TCR-T, cytokine-induced killer (CIK) cells, and γδ T cells-in the context of ovarian cancer. We highlight the mechanistic underpinnings of ACT, the immunosuppressive features of the ovarian tumor microenvironment, and cutting-edge advances in combinatorial regimens, genetic engineering, and cell design aimed at overcoming therapeutic resistance. In particular, we discuss antigen specificity, tumor immune evasion, and stromal barriers, and summarize current clinical trial progress, efficacy outcomes, and translational barriers. Together, these insights underscore the transformative potential of ACT in ovarian cancer and outline future directions for personalized and scalable immunotherapies.
    Keywords:  adoptive cell therapy; chimeric antigen receptor T cells; immunosuppression; ovarian cancer; tumor immune microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2026.1794716
  14. Rinsho Ketsueki. 2026 ;67(4): 342-348
    [Biomarkers for enhancing efficacy of CAR-T cell therapy].
    Seitaro Terakura.
      Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory hematologic malignancies, achieving remarkable response rates in B-cell acute lymphoblastic leukemia and lymphomas. However, treatment responses and toxicities vary substantially among patients, necessitating the establishment of robust predictive biomarkers for optimal patient stratification and treatment personalization. This review systematically categorizes key factors affecting CAR-T therapy efficacy into tumor-intrinsic and T cell-intrinsic components. Tumor-intrinsic factors include tumor burden, antigen expression heterogeneity, and immunosuppressive components within the tumor microenvironment, such as regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and inhibitory cytokines (e.g., TGF-β and IL-10). T cell-intrinsic factors encompass memory T cell subset composition, particularly central memory and stem cell memory populations, CAR expression density and transduction efficiency, polyfunctional cytokine production profiles, mitochondrial function and metabolic fitness, and expression of immune checkpoint molecules. Recent technological advances in single-cell RNA sequencing, comprehensive proteomics, and high-dimensional immunophenotyping combined with machine learning algorithms enable increasingly precise biomarker identification and predictive modeling. Integration of these multidimensional biomarkers into unified prediction models holds substantial promise for personalizing therapy, enhancing efficacy while minimizing adverse events, and ultimately achieving durable remission in patients receiving CAR-T therapy.
    Keywords:  Biomarkers; CAR-T cell therapy; T cell fitness; Tumor microenvironment
    DOI:  https://doi.org/10.11406/rinketsu.67.342
  15. Methods Mol Biol. 2026 ;2997 223-239
    Clinical Development of T-Cell Bispecific Antibodies: Review, Challenges, and Prospective Solutions in Solid Tumor.
    Chika Ogami, Takahiro Ishiguro.
      T-cell engaging bispecific antibodies (T-BsAbs) have emerged as a promising approach in cancer immunotherapy. This review explores the clinical development of T-BsAbs in solid tumors, highlighting their unique mechanism of action, which involves the simultaneous binding to tumor-associated antigens and the CD3 T-cell receptor, thereby redirecting T cells to tumor cells and activating them in an antigen-dependent manner. Despite their success in hematological malignancies, T-BsAbs face significant challenges in solid tumors, including on- and off-target toxicities, the selection of appropriate tumor-associated antigens, and the complexity of the tumor microenvironment. Safety concerns, such as cytokine release syndrome (CRS) and on-target, off-tumor toxicities, are major obstacles that need to be addressed. Recent advancements offer potential solutions to these challenges. This review provides a comprehensive overview of the current state of T-BsAb development, discussing recent advances, ongoing clinical trials, and emerging strategies to enhance their efficacy and safety in solid tumor treatment.
    Keywords:  CD3 T-cell receptor; Cancer immunotherapy; Cytokine release syndrome (CRS); Off-target toxicity; On-target toxicity; Solid tumors; T-cell engaging bispecific antibodies (T-BsAbs); Tumor microenvironment; Tumor-associated antigens (TAAs)
    DOI:  https://doi.org/10.1007/978-1-0716-5037-0_16
  16. Expert Rev Mol Med. 2026 May 15. 1-60
    A comprehensive evaluation of CAR-T cell gene therapy, tracing its revolutionary clinical breakthroughs and advancements toward next-generation engineering.
    Melike Aliciaslan, Ezgi Erbasan, Salih Sanlioglu.
      
    DOI:  https://doi.org/10.1017/erm.2026.10052
  17. NPJ Precis Oncol. 2026 May 14.
    Circadian engineering of in vivo CAR T cell therapy for precision oncology.
    Jhommara Bautista, Carolina E Echeverría, María Gabriella Rodríguez-Marcano, Andrés López-Cortés.
      Circadian rhythms shape antitumor immunity by regulating endocrine signaling, vascular permissiveness, leukocyte trafficking, metabolism, and suppressive features of the tumor microenvironment across the 24-h cycle. Here, we propose that biological time may represent an important design variable for CAR T-cell therapy. This concept may be particularly relevant to in vivo CAR T platforms, which could extend temporal control beyond infusion timing through repeatable induction, tunable amplitude, and reversible shutdown. We discuss evidence that CD8⁺ T-cell clocks, neuroendocrine oscillations, endothelial gatekeeping, and rhythmic tumor-microenvironment remodeling influence immune access, effector competence, exhaustion risk, and inflammatory toxicity. We further examine how viral vectors, lipid nanoparticles, and programmable control circuits might enable circadian-aware CAR installation and duty-cycling. Together, these observations support chrono-synthetic CAR T as a testable translational framework for precision immuno-oncology.
    DOI:  https://doi.org/10.1038/s41698-026-01464-4
  18. Mol Ther Adv. 2026 Jun 11. 34(2): 201730
    IL-12-engineered human PSMA-CAR T cells for the treatment of advanced prostate cancer.
    Lupita S Lopez, Ziyou Cui, Yukiko Yamaguchi, John P Murad, Zhiyuan Yang, Ke Zou, Jason Yang, Wen-Chung Chang, Stephen J Forman, Vivien W Chan, Saul J Priceman.
      Adoptive cell therapies used to treat advanced prostate cancer are being developed to target several tumor-associated antigens, including prostate-specific membrane antigen (PSMA). Chimeric antigen receptor (CAR) T cell therapy using the single-chain variable fragment (scFv) derived from the humanized murine mAb clone J591 as the antigen-binding domain has shown promising anti-tumor activity. However, it has also been associated with macrophage activation syndrome and other unwanted toxicities, highlighting the need for more specific and human-derived antigen-binders with optimized construct designs for improved safety and efficacy. Here, we optimize a human scFv-based PSMA-targeted CAR (hPSMA-CAR) with highly selective PSMA targeting. We further introduce a membrane-bound IL-12 (mbIL12) molecule, which enhances potency with increased T cell expansion, IFN-γ production, and anti-tumor cell activity in vitro. Using two clinically relevant bone-metastatic prostate cancer models, we show that mbIL12-engineered hPSMA-CAR T cells drive potent in vivo anti-tumor responses. In summary, we have developed a promising therapeutic that has potential to promote safe and effective treatment of advanced PSMA+ prostate cancer.
    Keywords:  T cell; adoptive cellular immunotherapy; chimeric antigen receptor; membrane-bound IL-12; prostate cancer; prostate specific membrane antigen
    DOI:  https://doi.org/10.1016/j.omta.2026.201730
  19. J Biotechnol. 2026 May 12. pii: S0168-1656(26)00156-2. [Epub ahead of print]416 175-186
    Increased mRNA-lipid nanoparticle transfection per ng mRNA by concentrating cells.
    Alina Kunitskaya, Sunny P Chen, Chia Hao Ho, Melaina Del Grosso, Anna K Blakney, James M Piret.
      The availability of T-cell therapies is limited in part due to their complex and costly biomanufacturing. Genetic engineering of T cells, such as to express chimeric antigen receptor (CAR), is commonly achieved using viral vectors, that are costly to produce and add to safety concerns. Non-viral alternatives have advantages, but a major barrier is their far lower efficiency of gene delivery. This has motivated the development of new strategies to increase nonviral gene delivery efficiencies, including using lipid nanoparticles (LNPs). We investigated the transfection of human T and NK cells with three formulations of green fluorescent protein (GFP) mRNA-LNPs and found that concentrating cells greatly increased transfection per ng mRNA, compared to conventional methods. We achieved ∼55% GFP+ T cells with both protocols, while using ∼40-fold less mRNA per million concentrated cells. This resulted in up to a 30-fold increase in the number of GFP+ cells per ng mRNA. The developed process should reduce manufacturing costs and would enable transient transfection with repeated dosing that could improve treatment safety and efficacy, making life-saving therapies available to more patients.
    Keywords:  CAR; Cell and gene therapy; Lipid nanoparticles; T cells; Transfection efficiency; mRNA
    DOI:  https://doi.org/10.1016/j.jbiotec.2026.05.003
  20. J Korean Med Sci. 2026 May 11. 41(18): e136
    Time Frame Analysis of Medical Device Approval, New Health Technology Assessment, and Reimbursement Decision-Making in Korea.
    Jin-Ho Kim.
       BACKGROUND: The time required for the health insurance listing, including health technology assessment (HTA) after medical device approval, has a significant impact on the medical device industry, clinical practice, and patient access to treatment. The aim of this study is to analyze the total time frame from device approval to health insurance listing via HTA and to examine the duration of each procedural step.
    METHODS: Using publicly available data, the study identified 34 medical technologies submitted for HTA and subsequently listed for health insurance coverage between 2021 and 2023. The study analyzed the time frame from device approval to health insurance listing, including evaluation periods for existing coverage category determination, HTA, and listing.
    RESULTS: The median time from device approval to health insurance listing was 6.0 years for all technologies (n = 34) and 2.4 years for moderate- to high-risk or novel devices requiring pre-market approval (n = 15). For technologies that utilized the parallel review track (n = 8), the median time was 1.5 years. Median durations for existing coverage category determination, HTA, and health insurance listing for all technologies were 64.0, 244.5, and 346.0 days, respectively, and for moderate- to high-risk or novel devices, 65.0, 240.0, and 339.0 days, respectively.
    CONCLUSION: The process from device approval to health insurance listing in Korea takes a considerable amount of time. Streamlining evaluation and reimbursement processes is essential to accelerating patient access to novel treatments. To support the timely adoption of new technologies, policymakers should prioritize efficiency while maintaining safety and effectiveness standards.
    Keywords:  Equipment and Supplies; Insurance, Health; Technology Assessment, Biomedical
    DOI:  https://doi.org/10.3346/jkms.2026.41.e136
  21. Bone Marrow Transplant. 2026 May 13.
    Experiences and expert panel consensus on bridging therapy before anti-BCMA CAR-T cell therapy in multiple myeloma.
    Leo Rasche, Maria Theresa Krauth, Hermine Agis, Christoph Renner, Irene Strassl, Raphael Teipel, Vladan Vučinić, Katja Weisel, Wolfgang Willenbacher, Marc S Raab.
      Use of anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy to treat relapsed/refractory multiple myeloma is increasing. Studies suggest that effective bridging therapy (BT) prior to anti-BCMA CAR-T therapy can enhance efficacy and safety outcomes. Through qualitative interviews and a consensus workshop, 10 European experts shared their clinical experience regarding optimal BT selection, efficacy, safety and outcomes post-CAR-T, focussing on heavily pretreated patients and emerging BT options, such as bispecific T-cell engagers. Experts agreed that BT should aim to reduce tumour burden and maintain or improve patient performance status, while avoiding treatment-related toxicity that could delay or prevent CAR-T infusion. The balance between treatment duration and achieving an adequate response is important, and patient characteristics are key for BT selection, especially in difficult-to-treat populations. Here, we discuss the unique therapy talquetamab, a GPRC5DxCD3 bispecific antibody, which demonstrates robust efficacy and rapid response rates in clinical trials, and is being considered as a BT option before anti-BCMA CAR-T therapy based on expert experience and real-world data. This consensus, based on clinical experience, aims to provide guidance on BT for healthcare professionals (HCPs) involved in anti-BCMA CAR-T therapy and aid standardisation of care in this rapidly advancing field.
    DOI:  https://doi.org/10.1038/s41409-026-02905-1
  22. Biophys Rep. 2026 Apr 30. 12(2): 100-115
    Rapid identification of antigen-specific TCRs for cancer immunotherapy.
    Min Jiang, Wenling Wang, Shuguang Tan.
      T cell receptors (TCRs) can recognize peptides presented by major histocompatibility complex (MHC) molecules, referred to as HLA in humans, which enables the targeted eradication of tumor cells expressing specific antigens. In recent years, TCR-engineered T cell (TCR-T) cell therapy has demonstrated substantial advancements in clinical trials targeting solid tumors. Notably, in August 2024, the U.S. FDA approved the first TCR-T drug for the treatment of advanced synovial sarcoma, representing a pivotal milestone in the field. For the development of TCR-T therapy, identifying tumor-associated antigen epitopes and high-functional TCRs are critical. Here, we present a comprehensive protocol outlining the process of identification of immunogenic epitopes and the efficient screening of antigen-specific TCRs from HLA transgenic mice. Additionally, the protocol encompasses methodologies for TCR-T cell preparation and their functional evaluation in vitro. These approaches provide a robust framework for advancing the development of tumor-specific TCRs and fostering the clinical translation of TCR-T therapies.
    Keywords:  Immunopeptide; Immunotherapy; Single-cell sequencing; T cell receptor; T cell receptor-engineered-T cell
    DOI:  https://doi.org/10.52601/bpr.2025.250003
  23. Mater Today Bio. 2026 Jun;38 103192
    Engineered artificial antigen-presenting cells for tumor immunotherapy: Design strategies, clinical applications, and translational challenges.
    Haojie Cai, Yaqian Zhao, Yifei Cai, Xiaomei Luo, Jianxiao Li, Yongsong Wu, Jiani Yang, Chao Wang, Yue Zhang, Hui Ding, Shanshan Cheng, Yu Wang.
      Immunotherapy has long played a pivotal role in cancer treatment, and antigen-presenting cell (APC)-based immunotherapy represents a promising strategy, though its full potential remains to be realized. This therapy stimulates T cell activation and proliferation through APCs, producing therapeutic effects. However, the use of natural APCs in immunotherapy faces several limitations, including inefficient T cell expansion, suboptimal targeting, and high treatment costs. Under such circumstances, artificial antigen-presenting cells (aAPCs) have garnered increasing interest. This review provides an overview of recent advancements in aAPCs research, systematically classifies aAPCs and critically evaluates their advantages and limitations. The underlying mechanisms of aAPCs, including activation and proliferation of T cells, strategies to overcome the immunosuppressive tumor microenvironment (TME), targeted antigen delivery and combination therapy, are discussed in detail. Their clinical applications are also debated. Existing challenges, including the absence of standardized protocols and regulatory frameworks, are highlighted. Furthermore, future directions in aAPCs technology are explored, including but not limited to the development of multifunctional aAPCs and the integration of artificial intelligence (AI) to assist in the design and optimization. Finally, to overcome these limitations, this review advocates for strengthened multidisciplinary collaboration and the adoption of emerging technologies.
    Keywords:  Artificial antigen-presenting cells; Cancer; Immunotherapy; T cells
    DOI:  https://doi.org/10.1016/j.mtbio.2026.103192
  24. Basic Clin Pharmacol Toxicol. 2026 Jun;138(6): e70243
    Environmental Aspects in Price and Reimbursement Decisions of Medicines-A Scoping Review.
    Lasse Alajärvi, Mirella Miettinen, Johanna Timonen.
      Environmental impacts of medicines are increasingly recognised but rarely embedded in their pricing and reimbursement (P&R) and related assessments. This scoping review mapped how environmental aspects, including antimicrobial resistance (AMR) stewardship, are or could be considered in P&R of medicines and identified challenges for their implementation. Electronic searches from PubMed, Scopus, Web of Science, Edilex, HeinOnline, Westlaw, Google Scholar and official agencies' websites were conducted. Eligible items covered developed country settings and described existing or proposed integration of environmental aspects into medicine pricing or reimbursement. Of 4476 publications, 21 were included. The publications were from 2013 to 2023, most of them addressing ecotoxicological and climate impacts. Six types of means to embed environmental aspects into P&R were identified: health technology assessment (HTA) integration, reimbursement criteria, pricing criteria, environmental classification, regulation and delinkage models. Most proposals were conceptual, whereas implemented or piloted examples focused on AMR-oriented means. Reported challenges for implementation included challenges regarding data availability, comparability and verification; valuation and methodological integration; incentive design and cost distribution; and equity and political feasibility. Environmental aspects are not yet routine in medicine P&R assessments due to a lack of standardised, verifiable product-level data, appraisal methods and equity-sensitive policy design.
    Keywords:  environment; medicine; policy; price; reimbursement
    DOI:  https://doi.org/10.1111/bcpt.70243
  25. Crit Rev Oncol Hematol. 2026 May 13. pii: S1040-8428(26)00260-X. [Epub ahead of print] 105373
    In Vivo Generation of CAR-T Cells: Current Obstacles, Strategic Solutions, and Clinical Translation.
    Ziyu Jiang, Shichu Xu, Wenying Li, Jiannan Chen, Zhigang Guo.
      Chimeric antigen receptor T (CAR-T) cell therapy has transformed the treatment of hematologic malignancies, but conventional ex vivo manufacturing remains costly, labor-intensive, and difficult to scale. In vivo CAR-T generation, which reprograms endogenous T cells directly within patients using engineered vectors, offers a simplified and potentially more accessible alternative. This review outlines the major barriers to in vivo CAR-T development-including inefficient systemic delivery, off-target transduction, the trade-off between transfection efficiency and biosafety, and limited persistence of CAR expression. We summarize emerging engineering strategies such as targeted vector systems, combinatorial T-cell recognition, tunable expression control, and approaches to enhance functional durability. Recent early-phase clinical trials demonstrate the feasibility of in vivo CAR-T induction. We also discuss future opportunities and challenges that will shape the translation of this rapidly evolving therapeutic paradigm.
    Keywords:  In vivo CAR-T; T-cell engineering; gene delivery; gene editing
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105373
  26. Cancer Immunol Res. 2026 May 15.
    Reprogramming CAR with cytokine signaling increases the efficacy of CAR-T cell therapy in solid tumour treatment and confers sustained immune memory.
    Rongchen Sun, Shang Liu, Xue Yang, Changshuai Che, Zhijie Zhang, Chengrui Zhang, Yunfan Wang, Youyou Yang, Xin Li, Jie Wang, Heng Zheng, Min Guo, Hongping Yin.
      Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable efficacy in hematologic malignancies but remains limited in solid tumors because of the immunosuppressive microenvironment, tumor heterogeneity, poor immune-cell infiltration, and progressive T-cell dysfunction. Because cytokine costimulation is critical for maintaining T-cell fitness, we developed a modular engineering strategy, distinct from previous approaches based on direct insertion of large cytokine receptor fragments, in which the intracellular CAR signaling domain was reconstructed to incorporate compact IL-2/IL-15 receptor-derived activation motifs, thereby enabling antigen-dependent coactivation while preserving the overall architecture of the parental CAR. Through systematic screening, we identified S71 as the optimal construct, with significantly greater antitumor activity than other mutants across multiple solid and hematologic tumor targets. Mechanistically, S71 rewired CAR signaling and reprogrammed tumor-induced metabolic responses through a self-sustaining mechanism, improving mitochondrial function and supporting durable T-cell activity. Functionally, S71 promoted enhanced persistence and robust immune memory responses against solid tumors. These findings demonstrate that modular integration of cytokine signaling motifs into CAR intracellular domains can improve CAR T-cell fitness and antitumor efficacy, and they establish S71 as a promising strategy for overcoming barriers to CAR T-cell therapy in solid tumors.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1490
  27. ACS Pharmacol Transl Sci. 2026 May 08. 9(5): 1021-1036
    Chimeric Antigen Receptor T‑Cell Therapy Targeting Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30) for Relapsed or Refractory Anaplastic Large Cell Lymphoma: Rationale, Strategies, and Emerging Clinical Evidence.
    Alberto Boretti.
      Chimeric Antigen Receptor (CAR) T-cell therapy has fundamentally altered the treatment paradigm for relapsed or refractory (R/R) B-cell malignancies. However, translating this success to T-cell lymphomas has been impeded by a critical biological barrier: fratricide. This process describes the self-destruction of therapeutic T-cells caused by their shared expression of target antigens, such as Tumor Necrosis Factor Receptor Superfamily Member 8 (CD30), following activation. Anaplastic Large Cell Lymphoma (ALCL), characterized by its uniform and high-level expression of CD30, represents both an ideal candidate for this approach and a significant scientific challenge. This comprehensive review begins by outlining the established landscape of approved CD19- and BCMA-directed CAR-T therapies to provide context. It then focuses specifically on the application of anti-CD30 CAR-T therapy for ALCL, examining the molecular mechanisms that drive fratricide. We explore the innovative engineering and manufacturing strategies developed to overcome this obstacle, including ultrarapid production protocols, the selection of virus-specific T-cells, and precise genetic disruption of the TNFRSF8 gene using CRISPR/Cas9 technology. An analysis of early phase clinical trial data reveals encouraging efficacy, with high rates of durable complete responses observed even in heavily pretreated patients who have failed brentuximab vedotin therapy. Furthermore, these initial studies report a remarkably favorable safety profile, characterized by a near absence of severe cytokine release syndrome and neurotoxicitya feature that distinctly contrasts with CD19-directed therapies. While these findings are promising, it is essential to acknowledge that the current evidence base remains preliminary, derived from small, heterogeneous patient cohorts and requiring validation in larger, more definitive trials with extended follow-up. By successfully addressing the challenge of fratricide, anti-CD30 CAR-T therapy holds the potential to become a transformative and potentially curative option for patients with R/R ALCL and may offer a valuable blueprint for developing effective immunotherapies against other T-cell malignancies.
    Keywords:  Anaplastic Large Cell Lymphoma (ALCL); CD30; Chimeric Antigen Receptor T-Cell (CAR-T); T-cell lymphoma; cellular immunotherapy; molecular immunology
    DOI:  https://doi.org/10.1021/acsptsci.6c00103
  28. Mol Ther Adv. 2026 Jun 11. 34(2): 201712
    Epigenetic editing balances TCR suppression and persistence in CAR T cells.
    Pascal Y Schönberg, Ángela Muñoz-Ovalle, Haidy A Saleh, Eugenia Crespo, Robert Kuhnert, Susanne Michen, Liliana Loureiro, Achim Temme, Anja Feldmann, Frank Buchholz.
      Allogeneic chimeric antigen receptor (CAR) T cell therapies offer a scalable, off-the-shelf option for cancer treatment, but their clinical use is limited by the risk of graft-versus-host disease (GvHD), mediated by the endogenous T cell receptor (TCR). Conventional strategies to eliminate TCR expression rely on genome editing tools such as CRISPR-Cas9 or base editing, which introduce permanent DNA changes and pose safety concerns. Here, we present an epigenetic editing approach that enables efficient, specific, and reversible silencing of the CD3ε gene, a critical component of the TCR complex, without altering the genome. We systematically optimized the epigenetic editor and guide RNA in a cell line and achieved robust TCR silencing in primary T and CAR T cells while preserving CAR expression, activation, and effector function. Transcriptome analysis confirmed minimal off-target effects. In vivo observations suggest the epigenetically silenced T cells to prevent GvHD while persisting longer than TCR-knockout cells, supporting the notion that transient TCR suppression may help balance safety and long-term efficacy. Our findings establish epigenetic editing as a non-genotoxic alternative to genome editing, offering a flexible and safer route to generate next-generation allogeneic CAR T cells.
    Keywords:  CAR T cell; CRISPR/Cas; T cell receptor; allogeneic therapy; epigenetic editing; genome editing; graft-versus-host disease
    DOI:  https://doi.org/10.1016/j.omta.2026.201712
  29. Mol Ther. 2026 May 14. pii: S1525-0016(26)00378-3. [Epub ahead of print]
    T cell Engineer: An interactive website to track CAR T cell negative regulators.
    Meghan B Ward, Hongbo Chi, Stephen Gottschalk, Giedre Krenciute.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.04.057
  30. Cytotherapy. 2026 Mar 05. pii: S1465-3249(26)00101-5. [Epub ahead of print]28(7): 102140
    Preclinical evaluation of a novel CD4 specific CAR NK cell therapy for T-cell malignancies.
    Katharina Eva Ruppel, Philipp Lückemeier, Alexander Scholz, Anika Stahringer, Kristin Reiche, Ulrike Köhl, Stephan Fricke, Marco Herling, Dominik Schmiedel.
       BACKGROUND: T-cell leukemias and lymphomas (TCL) are a rare and heterogeneous group of cancers with limited treatment options and an overall poor prognosis. In contrast to B-cell malignancies, the development of cellular therapies for TCL has not yet resulted in an approved product. The development of autologous CAR T cell approaches is challenging because of the shared antigens between the malignant T lymphocytes and healthy T cells, that can lead to fratricide, product contamination, manufacturing limitations, and T-cell aplasia.
    METHODS: To address these limitations, we developed CD4-specific chimeric antigen receptor (CAR) natural killer (NK) cells as an off-the-shelf immunotherapeutic strategy. CD4 CAR NK cells were generated from peripheral blood via retroviral transduction, and cytotoxicity was tested against 17 TCL cell lines representing six TCL subtypes. Additionally, RNA sequencing was performed to profile NK cell ligand expression across these cell lines. We further characterized CD4 CAR NK cells, cultivated in gas-permeable G-Rex culture plates, and assessed their killing capacities against primary patient-derived TCL samples.
    RESULTS: CD4 CAR NK cells showed CAR expression levels of up to 60% and demonstrated natural and specific cytotoxicity across T-cell malignancy cell lines. NK ligand analysis of the cell lines highlights how the balance of inhibitory versus activating signals shapes both natural and CAR-mediated responses. Using gas-permeable G-Rex culture plates, we developed a standardized manufacturing protocol, achieving over 15-fold expansion by day 14 and over 50-fold by day 21 post-isolation. Cells maintained high viability, transduction efficiency, and cytotoxic functionality, and exhibited potent activity against primary patient-derived TCL samples.
    CONCLUSIONS: Together, these findings demonstrate the feasibility, scalability, and therapeutic potential of CD4-directed CAR NK cells in T-cell malignancies, supporting their further development towards clinical application.
    Keywords:  CAR NK therapy; CD4 CAR; G-Rex cell culture; NK cells; T cell malignancies; cell therapy
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102140
  31. Front Immunol. 2026 ;17 1809907
    Oxidized mannan-MOG35-55 conjugate as a platform for antigen-specific immune modulation in multiple sclerosis.
    Athanasia Mouzaki, Anne-Lise de Lastic, Vasso Apostolopoulos, Ioannis Matsoukas.
      Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by autoreactive T-cell responses against myelin antigens. Current disease-modifying therapies (DMTs) broadly suppress immune activity but do not restore antigen-specific immune tolerance and may cause significant adverse effects. Antigen-specific immunotherapies offer a rational alternative aimed at selectively re-educating the immune system without compromising protective immunity. Structural determinants of myelin antigens, including arginine-dependent conformational stability and post-translational modifications such as citrullination, critically influence their immunogenic and tolerogenic properties. Recent advances highlight the potential of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein peptide (OM-MOG35-55) to modulate antigen-specific immune responses in experimental models and human immune cells. Studies suggest that OM-MOG35-55 can influence dendritic cell (DC)-mediated antigen presentation and favor the expansion of CD4+PD-1+ and CD4+CD25+Foxp3+ T-cell populations and the production of regulatory cytokines such as IL-10 and TGF-β1. When combined with vitamin D3 conditioning of DCs, the immunomodulatory potential of OM-MOG35-55 appears enhanced. Nevertheless, the precise mechanisms underlying OM-MOG-mediated immune modulation are not fully defined, and the antigenic heterogeneity of MS and the limited predictive value of EAE models highlight the need for cautious interpretation of preclinical findings. This mini-review integrates structural, immunological, and translational evidence supporting OM-MOG35-55 as a promising platform for antigen-specific immunotherapeutic design and proposes a roadmap toward clinical validation of this immunotherapeutic strategy for MS.
    Keywords:  MOG35-55; mannan conjugate; multiple sclerosis; myelin; peptides; personalized immunotherapy; regulatory T cells
    DOI:  https://doi.org/10.3389/fimmu.2026.1809907
  32. Cancer Treat Res Commun. 2026 Apr 21. pii: S2468-2942(26)00133-4. [Epub ahead of print]47 101222
    HHV-6 reactivation in the era of CAR T-cell therapy: A systematic review of emerging challenges.
    Pramod Singh, Asad Zaman, Ali Shan Hafeez, Abdul Rafae Faisal, Muhammad Faizan, Henna Qadri, Ahmar Jan Qureshi, Muhammad Atif Khan, Abat Khan.
       BACKGROUND: Human herpesvirus-6 (HHV-6) infection is a known complication of allogeneic hematopoietic stem cell transplantation, but its incidence and clinical impact following chimeric antigen receptor T-cell (CAR-T) therapy remain unclear.
    METHODS: A systematic review was conducted according to PRISMA 2020 guidelines to evaluate HHV-6 infection or reactivation after CAR-T therapy in adults. Searches of PubMed Central, Embase, and the Cochrane Library identified 50 records, of which 10 studies (five case reports, three case series, and two cohort studies) met inclusion criteria. Data on patient characteristics, timing, clinical manifestations, treatment, and outcomes were extracted and analyzed descriptively.
    RESULTS: Among 728 CAR-T recipients, HHV-6 infection or reactivation was reported in 22 patients (3.0%; 95% CI, 1.9%-4.5%) over a median follow-up of 2.8 months (range, 0.6-33.8). The median age was 56 years (range, 18-74), and 53.8% were male. HHV-6 infection occurred a median of 21 days (range, 16-84) after CAR-T infusion. Reported complications included encephalitis (n = 10), myelitis (n = 1), pancolitis (n = 1), and disseminated infection (n = 1). Antiviral therapy was administered in seven patients. Among 19 patients with available mortality data, 8 patients died from any cause (42.1%); 4 of these 8 deaths were attributed to HHV-6, corresponding to an HHV-6-attributable mortality of 21.1% among evaluable patients. Cytokine release syndrome was reported in all evaluable cases, and immune effector cell-associated neurotoxicity syndrome occurred in 11 of 17 patients.
    CONCLUSION: Although infrequent, HHV-6 infection or reactivation following CAR-T therapy is associated with substantial morbidity, particularly involving the central nervous system, and overlaps with CAR-T-related toxicities, underscoring the need for heightened clinical awareness.
    Keywords:  CT; Chimeric antigen receptor T-cell (CAR-T) therapy; HHV-6 reactivation; Human herpesvirus-6
    DOI:  https://doi.org/10.1016/j.ctarc.2026.101222
  33. Transplant Cell Ther. 2026 May 13. pii: S2666-6367(26)00331-3. [Epub ahead of print]
    Chimeric Antigen Receptor T-Cell Therapy in Autoimmune Disorders: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.
    Olalekan O Oluwole, Leslie Crofford, Andrew P Jallouk, Daniel W Lee, Rebecca Gardner, Amanda L Piquet, Shaun W Jackson, Alejandro Marinos Velarde, Everett Meyer, Tristan E Knight, Madhav R Seshadri, Sayeef Mirza, Kara Wacker, Erin Wilfong.
      Chimeric Antigen Receptor (CAR) T-cell therapy is a standard of care in many lymphoid malignancies and has emerged as potentially curative. A unique property of this one-time treatment is profound and long-lasting B cell depletion, hence the quest to explore its impact in the treatment of severe autoimmune disorders. Early trials in select populations have shown preliminary benefit. However, many questions persist as to how best to deploy this potentially highly effective therapy in the treatment of autoimmune disorders. The American Society for Transplantation and Cellular Therapy Committee on Cellular Therapy convened a group of experts in hematology, oncology, and autoimmunity to provide in a question and answer format a review of the existing publications on CAR-T cell therapy in autoimmune disorders including subtypes, discuss types of clinical trials, strategies to optimize patient safety, monitoring and toxicity management, tracking organ dysfunction in different types of autoimmune disorders, and financial considerations with the goal of providing a guide to physicians who want to be involved in CAR-T cell therapy in autoimmune disorders.
    Keywords:  Adults; Autoimmune disorder; CRS; Cellular therapy; Chimeric Antigen Receptor (CAR) T cells; ICANS; Pediatrics
    DOI:  https://doi.org/10.1016/j.jtct.2026.04.045
  34. Cytotherapy. 2026 Apr 03. pii: S1465-3249(26)00783-8. [Epub ahead of print]28(7): 102822
    Chimeric antigen receptor-natural killer cell therapy in first-relapse epithelial ovarian cancer: an early health-economic evaluation in the Netherlands.
    Abril Seyahian, Mirre Scholte, Chantal Gravesteijn, Petra L M Zusterzeel, Paul K J D De Jonge, Anna de Goede, Joop H Jansen, Ruud L M Bekkers, Petronella Beatrix Ottevanger, Harry Dolstra, Janneke P C Grutters.
       OBJECTIVE: To use early health economic modelling to evaluate the potential cost-effectiveness of adding a CAR-NK (chimeric antigen receptor-natural killer) cell therapy to standard of care (SOC) in patients with platinum-sensitive, high-grade epithelial ovarian cancer (EOC) at first recurrence in the Netherlands.
    METHODS: A partitioned survival model was developed from the Dutch healthcare perspective with a lifetime horizon and 3-week cycles, including progression-free, recurrent-disease and dead health states. Treatment regimens, varying by mutation status (BRCA, homologous recombination deficiency or no mutation), were compared with the same regimen plus repeated CAR-NK cell infusion (CAR-NK strategy). Two cost scenarios (€15 000 and €20 000 per CAR-NK cell therapy cycle) were analyzed. Costs and effects were discounted at 3% and 1.5% annually. Scenario and multivariate sensitivity analyses were conducted. A cost-effectiveness threshold of €80 000 per QALY was applied.
    RESULTS: The SoC strategy yielded 2.47 QALYs and 3.2 life-years at €34 340 per patient. CAR-NK strategy would require 0.76-0.95 additional QALYs (1.00-1.25 life-years) to be cost-effective. This corresponds to median gains of 3.08 months in progression-free survival and 10.82-13.60 months in overall survival. Cost-effectiveness was most sensitive to CAR-NK cell therapy costs, survival gains and utility values.
    CONCLUSIONS: A CAR-NK cell therapy could become cost-effective for platinum-sensitive EOC. To achieve this, it would need to deliver substantial overall survival gains. Early economic modeling provides strategic guidance for development, identifies key drivers of value and informs clinical trial design under uncertainty.
    Keywords:  Cost-Benefit Analysis; Early health technology assessment; Killer Cells, Natural; Ovarian Neoplasms; Receptors, Chimeric Antigen; Technology Assessment, Biomedical
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102822
  35. Lancet Reg Health Eur. 2026 Jul;66 101688
    A roadmap for supporting the development of advanced therapy medicinal products in a European framework.
    Johan Van Eldere, Alessandro Aiuti, Silvia Martin Lluesma, Bjarne Kuno Møller, Britt Elmedal Laursen, Celeste Lebbe, Alejandro Piris, Javier Carmona, Gady Goldsobel, Ulrich Kintscher, Peter Vandenberghe, Isabelle Huys, Bart Geers, Reuben Benjamin, Victoria Potter, Chiara Bonini, Fabio Ciceri, Gianvito Martino, Reno Debets, Hugo P H M van der Kuy, Stephan Mielke, Pontus Blomberg, Ewa Ellis, Antonia M S Müller, Nina Worel, Annette Künkele.
      Advanced therapy medicinal products (ATMPs) represent a paradigm shift in medicine; however, their implementation in European health systems is often hampered by EU regulations. Amidst a rapidly evolving and increasingly competitive global landscape, dominated by the US and China, it becomes imperative that Europe strengthens its position. This requires establishing a dialogue with European authorities to devise new regulatory mechanisms and incentives paving the way for innovation in drug development and implementation. Here, experts from the European University Hospitals Alliance (EUHA) specialising in ATMPs, share their vision on changes needed at the regulatory and organisational level to incentivise the development and clinical use of ATMPs and ensure an equitable and fast access for patients, largely inspired by the problems encountered in an academic environment and in developing ATMPs for rare diseases. To achieve real-world impact, these solutions should be supported by competent authorities at regional, national, and EU levels.
    Keywords:  Advanced therapy medicinal products (ATMPs); Clinical development of ATMPs; Decentralised production of ATMPs; Equitable clinical implementation of ATMPs; Hospital exemption; Manufacturing of ATMPs; Real world evidence; Regulatory framework for ATMPs; Reimbursement of ATMPs
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101688
  36. Methods Mol Biol. 2026 ;2997 47-90
    ImmTAC: A Novel Platform of T-Cell Receptor-Based Soluble Bispecifics.
    Benjamin P Oestringer, Annelise Vuidepot.
      Immune mobilizing monoclonal T-cell receptors Against Cancer (ImmTAC®) molecules are innovative immunotherapies designed to harness the body's immune system to fight cancer. They consist of a soluble affinity-enhanced T-cell receptor (TCR) as the targeting arm, covalently linked to an antibody fragment specific to CD3 as the effector arm, enabling T-cell redirection and cancer cell killing. TCRs can target the intracellular antigenic landscape via recognition of peptides presented by surface localized Human Leukocyte Antigen (HLA) proteins, unlocking a choice of targets that are specific to the tumor. The ImmTAC platform has been validated in the clinic with the approval of tebentafusp in 2022 for the treatment of metastatic uveal melanoma. It is the first TCR therapeutic and first soluble bispecific targeting a solid tumor to be approved for commercial use. Here, we describe the methods to produce soluble, affinity-enhanced TCRs and high-affinity ImmTAC molecules.
    Keywords:  Affinity enhancement; Biacore; HLA (human leukocyte antigen); IBs (inclusion bodies); ImmTAC (Immune mobilizing Monoclonal TCRs Against Cancer); Phage display; Protein expression; Protein purification; Protein refold; SPR (surface plasmon resonance); TCR (T-cell receptor); mTCR (monoclonal TCR)
    DOI:  https://doi.org/10.1007/978-1-0716-5037-0_4
  37. Nutrients. 2026 Apr 29. pii: 1400. [Epub ahead of print]18(9):
    The Gut Microbiota in Hematologic Malignancies: Mechanisms, Clinical Associations, and Translational Opportunities.
    Santino Caserta, Enrica Antonia Martino, Mamdouh Skafi, Ernesto Vigna, Antonella Bruzzese, Nicola Amodio, Marco Fiorillo, Eugenio Lucia, Graziella D'Arrigo, Virginia Olivito, Caterina Labanca, Francesco Mendicino, Maria Eugenia Alvaro, Giovanni Tripepi, Fortunato Morabito, Massimo Gentile.
      Hematologic malignancies arise and progress within a systemic ecosystem in which the gut microbiota is an increasingly recognized, partially modifiable component. Across acute leukemias, chronic lymphocytic leukemia, plasma cell disorders, lymphomas, and clonal myeloid neoplasms, human studies consistently report reduced microbial diversity, depletion of barrier-supportive, short-chain fatty acid-producing commensals, and enrichment of Gram-negative, pro-inflammatory, or hospital-adapted taxa. These alterations are associated with pre-leukemic clonal expansion, adverse genetic and immunological features, progression from precursor conditions, and inferior outcomes after chemotherapy, immunochemotherapy, chimeric antigen receptor T-cell therapy, and allogeneic hematopoietic stem cell transplantation. Mechanistic work in animal models and ex vivo systems demonstrates that microbiota-derived signals and metabolites-including Th17/IL-17-skewing consortia and the lipopolysaccharide intermediate ADP heptose sensed by the cytosolic receptor ALPK1-can actively modulate hematopoietic stem and progenitor cell fitness, inflammatory circuits, and malignant cell survival, supporting a causal role in disease biology. At the same time, major knowledge gaps remain because most human cohorts are small, single-center, and cross-sectional, frequently rely on 16S rRNA profiling, and are vulnerable to dietary, geographic, and treatment-related confounding. Within this context, three translational domains appear particularly promising: pharmaco-microbiomics, microbiome-informed risk stratification, and rational microbiota-targeted interventions, particularly diet-based strategies and antimicrobial stewardship. Here, we provide an integrated, disease-spanning synthesis of these data, emphasizing clonal hematopoiesis and myeloid neoplasms as emerging examples of microbiota-marrow crosstalk and outlining practical priorities for embedding microbiome science into future hematologic trials. Routine microbiome profiling or empiric microbiota-directed therapies cannot yet be recommended in everyday hematology practice, but integrating microbiome science into prospective therapeutic and transplant trials offers a realistic path to improved disease modeling, biomarker development, and rational adjunctive strategies to enhance outcomes for patients with hematologic malignancies.
    Keywords:  dysbiosis; gut microbiota; hematologic malignancies; immune–metabolic crosstalk
    DOI:  https://doi.org/10.3390/nu18091400
  38. MedComm (2020). 2026 May;7 e70753
    Development of CAR NK Cell Lines Selectively Targeting Cancer Cells Expressing Membrane Hsp70.
    Khouloud Hachani, Mina Yazdi, Charlotte Carcopino, Fatemeh Khademi Moghadam, Micholas Dean Smith, Anskar Trill, Marcel P Trefny, Morteza Hasanzadeh Kafshgari, Cosima C Hoch, Abdallah Gaballa, Bayan Alkotub, Jennifer Altomonte, A Graham Pockley, Ernst Wagner, Barbara Wollenberg, Sebastian Kobold, Gabriele Multhoff, Ali Bashiri Dezfouli.
      An effective chimeric antigen receptor (CAR)-based immunotherapy depends on both a suitable immune cell platform and a tumor-specific antigen to overcome barriers in solid tumors. Natural killer (NK) cell lines are promising platforms for CAR constructs due to their inherent tumor-killing ability, safety profile, and feasibility for standardized, off-the-shelf therapeutic use. Herein, four human NK cell lines (YT, KHYG1, NKL, and NK92) were retrovirally transduced with an anti-Hsp70 CAR targeting membrane-bound heat shock protein 70 (mHsp70), a tumor-specific antigen with broad expression on many solid tumors, but not normal cells. Computational modeling suggested a strong binding between the CAR and the extracellular domain of mHsp70. Although all NK cell lines exhibited successful CAR integration and surface expression, only NKL and NK92 cells maintained stable CAR expression and long-term viability. The anti-Hsp70 CAR NKL and NK92 cells demonstrated enhanced expression of activation markers and secretion of cytotoxic effector molecules, and robust target-specific killing of mHsp70-positive cancer cells, while sparing mHsp70-negative targets. Our findings validate the therapeutic potential of anti-Hsp70 CAR NK cells and the suitability of NKL and NK92 cells for advancing off-the-shelf CAR NK cell therapies, thereby offering a promising strategy for targeting a broad range of solid tumors expressing mHsp70.
    Keywords:  anti‐Hsp70 CAR NK cells; head and neck squamous cell carcinoma; immunotherapy; membrane‐bound Hsp70; tumor‐associated antigen
    DOI:  https://doi.org/10.1002/mco2.70753
  39. bioRxiv. 2026 Feb 23. pii: 2026.02.22.707331. [Epub ahead of print]
    Dynamic, single-cell monitoring of CAR T cell identity and activation with Raman spectroscopy.
    Ariel Stiber, Boi Quach, Babatunde Ogunlade, Antony Georgiadis, Kai Chang, Yuanwei Li, Patrick Quinn, Haoqing Wang, Kristin C Y Tsui, Charm Ang, Elena Sotillo, Crystal Mackall, Zinaida Good, Jennifer A Dionne.
      Chimeric antigen receptor (CAR) T cell therapies have reshaped treatment for cancers and immune-mediated diseases, yet their safety and efficacy depend on both the proliferation of engineered cells and their dynamic functional state - features that remain challenging to monitor in real-time clinical settings. Current methods require labels, extensive processing, and provide only static snapshots of cell identity and activation. Here, we introduce a surface-enhanced Raman spectroscopy and machine learning approach that enables label-free single-cell identification of engineered CAR T cells and time-resolved, semi-continuous monitoring of their functional activation state. Using the intrinsic vibrational signatures from live cells, we detect spectral differences resulting from engineered receptor expression in donor-derived CD19- and GD2-targeted CAR T cells (nine and five donors, respectively) with 81-85% donor-level accuracy and resolve dynamic antigen-specific activation trajectories with temporal precision. These capabilities stem from biochemical signatures consistent with processes such as receptor expression, tonic signalling, and immune synapse formation, demonstrating a single method that reports both cellular identity and activation state with biochemical specificity. Our results extend CAR T cell monitoring beyond static phenotyping and establish the potential of SERS-ML analysis for rapid, point-of-care assessment of engineered immune cells.
    DOI:  https://doi.org/10.64898/2026.02.22.707331
  40. J Biopharm Stat. 2026 May 13. 1-14
    Special issue: cell and gene causal inference in the design and analysis of gene therapy clinical trials.
    Debashis Ghosh, Nicole Mayer-Hamblett, Alexander M Kaizer.
      The introduction of gene therapies to treat and potentially cure various diseases has led to new considerations in the design, analysis and conduct of clinical trials involving these treatments. In this article, we consider the use of causal inference techniques to improve our understanding of aspects of these trials, focusing primarily on single-arm studies. While the ICH E9 R1 guidance provide a strong connection to causal inference ideas, we show how other aspects of gene therapy trials are amenable to causal thinking. We provide a review of the potential outcomes model and its assumptions. Next, we summarize the ICH E9 R1 guidelines on estimands. We then describe the implications of various aspects of causal inference for gene therapy clinical trials. Finally, we discuss how current and future clinical trials involving gene therapy in cystic fibrosis can benefit from causal inferential thinking.
    Keywords:  Causal inference; estimands; gene therapy; manufacturing
    DOI:  https://doi.org/10.1080/10543406.2026.2667329
  41. Comput Methods Programs Biomed. 2026 May 15. pii: S0169-2607(26)00188-4. [Epub ahead of print]283 109434
    Antiangiogenic therapy enhances CAR-T cell efficacy in solid tumors: Insights from a hybrid multiscale model.
    Sayyed Mohammad Ali Mortazavi, Bahar Firoozabadi.
       BACKGROUND AND OBJECTIVES: Despite the remarkable success of chimeric antigen receptor (CAR) T cells in hematological malignancies, their therapeutic efficacy in solid tumors is still limited, largely due to the insufficient infiltration of CAR-T cells and the immunosuppressive tumor microenvironment (TME). Recently, murine studies have shown that anti-angiogenic therapy can improve the efficacy of CAR-T cells. However, extensive research is required to unveil the underlying mechanism and develop effective therapeutic protocols.
    METHODS: Here, we developed a hybrid discrete - continuous multi-scale computational model to study solid tumor growth, angiogenesis, and CAR-T cell infiltration. Our model considers the intravenous infusion of CAR-T cells, their extravasation through the endothelium, and their cytotoxic effect in the TME. Therefore, this model enables us to robustly investigate the impact of anti-angiogenic therapy on the efficacy of CAR-T cells.
    RESULTS: Our findings showed that anti-angiogenic therapy enhances the delivery and efficacy of CAR-T cells in solid tumors. Subsequently, we evaluated different therapeutic regimens. The results revealed that although both adjuvant and neoadjuvant anti-angiogenic therapy can improve outcome, the neoadjuvant regimen yields higher survival rates. Moreover, our model suggested an optimal dosing schedule to maximize survival.
    CONCLUSIONS: Our results provide profound insight into the therapeutic dynamics of combined anti-angiogenic and CAR-T cell therapy. Additionally, the model establishes a computational framework for selecting treatment regimens for clinical trials.
    Keywords:  Anti-VEGF; CAR-T cell; Combination therapy; Computational oncology; Tumor microenvironment; Vascular normalization
    DOI:  https://doi.org/10.1016/j.cmpb.2026.109434
  42. Expert Opin Biol Ther. 2026 May 11. 1-4
    Next-generation CAR-NK cell therapy for glioblastoma: strategies to overcome antigen escape and the immunosuppressive tumor microenvironment.
    Samuel J Steuart, Eric P Grewal, Jing Sun, Leland G K Richardson, Uriel S Bulow, Wilfredo F Garcia-Beltran, William T Curry, Bryan D Choi.
      
    Keywords:  Glioblastoma; adoptive immunotherapy; chimeric antigen receptors; glioma; natural killer cells; neoplastic stem cells; tumor escape; tumor microenvironment
    DOI:  https://doi.org/10.1080/14712598.2026.2672421
  43. STAR Protoc. 2026 May 15. pii: S2666-1667(26)00224-8. [Epub ahead of print]7(2): 104571
    Protocol for a multi-modal performance-profiling workflow of CAR T cell products.
    Sarah Schulenberg, Michelle Loeser, Michael Schmueck-Henneresse.
      Functional characterization of engineered T cell products is essential for adoptive cell therapy development. Here, we present multi-modal profiling of CAR T cell products combining 33-marker full-spectrum flow cytometry (FSFC) with live-cell serial tumor-killing imaging. We describe steps for cell preparation, antibody staining, acquisition, serial killing assay, and integrated data analysis. This protocol is readily adaptable to other engineered T cell therapies. For complete details on the use and execution of this protocol, please refer to Schulenberg et al.1.
    Keywords:  Cancer; Cell-based Assays; Flow Cytometry; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104571
  44. J Transl Med. 2026 May 11.
    Foundation models in healthcare: a comprehensive review from technical advances to clinical translation.
    Zhaoying Wang, Yuanyuan Fang, Qi Li.
       BACKGROUND: As artificial intelligence (AI) has evolved through a series of discrete leaps, the Foundation model (FM) has demonstrated substantial potential for applications in the medical domain. Built on scalability, multimodal processing, and adaptability to diverse downstream tasks, FMs offer a flexible framework that can be tailored to various clinical needs. Nevertheless, the translation of FMs into clinical practice remains challenged by concerns regarding data privacy and security, bias and fairness, interpretability and sustainability. Therefore, a clinically oriented review is needed not only to summarize current advances and limitations but also to emphasize the clinical relevance, practical significance, and translational implications of FMs in medicine.
    MAIN BODY: This review outlines the development history of AI and introduces the FM basic theory, summarizes recent advances in their medical applications, and examines how FMs may support clinicians, enhance workflow efficiency, and improve patient outcomes. In addition to summarizing existing work, this review places particular emphasis on the clinical relevance, practical significance, and translational challenges of FMs across healthcare. Furthermore, privacy, safety, transparency, computational resources, clinical feasibility and sustainability issues are further discussed. Finally, the future direction of FMs in the medical field was projected.
    CONCLUSION: A central concept of this review is that the clinical translation of FMs requires interdisciplinary collaboration among AI developers, clinicians, and policymakers, supported by careful evaluation frameworks and continuous oversight to ensure clinical benefit and minimize risk.
    Keywords:  Artificial intelligence; Foundation models; Generative artificial intelligence; Large models
    DOI:  https://doi.org/10.1186/s12967-026-08211-0
  45. Methods Mol Biol. 2026 ;2997 241-272
    Clinical Development of Bispecific Antibodies: Review, Advances, and Challenges in Hematological Malignancies.
    Anri Saitoh.
      Precision therapies such as monoclonal antibodies (mAbs), immune-checkpoint inhibitors (ICIs), and chimeric antigen receptor T (CAR T)-cell therapies have revolutionized the treatment of cancer. Of these, bispecific antibodies (bsAbs) are gaining attention for their ability to simultaneously target two distinct molecular antigens, aimed at engaging T cells to circumvent cancer immune evasion mechanisms, resulting in tumor cytolysis. Several bsAbs have now been approved in the United States, Europe, and Japan for the treatment of hematological malignancies, most of which are CD3-redirecting bsAbs, although other immune-activating mechanisms are also being explored. This chapter reviews bsAbs in clinical development for hematological malignancies, their basic structure and mechanism of action, and efficacy and safety results of the most advanced bsAbs under clinical investigation.
    Keywords:  Antibodies; B-cell malignancies; Bispecific T-cell engagers; Bispecific antibodies; Hematological malignancies; Leukemia; Lymphoma; Multiple myeloma
    DOI:  https://doi.org/10.1007/978-1-0716-5037-0_17
  46. Cureus. 2026 Apr;18(4): e106893
    Pseudo-autologous Stem Cell Transplant for the Treatment of Secondary Central Nervous System Lymphoma.
    Dennis L Cooper, Andrew Wollowitz, Jhannine A Verceles, Amanda Lombardo, Mendel Goldfinger, Ioannis Mantzaris, Amit Verma.
      In patients who have previously undergone allogeneic stem cell transplantation and later have stem cells collected for an autologous transplant, the collected cells are sometimes referred to as "pseudo-autologous" to indicate that they are donor-derived. The use of pseudo-autologous stem cell transplantation (pASCT) has rarely been reported. We describe a case of pASCT in a 66-year-old man with multiple relapses of diffuse large B-cell lymphoma (DLBCL) despite prior chimeric antigen receptor T-cell (CAR T) therapy and a subsequent matched unrelated donor transplant. His most recent relapse after allogeneic transplantation was limited to the central nervous system (CNS) and presented with multiple cranial nerve palsies. Although previously collected autologous stem cells and donor-derived allogeneic stem cells were available, pseudo-autologous stem cells were collected during recovery from a modified salvage chemotherapy regimen (methotrexate (MTX), cytarabine, thiotepa, and rituximab (MATRix)). He subsequently received high-dose therapy with busulfan and thiotepa followed by pASCT. Despite receiving only brief (<1 month) graft-versus-host disease (GVHD) prophylaxis, he did not develop GVHD and remains disease-free 23 months after transplant. We discuss the rationale for selecting pASCT despite the availability of stored autologous and allogeneic stem cells.
    Keywords:  allogeneic stem cell transplant (allo-sct); autologous stem cell transplant (asct); car t cell therapy; diffuse large b cell lymphoma (dlbcl); pseudo-autologous stem cell transplant (pasct); secondary central nervous system lymphoma
    DOI:  https://doi.org/10.7759/cureus.106893
  47. Curr Opin HIV AIDS. 2026 May 15.
    Natural killer cells in pediatric HIV cure strategies: from viral control to immunotherapeutics.
    Nicola Cotugno, Lesley de Armas, Paolo Palma.
       PURPOSE OF REVIEW: Perinatal HIV infection occurs during a critical window of immune development, in a predominantly naïve immune system, resulting in distinct and unique virologic and immunologic outcomes compared with adult-acquired infection. Innate immunity and specifically natural killer (NK) cells play a role in early viral control and critically shape both size and composition of the HIV reservoir established in infancy. This review examines how NK cell function during acute infection and treatment interruption may contribute to virological outcomes.
    RECENT FINDINGS: Emerging data show that NK cell phenotypic and functional diversity associates with reservoir size and persistence. Immune-genetic factors, including HLA and KIR interactions and sex-specific differences, can significantly modulate NK-mediated HIV control. Studies also highlight how perinatal HIV exposure and co-infections alter innate immune networks involving monocytes and CD8 T cells, further influencing reservoir dynamics.
    SUMMARY: Insights into pediatric NK cell immunity reveal unique mechanisms of early HIV control and reservoir shaping that differ from adults. Understanding how NK cell function influences virological outcomes during acute infection and analytic treatment interruption (ATI) provides a critical foundation for designing cure strategies tailored to children. These include leveraging antibody-based interventions and emerging NK-directed immunotherapies to enhance reservoir clearance and support safer, more effective ATI-informed cure approaches.
    Keywords:  HIV cure; natural Killer immunity; perinatally HIV infected children
    DOI:  https://doi.org/10.1097/COH.0000000000001034
  48. Ageing Res Rev. 2026 May 11. pii: S1568-1637(26)00166-2. [Epub ahead of print] 103174
    Immunotherapy for Senescent Cell Clearance: Hallmarks, Strategies and Translational Challenges.
    Wenjie Zhang, Shihong Chen, Xianghua Zhuang.
      Cellular senescence, a complex multifactorial process, is involved in the pathophysiology of various age-related diseases, such as cardiovascular disease and neurodegenerative disorders. Traditional interventions targeting single mechanisms yield limited efficacy. As a core hallmark and driver of aging, immunosenescence provides a critical target for precision interventions. This systematic review examines the hallmarks of aging, including cellular damage, epigenetic abnormalities, and immunosenescence. It highlights immunotherapy strategies targeting senescent cells, including CAR-T/NK cell therapies, vaccines, and immune checkpoint blockade. These approaches have demonstrated significant efficacy in animal models by eliminating senescent cells and improving senescence phenotypes. Simultaneously, it analyzes current challenges such as insufficient target specificity, safety and cost concerns in cell therapies, and species differences. It also explores future directions including multi-target synergistic strategies, AI-assisted target screening, and the integration of precision medicine technologies. Immunotherapy offers a revolutionary paradigm for aging intervention, holding promise to extend healthy lifespan by regulating the immune system. However, further breakthroughs are needed for its clinical translation.
    Keywords:  CAR-T cell; hallmarks of aging; immunosenescence; immunotherapy; senescence
    DOI:  https://doi.org/10.1016/j.arr.2026.103174
  49. J Control Release. 2026 May 14. pii: S0168-3659(26)00422-0. [Epub ahead of print] 115019
    mRNA therapeutics: Molecular mechanisms, delivery platforms, regulatory frameworks, and equitable global access.
    Taruna Ikrar, Wachyudi Muchsin, Alfi Sophian.
      Messenger RNA (mRNA) therapeutics represent a transformative pharmaceutical modality, with three products approved by 2024 across infectious disease and rare metabolic indications. This review critically examines: (i) mRNA molecular architecture including nucleoside modification strategies for immune evasion and platforms beyond conventional mRNA (self-amplifying RNA [saRNA], circular RNA); (ii) lipid nanoparticle (LNP) delivery mechanisms encompassing endosomal escape limitations, selective organ targeting (SORT), and emerging alternative delivery systems including single-component carriers; (iii) the clinical application landscape spanning vaccines, personalised cancer immunotherapy, protein replacement, and CRISPR genome editing; (iv) translational challenges including stability, tissue-targeting, immunogenicity, and manufacturing scalability; and (v) the critically underrepresented dimensions of regulatory science and equitable global access in low- and middle-income countries (LMICs), drawing on Indonesia's BPOM as a policy case study contextualised within the broader LMIC regulatory landscape. Concrete capacity-building recommendations - including establishment of regional mRNA reference standard laboratories, low-cost dsRNA analytical platforms, and harmonised pharmacovigilance systems - are proposed. This review provides a molecularly grounded and policy-relevant synthesis for drug delivery scientists and regulators advancing equitable mRNA therapeutic access.
    Keywords:  Genome editing; Lipid nanoparticle; Low-income countries; Nucleoside modification; Protein replacement; Regulatory science; cancer immunotherapy; mRNA
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115019
  50. Brain Behav Immun Health. 2026 Jul;54 101251
    Mania and psychosis following chimeric antigen receptor T-cell therapy: A report of two cases and mechanistic discussion.
    Todd M Stollenwerk, Morgan E Barnett, Angela S Steineck, Nirav N Shah, Jennifer M Knight.
      CD20. CD19-targeted chimeric antigen receptor modified T-cell immunotherapy (CAR T-cell therapy) is an experimental CAR with increasing use for the treatment of lymphoid malignancies. Although acute neuropsychiatric toxicities are well described following CAR T-cell therapies, late-onset persistent neuropsychiatric symptoms, including mania and psychosis, are poorly characterized, and their underlying mechanisms are unknown. Here, we present two cases of new-onset mania and psychosis in the months following dual targeted CD20. CD19 CAR T-cell therapy, contributing significantly to the literature wherein no cases of such have been reported. We discuss the published literature on chronic neuropsychiatric symptoms following CAR T-cell therapy as well as potential neurobiological mechanisms for these effects. Finally, we discuss therapeutic considerations including the potential role of second-generation antipsychotics, such as olanzapine, which may be effective in the treatment of late-onset and persistent neuropsychiatric symptoms, including psychosis, following CAR-T cell treatment.
    Keywords:  CAR T-cell therapy; Mania; Olanzapine; Psychosis
    DOI:  https://doi.org/10.1016/j.bbih.2026.101251
  51. Farm Hosp. 2026 May 14. pii: S1130-6343(26)00077-2. [Epub ahead of print]
    Orphan drug regulation: a global comparison of the United States Food and Drug Administration, European Medicines Agency, and Japanese pharmaceuticals and medical devices agency approaches.
    Robinraja Elango, Russell Martin, Shivanand K Mutta.
       OBJECTIVE: To perform a comparative review of orphan drug policies and designation criteria implemented by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), assessing their influence on development, approval, and access.
    METHOD: A targeted review of legislation, guidance documents, and peer-reviewed analyses from each regulatory body was conducted.
    RESULTS: The FDA accelerates development via robust tax credits and seven-year market exclusivity, though high pricing remains challenging. The EMA emphasizes unmet medical needs and ten-year exclusivity, ensuring more homogeneous pricing despite slower approvals. Japan's PMDA utilizes specific subsidies and the Sakigake designation to counter "drug loss" and encourage innovation. Despite expedited pathways globally, significant disparities in affordability and patient access persist.
    CONCLUSIONS: While national incentives successfully boost orphan drug approvals, global access inequities remain unresolved. Harmonizing regulatory criteria and promoting international collaboration on evidence requirements are essential for equitable and sustainable access to rare disease therapies worldwide.
    Keywords:  Administración de Alimentos y Medicamentos de Estados Unidos; Agencia Europea de Medicamentos; Agencia Japonesa de Productos Farmacéuticos y Dispositivos Médicos; Aprobación de medicamentos; Drug approval; Enfermedades raras; European Medicines Agency; Japanese Pharmaceuticals and medical devices agency; Orphan drug regulation; Rare diseases; Regulación de medicamentos huérfanos; United States Food and Drug Administration
    DOI:  https://doi.org/10.1016/j.farma.2026.04.003
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