bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–06–14
47 papers selected by
Luca Bolliger, lxBio
  1. CAR-T Cell-Derived Exosomes and Cancer Immunotherapy: Advancing Production and Delivery Through Biofabrication.
  2. Reprogramming immunity: the promise and challenges of CAR T cell therapy in multiple sclerosis.
  3. Circadian rhythm-guided cellular therapy in hematologic malignancies: mechanisms, clinical evidence, and optimization strategies.
  4. A clinical-grade automated platform for the manufacturing of CAR-γδ T cells for immunotherapy.
  5. Anti-CD19 CAR T cell therapy promotes skin remodelling in systemic sclerosis.
  6. Manufacturing strategies for prolonged CAR-T cell persistence.
  7. Insight into human allogenic CAR-T therapy: an open-access dataset.
  8. Adoptive T-cell therapies in the clinic.
  9. Folate receptor beta targeting of tumor-associated macrophages improves lymphoma cell responses to CD19 CAR T cells.
  10. A chemokine "leverage regulation" biomimetic nanoformulation enhances CAR-T cells against solid tumors by reshaping immune cell niches.
  11. Dual-target CAR-T cell therapy: latest updates from the 2025 ASH annual meeting.
  12. CAR-T Cell Therapy and Its Complications: Role of the Pathologist in Diagnosis.
  13. Mapping Therapeutic Regulatory T Cell Fate with MRI: Current Strategies and Translational Outlook.
  14. Optimizing CAR T cell therapy in pancreatic cancer through clinically actionable combinations.
  15. Nano-enabled strategies for enhancing cancer immunotherapy: challenges, progress and perspective.
  16. Chimeric antigen receptor T-cell therapy in rheumatoid arthritis.
  17. The TNFR2M196R germline variant confers dual impact on CAR-T cell immunotherapy by enhancing T-cell survival and tumor proliferation.
  18. Cellular therapies in systemic lupus erythematosus: recent progress and future directions.
  19. CCL19-armed oncolytic adenovirus synergizes with CCR7-expressing CAR-T cells to suppress ovarian tumor growth.
  20. Beyond the chimeric antigen receptor T cells and bispecific antibody duopoly: ex vivo armed T cells for solid tumors.
  21. Engineering nanoplatforms for autoimmune treatment: From synthetic strategies to bioinspired designs.
  22. The Landscape of Advanced Therapy Medicinal Products in Slovenian Transfusion Medicine: A Review of Past and Future Outlook.
  23. Infectious complications after CAR T-cell therapy: mechanisms, risk stratification, and prevention.
  24. T-Cell Lymphoma Associated with CAR-T Cell Therapy: A Bayesian Disproportionality Analysis of a National Database.
  25. Chimeric antigen receptor T-cell therapy induces complete remission in a patient with concurrent CLL with CNS involvement and multiple sclerosis.
  26. T cell-macrophage crosstalk in GVHD and cancer immunotherapy.
  27. Effector Vδ1 γδT cells mediate anti-tumor immunity and are reprogrammed by imatinib in human gastrointestinal stromal tumor.
  28. Ready-to-load MHC-I nanoparticles for high-throughput T cell screening studies.
  29. A novel triple-knockout allogeneic BCMA CAR T cell therapy (CT0590) in multiple myeloma: preclinical and phase I study.
  30. Development and in vivo evaluation of novel humanized CD19 CAR-T cells for advanced B cell malignancies.
  31. Heparanase-Loaded CAR T Extracellular Vesicles Remodel the Colorectal Tumour Microenvironment and Boost T Cell Antitumor Immunity.
  32. Longitudinal Cognitive Assessment After CAR-T Cell Immunotherapy: A Prospective Cohort Study.
  33. Molecular Insights and Novel Therapies for Lymphoproliferative Disorders.
  34. Microbiome-orchestrated cross-organ immunity in autoimmunity: from metabolites to therapeutic targets.
  35. Combined targeting of mesothelin and tenascin-C enhances CAR-T cell function and tumor microenvironment modulation in ovarian cancer.
  36. Antibody Format Matters: A Comparative Analysis of VHH and scFv Domains Reveals Superior In Vivo CAR T Cell Function with VHH Domains.
  37. Future trends and the role of artificial intelligence in pharmaceutical project management.
  38. Neighborhood socioeconomic disadvantage and distance from treatment center do not impact survival outcomes of patients with non-Hodgkin lymphoma and multiple myeloma treated with CAR T-cell therapies.
  39. Experimental Therapies in Multiple Sclerosis: Epstein-Barr Virus and Potential EBV-Related Therapeutic Strategies-A Systematic Review.
  40. NKG2D-based CAR-T cells for synovial sarcoma: A preclinical proof-of-concept study.
  41. Reductions in Immunoglobulin Levels, Atopic Disease, and Asthma Following CAR T-Cell Therapy.
  42. Optimizing CAR-T therapy delivery in the Italian healthcare system: economic and organizational insights in follicular lymphoma.
  43. A bibliometric analysis of global research trends in adoptive cell therapy for triple negative breast cancer over the past 15 years.
  44. Building a single market for data: Data spaces as pro-competitive infrastructure.
  45. Natural Killer Cells: Dual Regulators and Therapeutic Targets in Multiple Sclerosis Immunopathogenesis.
  46. Advancing CAR-T therapy in multiple myeloma: a critical appraisal of CARTITUDE-4 and the path toward earlier lines.
  47. From viral drift to tumor drift: why cancer immunotherapy needs B cells and dynamic adaptation.
  1. Biofabrication. 2026 Jun 09.
    CAR-T Cell-Derived Exosomes and Cancer Immunotherapy: Advancing Production and Delivery Through Biofabrication.
    Mahmood Razzaghi, Mohammad Hossein Karimi, Jamshid Hadjati, Colin Collins, Mohsen Akbari.
      Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, but it still faces some major barriers in solid tumors because of poor infiltration, the immunosuppressive microenvironment, and sometimes severe toxicities. The CAR-T cellderived exosomes (CAR-T-EXOs) have been emerging as safer and more scalable acellular alternatives that can preserve the tumor-specific CAR recognition and cytotoxic effect or functions, while avoiding the cytokine release syndrome (CRS) and neurotoxicity issues. These nanosized vesicles can penetrate the dense tumor stroma and reprogram the immunosuppressive niches more effectively than the cellular therapies. The recent advances in biofabrication are now enabling the high-yield production, functional validation, and more precise delivery of CAR-T-EXOs. The biofabricated models, including the three-dimensional (3D) spheroids, organoids, bioprinted constructs, and tumor-on-chip systems, offer more physiologically relevant platforms for evaluating exosome trafficking and efficacy. Meanwhile, smart delivery systems such as stimuli-responsive hydrogels, nanofiber scaffolds, and hybrid nanovesicles provide spatiotemporal control over the exosome release. Despite all this promise, the clinical translation is still hindered by the variability in isolation methods, characterization procedures, and the regulatory frameworks. This review tries to integrate immunology, bioengineering, and translational perspectives to outline the biological advantages of the CAR-T-EXOs, to survey the latest biofabrication strategies, and to discuss the regulatory challenges. We also highlight some emerging paradigms, like exosome mimetics, nanorobotics, and personalized tumor-on-chip testing, that are likely to speed up the next generation of safer and more effective exosome-based immunotherapies for solid tumors.
    Keywords:  Biofabrication; CAR-T Cell-Derived Exosomes; CAR-T Cell-Derived Exosomes Biofabrication Exosome Delivery Systems Cancer Immunotherapy Cancer Models Solid Tumor Advanced ther; Cancer Immunotherapy; Cancer Models; Exosome Delivery Systems; Solid Tumor Advanced therapy medicinal products
    DOI:  https://doi.org/10.1088/1758-5090/ae7b0b
  2. Inflammopharmacology. 2026 Jun 12.
    Reprogramming immunity: the promise and challenges of CAR T cell therapy in multiple sclerosis.
    Nitik Kumawat, Aarti Sharma, Shubham Upadhayay.
       INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy was initially used to treat B-cell malignancies, and it is now considered an effective treatment option for multiple sclerosis (MS). CAR-T therapy selectively targets and depletes pathogenic B cells within lymphoid tissue and the central nervous system (CNS), showing promise for achieving deep, sustained remission and long-term treatment-free disease control in patients with refractory MS.
    METHODOLOGY: A comprehensive analysis was carried out by searching multiple keywords with combinations such as "CAR-T", "MS", "Demyelination", "Autoimmunity", "CD19", "Inflammation", "B cells", T cells", "Neurodegeneration ", "Neurological Disorders", "Immunity", etc. The review included preclinical and clinical research articles publicly available till March 2026. This study was conducted to explore the mechanisms of action, clinical effectiveness, safety profile, and prospects for CAR-T treatment for MS.
    RESULTS: From the beginning clinical testing indicates that CD19 targeted CAR-T cells can efficiently and permanently destroy through B-cells, leading to a significant decrease in disease progression, a recovery of impairment, and an immense reduction in inflammatory markers in individuals who have progressive MS. New techniques for engineering such as allogeneic CAR-T cells and enhanced CRISPR-based safety switches, are being investigated for making things safer and easier for individuals.
    CONCLUSION: CAR-T treatment represents a revolutionary approach for individuals with refractory MS. With ongoing improvements in safety and specificity, it has the potential to transform the therapeutic paradigm toward a sustainable immunological reset and prolonged remission in clinical neuroimmunology.
    Keywords:  Autoimmunity; Chimeric antigen receptor T-cell (CAR-T); Multiple sclerosis; Neuroimmunology
    DOI:  https://doi.org/10.1007/s10787-026-02295-2
  3. Biomark Res. 2026 Jun 10.
    Circadian rhythm-guided cellular therapy in hematologic malignancies: mechanisms, clinical evidence, and optimization strategies.
    Yao Teng, Xiaoyan Zhao, Aiguo Liu.
      Circadian rhythms are endogenous 24-hour timing systems that coordinate hematopoiesis and immune function through central and peripheral clocks. Increasing evidence indicates that the initiation and progression of hematologic malignancies are frequently accompanied by circadian disruption, which not only contributes to malignant transformation and disease progression but also anti-tumor immunity and variable treatment responses. Cellular therapies, particularly hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T-cell therapy (CAR-T), have emerged as transformative modalities for hematologic malignancies, demonstrating remarkable clinical efficacy. However, their outcomes and toxicities are significantly influenced by circadian regulation. This review summarizes circadian mechanisms in hematologic malignancies and chronotherapy evidence for HSCT and CAR-T. And we discuss chronotherapeutic opportunities, including timed cell collection, manufacturing, infusion, and post-treatment care. We further highlight the clinical relevance of individualized circadian phase assessment as a foundation for personalized treatment scheduling. Collectively, integrating circadian principles into hematologic cellular therapy may improve engraftment, enhance antitumor efficacy, reduce toxicity, and provide a practical framework for more precise and personalized treatment.
    Keywords:  CAR-T; Chronotherapy; Circadian rhythm; HSCT; Hematological malignancies
    DOI:  https://doi.org/10.1186/s40364-026-00952-w
  4. Front Immunol. 2026 ;17 1779035
    A clinical-grade automated platform for the manufacturing of CAR-γδ T cells for immunotherapy.
    Jan Kuska, Julia Kostyra, Lorraine Pinot, Evgeny Egorov, Nojan Jelveh, Lilian A Martinez Carrera, Congcong Zhang, Svetlana Khorkova, Mario Assenmacher, Rimas Orentas, Sabine Mueller, José Villacorta Hidalgo.
      Gamma delta (γδ) T cells are promising candidates for adoptive immunotherapy due to their unique biological and safety profiles. In particular, ex vivo expanded Vγ9Vδ2 T cells engineered with chimeric antigen receptors (CARs) have gained considerable interest, as they combine potent innate-like antitumor activity with a low risk of graft-versus-host disease and cytokine release syndrome, making them ideal for off-the-shelf cancer immunotherapies. However, as they represent only 1-5% of peripheral T cells, effective activation and expansion protocols are essential to generate sufficient numbers for clinical use. In this study, we describe an automated and highly efficient process for the expansion of Vγ9Vδ2 T cells and the manufacturing of CAR γδ T cells using the CliniMACS Prodigy closed system. This platform integrates cell separation, activation, genetic modification and expansion ensuring reproducibility and compliance with GMP standards. Starting with an alpha-beta (αβ) T cell and B cell magnetic depletion, we achieved a 4.59-log αβT cell depletion and a 3.97-log B cell depletion. By carefully optimizing activation, transduction and expansion, we were able to achieve up to 374-fold increase in Vγ9Vδ2 T cells, resulting in an average number of 6.64 x 109 (4.76×109 - 8.98×109) cells after 14 days of culture using the TCT-LS process. Using a GMP-grade lentiviral vector pseudotyped with the envelope protein from baboon endogenous virus (BaEV) encoding a CD123 chimeric antigen receptor (CAR) at a multiplicity of infection (MOI) of 0.12, we achieved a mean γδ T cell transduction efficiency of 57.4%. Flow cytometry analysis of the final cell product showed an average composition of 89.83% γδ T cells, 9.82% NK cells, and 0.012% residual αβ T cells. The low average vector copy number (VCN) of 1.4 underscores the safety and efficiency of the transduction protocol. Functional assays against a leukemic cell line confirmed robust anti-tumor activity of CAR-γδ T cells produced using this platform, demonstrating the feasibility of large-scale manufacturing and highlighting their potential for future clinical immunotherapy applications.
    Keywords:  allogeneic cell therapy; cancer immunotherapy; gamma delta T cell transduction; gamma delta T cells; large scale manufacturing
    DOI:  https://doi.org/10.3389/fimmu.2026.1779035
  5. Nat Rev Rheumatol. 2026 Jun 08.
    Anti-CD19 CAR T cell therapy promotes skin remodelling in systemic sclerosis.
    Holly Webster.
      
    DOI:  https://doi.org/10.1038/s41584-026-01396-0
  6. Cytotherapy. 2026 Mar 11. pii: S1465-3249(26)00739-5. [Epub ahead of print]28(8): 102778
    Manufacturing strategies for prolonged CAR-T cell persistence.
    Noriko Shimasaki.
      Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, achieving durable remission in patients who are refractory to conventional therapies. However, the limited persistence of infused CAR-T cells, due to T-cell exhaustion and the loss of CAR-T cells, remains a major obstacle to sustained therapeutic efficacy. Recent studies have demonstrated that CAR-T cell products enriched for less-differentiated memory T cell subsets exhibit superior long-term persistence, greater cytotoxicity, and improved clinical outcomes compared with conventional CAR-T cell products. To enrich for less-differentiated memory T cells, various strategies have been explored throughout the manufacturing process. These strategies include selecting cell sources enriched for less-differentiated memory T cells and delaying their differentiation into terminally differentiated states by regulating signaling pathways, remodeling epigenetics, and modulating metabolism. This review provides an overview of current and emerging manufacturing strategies for CAR-T cells, focusing on enhancing their prolonged persistence. Further investigations are warranted to determine the optimal composition of differentiated and less-differentiated T cells in CAR-T cell products under the respective clinical conditions. This could facilitate the personalized manufacturing of CAR-T cell products with the ideal cell composition, thereby maximizing the efficacy of CAR-T cell therapy.
    Keywords:  CAR-T cells; differentiation; exhaustion; manufacturing; memory T cells; persistence
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102778
  7. Drug Discov Today. 2026 Jun 08. pii: S1359-6446(26)00119-4. [Epub ahead of print] 104714
    Insight into human allogenic CAR-T therapy: an open-access dataset.
    Natalia Obajtek, Bartek Lisowski, Seweryn Ulaszek, Monika Jesionek, Marcin Piejko, Sebastian Polak.
      Chimeric antigen receptor T-cell (CAR-T) therapy demonstrates significant efficacy in various cancers, predominantly as a subsequent treatment line following multiple prior therapies. When compared to autologous options, allogeneic CAR-T products offer distinct advantages related to cell quality and cost-effectiveness. Because CAR-T cells differ fundamentally from conventional pharmaceuticals, mathematical modeling is essential to elucidate their exposure-response relationships. However, model utility depends on robust parametrization, which requires high-quality data. Although clinical data are expanding rapidly, challenges remain due to their limited availability and fragmentation across different sources. To address this limitation, this work introduces a comprehensive dataset aggregating human clinical trials that utilize allogeneic CAR-T cells for hematological disorders.
    Keywords:  CAR-T therapy; CAR‑T cell kinetics; allogeneic CAR-T; database
    DOI:  https://doi.org/10.1016/j.drudis.2026.104714
  8. Bioeng Transl Med. 2026 May;11(3): e70086
    Adoptive T-cell therapies in the clinic.
    Suyog Shaha, Leah Lourenco, Zongmin Zhao, Samir Mitragotri.
      T cells, as one of the most abundant immune cell types in the human body, play a central role in therapeutic applications and currently dominate the clinical landscape of cell therapies. Their target specificity and capacity to generate durable therapeutic responses make them a powerful modality for precision therapy. T cell therapies represent a leading frontier in cellular medicine and have been investigated for a broad spectrum of indications, from cancers to autoimmune diseases. Here, we provide a detailed overview of the clinical landscape of T cell therapies. We outline the historical developments that shaped the evolution of T cells into transformative therapies and present a comprehensive analysis of their clinical translation. We discuss key milestones in T cell discovery and provide an overview of the 19 globally approved T cell therapy products. We then examine the core features of these approved products and conduct an in-depth analysis of 2570 clinical trials involving T cell therapies, identifying three distinct time intervals of growth in clinical activity. Furthermore, we evaluate the evolution of critical trial parameters, such as cell source, disease indication, target selection, and delivery route, highlighting emerging trends and key inflection points. Lastly, we discuss the biological and logistical challenges that limit the broader clinical translation of T cell therapies to new indications and diverse patient populations. Our findings indicate a steady rise in clinical studies and regulatory approvals for T cell therapies, with a notably higher rate of approved products in recent years compared to stem cell therapies. This growth exhibits a phased pattern, with each interval characterized by a major inflection point in scientific advancement and clinical translation. Our discussions will provide a quantitative and contextualized overview of this clinical progress in T cell therapy, offering insights into its current trajectory and future potential as a transformative class of therapeutics.
    Keywords:  CAR‐T; T cell; adoptive cell transfer; cell therapy; clinical translation; clinical trials
    DOI:  https://doi.org/10.1002/btm2.70086
  9. Hemasphere. 2026 Jun;10(6): e70390
    Folate receptor beta targeting of tumor-associated macrophages improves lymphoma cell responses to CD19 CAR T cells.
    Kerttu Kalander, Katri Oksa, Selma Sorri, Hector Monzo, Suvi-Katri Leivonen, Päivi M Ojala, Sirpa Leppä.
      Chimeric antigen receptor (CAR) T cell therapies have revolutionized the treatment of patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, approximately half of the patients experience lymphoma progression after CD19 CAR T cell therapy. Immunosuppressive, M2-like tumor-associated macrophages (TAMs) contribute to the immunosuppressive tumor microenvironment (TME) and may facilitate resistance to CAR T cell therapy. Here, we identified folate receptor beta (FRβ) as a specific marker of M2-like TAMs and a predictor of poor survival in multiple independent DLBCL cohorts. Co-culture studies of lymphoma-macrophage spheroids revealed reciprocal interactions between lymphoma cells and M2-like macrophages. Lymphoma cell co-cultures promoted the differentiation of monocytes into M2-like macrophages, while M2-like macrophages fostered lymphoma cell growth and interfered with CD19 CAR T cell-mediated killing of lymphoma cells. We demonstrated that M2‑like macrophages drive CAR T cells toward an exhausted phenotype and validated this finding using data from patients treated with CD19 CAR T cell therapy. Lastly, we generated FRβ-targeting CAR T cells and used them prior to CD19 CAR T cells to successfully improve lymphoma cell killing. Taken together, the results suggest active crosstalk between lymphoma cells and M2-like macrophages, as well as TAM-mediated resistance mechanisms to CD19 CAR T cells, which can be circumvented by FRβ CAR T cells targeting the M2-like TAMs. These results support the use of macrophage-targeting to improve CAR T cell therapy outcomes in DLBCL.
    DOI:  https://doi.org/10.1002/hem3.70390
  10. J Control Release. 2026 Jun 05. pii: S0168-3659(26)00467-0. [Epub ahead of print]396 115064
    A chemokine "leverage regulation" biomimetic nanoformulation enhances CAR-T cells against solid tumors by reshaping immune cell niches.
    Xiu Zhao, Kaikai Zhao, Mengfei Yi, Ruohan Yang, Xuyang Cui, Yi Zhang, Feng Li, Junjie Liu.
      Tumor chemokines that drives abnormal immune cell niches play a crucial role in impairing the chimeric antigen receptor (CAR)-T cell therapy against solid tumors. Here we develop a biomimetic nanoformulation with chemokine "leverage regulation" capabilities, which can establish matching migration signals to creat an immune cell niche that supports CAR-T cell therapy. The system is constructed using celecoxib (CXB)-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles and subsequently camouflaging them with mesenchymal stem cell membranes with high CXCR4 expression. Leveraging the characteristic of tumors abnormally upregulating the chemokine CXCL12 to recruit CXCR4-positive immunosuppressive cells, the biomimetic nanoformulations can achieve efficient accumulation in the tumor tissue. These nanoformulations remodel the tumor chemokine milieu by upregulating immunogenic chemokines (CXCL9, CXCL10) to selectively recruit CAR-T cells, while simultaneously serving as a nanobait to neutralize CXCL12, thereby reducing the influx of immunosuppressive cells (such as CAR-Tregs and MDSCs) to enhance the killing efficacy of CAR-T cells. This dual modulation of the chemokine network significantly improves the therapeutic efficacy of CAR-T cells against solid tumors. Our approach represents a promising strategy for advancing CAR-T cell therapy toward clinical applications for soild tumors.
    Keywords:  CAR-T cell therapy; Chemokine regulation; Nanoformulation; Soild tumors
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115064
  11. Exp Hematol Oncol. 2026 Jun 12. pii: 50. [Epub ahead of print]15(1):
    Dual-target CAR-T cell therapy: latest updates from the 2025 ASH annual meeting.
    Shi Feng, Ran Kong, Li Xiao, Xiangxiang Zhou.
      Dual-target chimeric antigen receptor T (CAR-T) cell therapy has emerged as a promising strategy to address the key limitations of single-target CAR-T approaches, including antigen heterogeneity and antigen-negative escape. Recent studies have reported rapid progress in the engineering of dual-target CAR-T, incorporating diverse receptor architectures, logic-gated designs, and novel manufacturing platforms. Preclinical data demonstrate improved disease control across B-cell malignancies, acute myeloid leukemia, and autoimmune disease models. Here, we summarize the latest advancements in the preclinical investigations and clinical trials of dual-target CAR-T cell therapy presented at the 2025 ASH annual meeting.
    Keywords:  Cellular therapy; Dual-target CAR-T; Hematological malignancies
    DOI:  https://doi.org/10.1186/s40164-026-00790-4
  12. Hum Pathol. 2026 Jun 08. pii: S0046-8177(26)00168-1. [Epub ahead of print] 106199
    CAR-T Cell Therapy and Its Complications: Role of the Pathologist in Diagnosis.
    Iman Sarami, L Jeffrey Medeiros.
      CAR-T cell therapy has transformed the treatment of patients with hematologic malignancies but has also introduced a spectrum of post-therapy complications that frequently require histopathologic evaluation. While clinical toxicities such as cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS) are well characterized, the pathologist's role in interpreting post-CAR-T biopsy specimens remains underdefined and challenging. In this review, we focus on the histopathologic, immunophenotypic, and molecular features of post-CAR-T complications, including cytopenias, immune effector cell-associated syndromes, therapy-related myeloid neoplasms, secondary malignancies, and CAR-derived lymphoproliferations. We emphasize diagnostic pitfalls, differential diagnoses, and practical approaches to distinguishing reactive, inflammatory and neoplastic processes. Our aim in this review is to provide a pathology-centered framework to guide accurate diagnosis, prevent misclassification and support clinical decision-making in the evolving landscape of CAR-T therapy.
    Keywords:  CAR-T therapy; CAR-T–associated T-cell proliferations (CARToma); Post-CAR-T complications; Post–CAR-T cytopenias; Therapy-related myeloid neoplasms (t-MDS/AML)
    DOI:  https://doi.org/10.1016/j.humpath.2026.106199
  13. Nanomaterials (Basel). 2026 Jun 01. pii: 691. [Epub ahead of print]16(11):
    Mapping Therapeutic Regulatory T Cell Fate with MRI: Current Strategies and Translational Outlook.
    Yu Ping, Lydia Chen, Jacob Joel Hoenig, Xiaohan Yang, Fanny Chapelin.
      Adoptive cell therapies, and more specifically, regulatory T cell (Treg) therapies, have shown significant therapeutic promise across multiple immune-mediated diseases including graft-versus-host disease (GvHD), solid organ transplant (SOT) rejection, and autoimmune diseases. One key challenge is the lack of insight into the biodistribution and fate of adoptively transferred T cells and Tregs in living organisms. These uncertainties delay progress on establishing optimal dosage(s), infusion timing and route, as well as investigations into off-target effects. Magnetic resonance imaging (MRI) cell tracking is particularly beneficial in this setting because it enables real-time, deep-tissue coverage without ionizing radiation. In this review, we compare existing MRI T cell tracking strategies using iron oxide particles and fluorinated agents. We describe preclinical and clinical applications of MRI for cell therapy tracking and provide a perspective on the potential impact on the field.
    Keywords:  MRI cell tracking; adoptive cell therapy; fluorine-19 MRI; graft-versus-host disease; regulatory T cells; superparamagnetic iron oxide; transplantation
    DOI:  https://doi.org/10.3390/nano16110691
  14. Mol Ther Oncol. 2026 Jun 18. 34(2): 201231
    Optimizing CAR T cell therapy in pancreatic cancer through clinically actionable combinations.
    Giulia Escobar, Marcela V Maus.
      
    DOI:  https://doi.org/10.1016/j.omton.2026.201231
  15. Immunopharmacol Immunotoxicol. 2026 Jun 09. 1-26
    Nano-enabled strategies for enhancing cancer immunotherapy: challenges, progress and perspective.
    Hazem Mathkour.
       OBJECTIVE: To review the role of nanotechnology in enhancing cancer immunotherapy, particularly immune checkpoint blockade (ICB), adoptive cell therapy (ACT), and cancer vaccines. It addresses key challenges in solid tumors, including poor drug delivery, immunosuppressive tumor microenvironment (TME), immune resistance, and treatment-related toxicity.
    METHODS: A narrative review of recent preclinical and clinical studies was conducted to evaluate how nanoplatforms improve targeted delivery, modulate the TME, enhance immune activation, and support immunotherapeutic efficacy. Challenges related to biosafety, biodistribution, scalability, and clinical translation were also discussed.
    RESULTS: Current findings demonstrate that nanotechnology-based platforms can significantly improve cancer immunotherapy outcomes. Nanomedicines enhance ICB by increasing intratumoral drug accumulation and reversing immune suppression within the TME. In ACT, nanoplatforms improve T cell persistence, function, and tumor infiltration. Nanoformulations also strengthen cancer vaccines through more efficient antigen delivery and enhanced antigen presentation.
    CONCLUSION: Preclinical and early clinical studies suggest that nano-immunotherapies can overcome important biological barriers and enhance antitumor immune responses while reducing systemic toxicity.
    DISCUSSION: Overall, nano-immunotherapy represents a promising strategy for improving the efficacy of cancer immunotherapy, particularly in solid tumors. Despite progress, several challenges remain, including long-term safety concerns, variability in nanoparticle design, manufacturing scalability, regulatory issues, and limited clinical data. Further researches are needed to optimize delivery systems, ensure safety, and facilitate successful clinical translation toward more effective and personalized cancer treatments.
    Keywords:  Cell therapy; combination therpy; nanovaccine; neoantigen; targeted agent
    DOI:  https://doi.org/10.1080/08923973.2026.2673541
  16. J Pharmacol Exp Ther. 2026 May 20. pii: S0022-3565(26)01150-X. [Epub ahead of print]393(7): 104951
    Chimeric antigen receptor T-cell therapy in rheumatoid arthritis.
    Paweł Dec, Adam Kubisa, Paulina Plewa, Andrzej Pawlik.
      Chimeric antigen receptor T-cell (CAR-T) therapy, previously used primarily in oncology, is emerging as a promising immunomodulatory strategy for rheumatoid arthritis. Its mechanism of action is based on T-cell engineering, enabling the selective elimination of autoreactive B cells, long-lived plasma cells, and other effector populations that sustain chronic inflammation. The most advanced constructs (including CD19-directed CAR-T therapy, B-cell maturation antigen-directed CAR-T therapy, and modular anti-fluorescein isothiocyanate CAR-T therapy) demonstrate the ability to achieve profound and sustained depletion of pathogenic immune cells, reduce proinflammatory cytokine levels, and induce remission in patients refractory to biological therapies. Advances in the design of subsequent generations of CARs, together with safety-enhancing technologies such as inducible caspase-9, herpes simplex virus thymidine kinase, and monoclonal antibody-based safety switches, have significantly improved control of adoptive lymphocyte activity and reduced the risk of cytokine release syndrome and persistent immunosuppression. However, therapeutic efficacy depends on multiple immunological factors, including the anticitrullinated protein antibody status, cytokine profile, and the functional reserve of T cells used for genetic modification. Preclinical evidence and early clinical observations suggest that CAR-T therapy may represent a new class of disease-modifying treatment for rheumatoid arthritis, with the potential to achieve durable remission and inhibit joint destruction. Nevertheless, further well controlled studies are required to optimize target selection, establish long-term safety, and define how this technology can be effectively integrated with existing therapeutic strategies. SIGNIFICANCE STATEMENT: This article discusses the possibility of a new application of chimeric antigen receptor T-cell (CAR-T) therapy in the treatment of patients with rheumatoid arthritis (RA). CAR-T therapy represents a novel approach for treatment of autoimmune diseases, including RA. Originally developed for hematological malignancies, this technology involves genetic modification of T cells to enable specific recognition and elimination of autoreactive B cells. Recently, increasing research into CAR-T therapy for RA has highlighted both substantial therapeutic potential and important safety concerns.
    Keywords:  Chimeric antigen receptor T-cells; Rheumatoid arthritis; Therapy
    DOI:  https://doi.org/10.1016/j.jpet.2026.104951
  17. J Genet Genomics. 2026 Jun 05. pii: S1673-8527(26)00188-8. [Epub ahead of print]
    The TNFR2M196R germline variant confers dual impact on CAR-T cell immunotherapy by enhancing T-cell survival and tumor proliferation.
    Nan Liu, Lu Han, Yuting Lu, Yelei Guo, Jiajia Li, Qi Zhu, Yao Wang, Zhiqiang Wu, Xin Lin, Jianshu Wei, Weidong Han.
      Despite its remarkable efficacy in hematologic malignancies, chimeric antigen receptor T-cell (CAR-T) therapy is often limited by atypical clinical outcomes, necessitating predictive biomarkers. Here, prompted by a patient with low-tumor-burden non-Hodgkin lymphoma who develops severe and persistent cytokine release syndrome (CRS), we identify the germline TNFR2M196R single-nucleotide polymorphism, rs1061622, as a candidate genetic determinant of atypical responses. The TNFR2M196R variant is found to enhance the antitumor efficacy of CAR-T cells by reducing their apoptosis. Paradoxically, however, patients carrying the TNFR2M196R variant exhibit higher rates of early tumor progression. Further investigation reveals that while the TNFR2M196R mutation increases tumor susceptibility to CAR-T-mediated killing, it also accelerates tumor proliferation kinetics. Together, these results establish the TNFR2M196R SNP as a dual-function genetic determinant that modulates both CAR-T cell efficacy and intrinsic tumor behavior, highlighting the critical impact of germline genetics on cancer immunotherapy.
    Keywords:  Apoptosis; Biomarker; CAR-T cells; Germline variant; Proliferation; TNFR2(M196R)
    DOI:  https://doi.org/10.1016/j.jgg.2026.05.014
  18. Clin Rheumatol. 2026 Jun 08.
    Cellular therapies in systemic lupus erythematosus: recent progress and future directions.
    Ansaam Daoud, Omer N Pamuk.
      Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by dysregulated immune responses, chronic inflammation, and progressive organ damage. Despite substantial advances in understanding disease pathogenesis and the development of targeted therapies, a significant proportion of patients remain refractory to conventional immunosuppressive and biologic treatments, particularly those with severe or relapsing disease manifestations such as lupus nephritis. Persistent disease activity and cumulative treatment toxicity continue to contribute to irreversible organ damage and increased morbidity. Recent advances in cellular immunotherapy have positioned chimeric antigen receptor (CAR) T-cell therapy as a promising novel therapeutic approach in SLE. By targeting B-cell-associated antigens, CAR T-cell therapy enables deep and sustained B-cell depletion, potentially overcoming the limitations of monoclonal antibody-based B-cell-directed therapies. Early clinical reports and emerging trial data demonstrate that CD19-directed CAR T-cell therapy can induce profound immunologic remission and sustained, drug-free clinical remission in patients with refractory SLE. These findings suggest that CAR T-cell therapy may not only control disease activity but also fundamentally reset autoimmune immune responses. In this review, we summarize the immunopathogenic rationale for CAR T-cell therapy in SLE, review available preclinical and clinical evidence, and discuss ongoing efforts to develop more selective and safer CAR constructs targeting B-cell subsets relevant to lupus pathogenesis. We also address key challenges, including safety considerations, durability of response, patient selection, and long-term immunologic consequences. Collectively, CAR T-cell therapy represents a transformative and potentially disease-modifying strategy for SLE, warranting further investigation in well-designed clinical trials.
    Keywords:  CAR T-cell therapy; Cellular therapies; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s10067-026-08211-x
  19. Int Immunopharmacol. 2026 Jun 06. pii: S1567-5769(26)00826-X. [Epub ahead of print]185 116980
    CCL19-armed oncolytic adenovirus synergizes with CCR7-expressing CAR-T cells to suppress ovarian tumor growth.
    Chunye Zhao, Wanying Zhao, Yaru Zhao, Shangwu Chen, Yigang Wang, Yulong Xia.
      Solid tumors remain refractory to chimeric antigen receptor (CAR) T cell therapy largely because they fail to infiltrate the tumor bed. We show that in vitro expanded HER2 CAR-T cells are more than 80% CCR7+ cells that migrate vigorously to CCL19. An E1B-55 kDa-deleted oncolytic adenovirus expressing CCL19 retained full oncolytic potency, secreted bioactive CCL19 and tripled CAR-T migration. In NSG mice bearing SKOV3 ovarian tumors, two intratumoral oAd-CCL19 injections followed by intravenous HER2-CAR-T cells achieved most effective inhibition of tumor growth without significant toxicity, accompanied by increased intratumoral CAR-T cells. Thus, CCL19-armed oncolytic adenovirus safely converts ovarian tumors into chemokine-rich targets that recruit CAR-T cells, providing a readily translatable strategy for solid-tumor CAR-T therapy.
    Keywords:  CAR-T cell; CCL19; Migrate; Oncolytic adenovirus; Safe
    DOI:  https://doi.org/10.1016/j.intimp.2026.116980
  20. Front Immunol. 2026 ;17 1822523
    Beyond the chimeric antigen receptor T cells and bispecific antibody duopoly: ex vivo armed T cells for solid tumors.
    Jeong A Park, Nai-Kong V Cheung.
      While monoclonal antibodies (mAbs) continue to dominate the overall immunotherapy landscape, the field of T-cell-based therapeutics is rapidly evolving. Although chimeric antigen receptor T cells (CAR-T) and bispecific antibodies (BsAbs) currently represent the pillars of T-cell-directed therapy, the complexity of solid tumors demands a more diversified therapeutic arsenal. By combining antibody-mediated tumor targeting with the robust effector function of ex vivo expanded T cells, BsAb-armed T cells (BATs)-also referred to as Ex vivo Armed T cell (EATs)-provide a 'third way' that addresses the unmet needs of solid tumor immunotherapy. They can overcome the quantitative and qualitative deficiencies of endogenous immune effector cells in cancer patients. By offering personalized multi-antigen targetability and the prospect of off-the-shelf therapy, EATs have the potential to address critical challenges, such as poor tumor infiltration, immune escape via heterogeneity and target antigen loss, and treatment-related toxicities like cytokine release syndrome. In this review, we discuss the characteristics of EAT therapy, distinct from CAR-T and BsAb therapy, as an independent and alternative niche. We explore strategies to accelerate their clinical translation, encompassing BsAb optimization, modulation of the tumor microenvironment (TME) and cytokines, and simultaneous engagement of multiple antigens, which are essential for boosting EAT potency and overcoming the limitations of solid tumors. In this evolving landscape, EATs could play a unique and independent role, expanding the CAR-T and BsAb-dominated paradigm to address unmet clinical needs.
    Keywords:  T cell immunotherapy; bispecific antibody; chimeric antigen receptor T cell; ex vivo armed T cell; multi-antigen targeting strategy; on-target off-tumor toxicity; tumor heterogeneity; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1822523
  21. J Control Release. 2026 Jun 09. pii: S0168-3659(26)00486-4. [Epub ahead of print]396 115083
    Engineering nanoplatforms for autoimmune treatment: From synthetic strategies to bioinspired designs.
    Yihan Wang, Celine Ninsuvannakul, Gloria Zhang, Shiseido Robinson, Mohammad Mahdi Hasani-Sadrabadi.
      Autoimmune diseases encompass a diverse group of disorders with distinct clinical manifestations but a unifying defect, the breakdown of immune self-tolerance that drives dysregulated immune activation. Current therapies broadly suppress immunity rather than reestablishing regulatory balance and therefore provide limited and often transient control. Building on recent advances in nanomedicine, we introduce an immunoengineering framework that restores immune balance by delivering antigens, co-signals, and tissue repair cues with spatial and temporal precision. This review systematically examines synthetic (liposomes, polymeric nanoparticles, 2D materials), biologically derived and bioinspired (extracellular vesicles, bacterial/viral and cell-membrane vesicles), and hybrid systems, outlining design rules including size and shape, surface chemistry and ligand valency, cargo architecture, and stimuli responsiveness, that govern biodistribution, cellular uptake, and immune programming. Mechanistic principles are illustrated across distinct contexts (e.g., alloantigen responses, mucosal barrier failure, β-cell autoimmunity), emphasizing strategies that induce antigen-specific tolerance, reprogram innate compartments, and repair barriers while preserving protective immunity. We also map key translational needs: standardized characterization and potency assays, long-term safety and biodistribution, scalable manufacturing, regulatory fit, and cost-effectiveness. Together, these insights provide a blueprint for precision nanomedicine to move autoimmunity treatment from blanket suppression toward durable, mechanism-based remission.
    Keywords:  Autoimmune disease; Bioinspired nanoplatforms; Immune tolerance; Immunoengineering; Nanomedicine
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115083
  22. Transfus Med Hemother. 2026 Jun;53(3): 145-155
    The Landscape of Advanced Therapy Medicinal Products in Slovenian Transfusion Medicine: A Review of Past and Future Outlook.
    Urban Švajger, Primož Poženel, Primož J Rožman, Marko Cukjati.
       Background: Advanced therapy medicinal products (ATMPs) represent a transformative class of biological therapies, including gene therapies, somatic cell therapies, and tissue-engineered products, designed to address complex and often treatment-resistant conditions. This review provides a comprehensive overview of the evolving landscape of ATMP development and clinical implementation in Slovenian transfusion medicine.
    Summary: Historically rooted in blood and cell processing, the Slovenian Institute for Transfusion Medicine (SITM) has leveraged its infrastructure and regulatory frameworks to pioneer early-phase ATMP trials, as well as ATMP use under the hospital exemption scheme. Clinical experiences include CD34+ cell therapy for cardiomyopathies, dendritic-tumor cell hybrid vaccines for prostate cancer, and mesenchymal stromal cell applications in knee osteoarthritis, xerostomia, and kidney transplant rejection. While challenges persist, such as limited funding, small patient populations, and the need for regulatory adaptation, Slovenia possesses strong institutional capabilities and a geographical positioning that is conducive to regional collaboration. The SITM plays a central role in GMP-compliant manufacturing, quality control, and clinical support.
    Key Messages: The SITM plays a central national role in GMP-compliant manufacturing, quality control, and clinical support. To fully realize the potential of ATMPs, coordinated national strategies, targeted investment, and integration with European initiatives are essential. This review highlights Slovenia's progress, identifies key bottlenecks, and outlines opportunities for growth, emphasizing the role of transfusion medicine as a national platform for responsible and innovative ATMP development.
    Keywords:  Advanced therapy medicinal products; Cell therapy; Gene therapy; Slovenia; Transfusion medicine
    DOI:  https://doi.org/10.1159/000548150
  23. Blood Res. 2026 Jun 11. pii: 30. [Epub ahead of print]61(1):
    Infectious complications after CAR T-cell therapy: mechanisms, risk stratification, and prevention.
    Eunseuk Lee, Ji Hyun Lee, Hye Ryeon Kim, Seok Jae Huh, Suee Lee, Sung-Yong Oh, Sung-Hyun Kim, Hojin Lee.
      Chimeric antigen receptor (CAR) T-cell therapy is an established treatment for relapsed or refractory B-cell malignancies. Despite therapeutic success, infectious complications remain a major contributor to non-relapsed morbidity and mortality. The risk of infection reflects a prolonged and multifactorial state of immunosuppression resulting from lymphodepleting chemotherapy, treatment-related cytopenia, sustained CD4+ T-cell lymphopenia, B-cell aplasia with hypogammaglobulinemia, and the use of corticosteroids or cytokine-directed therapies for the management of immune effector cell-associated toxicities (i.e., cytokine-release syndrome and immune effector cell-associated neurotoxicity). The spectrum of infections has evolved over time. Bacterial infections are observed most frequently in the early post-infusion period, whereas viral and opportunistic infections become more prominent later, particularly in patients with delayed immune recovery. Infection risk is also influenced by the underlying malignancy, prior exposure to treatment, and the type of CAR T-cell product used. For example, BCMA-directed CAR T-cell therapy has been associated with a higher infection burden, likely related to profound plasma cell depletion and sustained impairment of humoral immunity. Preventing infections in this setting requires a structured and individualized approach. Common strategies include antiviral and Pneumocystis jirovecii pneumonia prophylaxis, the selective use of antibacterial and antifungal prophylaxis during periods of severe or prolonged cytopenia, immunoglobulin replacement in patients with clinically significant hypogammaglobulinemia, and vaccination schedules guided by immune recovery. Therefore, coordinated and risk-adapted prevention is essential to minimize infectious complications and to improve long-term outcomes after CAR-T cell therapy. This review summarizes the current evidence and major recommendations of international guidelines to provide an updated overview of infection mechanisms, risk stratification, and preventive strategies for patients receiving CAR T-cell therapy.
    Keywords:  Antimicrobial prophylaxis; CAR T-cell therapy; Hypogammaglobulinemia; Immunodeficiency; Infection; Vaccination
    DOI:  https://doi.org/10.1007/s44313-026-00145-2
  24. Transplant Cell Ther. 2026 Jun 11. pii: S2666-6367(26)00484-7. [Epub ahead of print]
    T-Cell Lymphoma Associated with CAR-T Cell Therapy: A Bayesian Disproportionality Analysis of a National Database.
    Connor Frey.
      
    Keywords:  Bayesian Analysis; CAR-T Cell Therapy; Ciltacabtagene Autoleucel; Secondary Primary Malignancy; T-Cell Lymphoma
    DOI:  https://doi.org/10.1016/j.jtct.2026.06.016
  25. Leuk Lymphoma. 2026 Jun 07. 1-14
    Chimeric antigen receptor T-cell therapy induces complete remission in a patient with concurrent CLL with CNS involvement and multiple sclerosis.
    Dermot J Murphy, Siba El Hussein, Angela Applebee, Alissa Thomas, James N Gerson.
      In a patient with chronic lymphocytic leukemia (CLL) involving the central nervous system, and concurrent multiple sclerosis (MS), CD19-directed CAR T-cell therapy led to complete remission of CLL and marked improvement in MS disease burden.
    Keywords:  Neoplasia; adoptive cellular therapies; chronic lymphocytic leukemia; multiple sclerosis
    DOI:  https://doi.org/10.1080/10428194.2026.2682293
  26. Cell Investig. 2025 Dec;pii: 100035. [Epub ahead of print]1(4):
    T cell-macrophage crosstalk in GVHD and cancer immunotherapy.
    Qingxiao Song, Kiranj Chaudagar, Xi Zhang, Edmund K Waller.
      The immune microenvironment is pivotal in regulating two complementary adverse outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT): graft-versus-host disease (GVHD) and tumor progression. While GVHD manifests as immune hyperactivation, causing tissue injury, cancer subverts immune surveillance by immunosuppressive strategies. Although initial studies focused on distinct mechanisms involving T-B interactions in GVHD and T-tumor cell interactions in cancer immunotherapy, it is increasingly clear that dysregulated T cell-macrophage interactions drive immunopathology in GVHD, with comparative insights into cancer immunotherapy. Here, we discuss recent advances and elucidate three core regulatory paradigms governing these immunostimulatory vs immunosuppressive interactions: (1) cytokine networks, (2) immune checkpoint regulation, and (3) metabolic reprogramming. Based on functional pre-clinical studies and clinical evidence, we describe the dynamic, reciprocal immune crosstalk between T cells and macrophages that underlies GVHD after allo-HSCT and the immunosuppressive tumor microenvironment. Finally, we outline emerging therapeutic approaches that target T cell and macrophage interactions to prevent GVHD and overcome an immunologically "cold" microenvironment in the cancer.
    Keywords:  Crosstalk; Graft-versus-host disease (GVHD); Immunotherapy; Macrophage; T cell; Tumor
    DOI:  https://doi.org/10.1016/j.clnves.2025.100035
  27. Res Sq. 2026 Jun 01. pii: rs.3.rs-9557741. [Epub ahead of print]
    Effector Vδ1 γδT cells mediate anti-tumor immunity and are reprogrammed by imatinib in human gastrointestinal stromal tumor.
    Ronald DeMatteo, Shan Zeng, Jonathan Sussman, Montana Morris, Yuntian Fu, Juan Perez, Jiazhen Rong, Katherine Tardy, Hyunjee Kwak, Taylor Hartlein, Shujing Liu, Kevin Do, Ferdinando Rossi, Jennifer Zhang, Xiaowei Xu.
      Gamma-delta (γδ) T cells are emerging effectors of anti-tumor immunity, but their relevance to gastrointestinal stromal tumor, the most common human sarcoma, is not defined. Here, we integrate single-cell transcriptomics, immunophenotypic and T cell receptor profiling, and functional assays of circulating and intratumoral γδ T cells across 68 human GIST specimens. Vδ1 cells predominated within tumors, and their abundance correlated with improved outcomes across 3 separate patient cohorts. γδ T cells from untreated tumors were cytotoxic ex vivo, but tumors that had become resistant to the tyrosine kinase inhibitor imatinib had lower Vδ1 composition, effector function, and altered clonality, and were enriched for apoptosis, IL-17 signaling, and checkpoint pathways. In a genetically engineered murine GIST model, PD-L1 blockade enhanced imatinib efficacy and restored tumor γδ T cell function. Thus, γδ T cells contribute to tumor immunity in GIST and are reprogrammed during imatinib resistance, making them an attractive immunotherapy target.
    DOI:  https://doi.org/10.21203/rs.3.rs-9557741/v1
  28. Sci Adv. 2026 Jun 12. 12(24): eadv2687
    Ready-to-load MHC-I nanoparticles for high-throughput T cell screening studies.
    Hoang Anh T Phan, Soomin Eom, Daniel Hwang, Michael C Young, Shirley M Sun, Molly C Erdman, Yi Sun, Leena Mallik, Photis Rotsides, Mark M Painter, E John Wherry, Dimitri S Monos, Nikolaos G Sgourakis.
      MHC-I proteins present epitopic peptides to CD8+ T cells to elicit multifaceted adaptive immune responses. The affinity and avidity of interactions between peptide-MHC molecules and their cognate T cell receptors (TCRs) are fundamental parameters that contribute to the induction of activated or anergic T cell states. Here, we present a multivalent, loadable platform, VLP-Open HLA, featuring a virus-like particle (VLP) which can display up to 60 peptide/HLA [human leukocyte antigen (HLA)] molecules. VLP-Open HLA can be used to stain antigen-specific CD8+ T cells, providing a screening tool for orphan TCRs. When combined with costimulation, VLP-Open HLA acts as an artificial antigen-presenting platform to induce antigen-specific T cell activation and expansion, providing a facile alternative to autologous antigen-presenting cells. Our platform can be adapted to encompass multiple HLA allotypes and costimulatory molecules as mosaic nanoparticles, enabling a range of applications in experimental immunology.
    DOI:  https://doi.org/10.1126/sciadv.adv2687
  29. Blood. 2026 Jun 11. pii: blood.2025032112. [Epub ahead of print]
    A novel triple-knockout allogeneic BCMA CAR T cell therapy (CT0590) in multiple myeloma: preclinical and phase I study.
    Song Jin, Zhaohui Liao, Shuang Yan, Lingzhi Yan, Weiqin Yao, Jingjing Shang, Fang Tang, Ziling Zhu, Depei Wu, Nishanthan Rajakumaraswamy, Yi Luo, Daijing Yuan, Hua Jiang, Zonghai Li, Chengcheng Fu.
      Host-versus-graft reaction (HvGR) is a major challenge in allogeneic chimeric antigen receptor (CAR) T cell therapy. To counter host natural killer (NK) cell attacks, we armored allogeneic, human leukocyte antigen (HLA)-I deficient, B-cell maturation antigen (BCMA)-targeting CAR T cells with an NKG2A CAR. In vitro and animal studies demonstrated that allogeneic CAR-NKG2A T cells effectively resisted host NK cell-mediated killing. BCMA and NKG2A dual-targeting allogeneic CAR T cells (CT0590) resisted killing by NK cells and showed robust antitumor activity in preclinical in vivo models. On the basis of these data, a first-in-human study (NCT05066022) enrolled five patients (four with relapsed and refractory multiple myeloma [RRMM] and one with primary plasma cell leukemia [pPCL]). CT0590 was well-tolerated and caused no dose-limiting toxicities, treatment-related death, or graft-versus-host disease. Three patients achieved confirmed responses, including two with stringent complete response (sCR). Notably, sCR in the patient with RRMM was still ongoing (duration of response > 23 months) at the time of data cutoff, and sCR in the patient with pPCL lasted for 20 months. Both patients showed robust expansion of universal CAR (uCAR) T cells (Cmax > 280,000 copies/µg gDNA) and higher baseline NKG2A expression on NK cells than nonresponders. These results suggest that CAR-NKG2A technology may overcome HvGR, especially in patients with elevated NKG2A expression on NK cells. Further studies of CT0590 in RRMM and pPCL are warranted.
    DOI:  https://doi.org/10.1182/blood.2025032112
  30. Front Immunol. 2026 ;17 1798748
    Development and in vivo evaluation of novel humanized CD19 CAR-T cells for advanced B cell malignancies.
    Clara de Oliveira Andrade, Marcus Rafael Lobo Bezerra, Isabel Garcia Sousa, Eduardo Mannarino Correia, Ana Julia Ferreira Lima, Luiza Abdo, Emmanuel Arthur Albuquerque Aragão, Ronny Petterson Dos Santos Araujo, Daniel Pasqualino Pinheiro, Igor Cabral Studart, João Vitor Steimbach, Marco Antônio Pretti, Gilvan Pessoa Furtado, Marcos Roberto Lourenzoni, Marcelo Macedo Brigido, Andréa Queiroz Maranhão, Martín Hernán Bonamino.
       Background: Chimeric antigen receptor T-cell therapy targeting CD19 has revolutionized the treatment of B-cell malignancies; however, limitations related to immunogenicity, persistence, and manufacturing costs remain significant barriers to broader clinical application. Most approved CD19-directed CAR-T products rely on murine-derived single-chain variable fragments, which may elicit anti-mouse immune responses and compromise long-term efficacy.
    Methods: Here, we report the design, characterization, and preclinical validation of two novel humanized anti-CD19 CAR constructs derived from the FMC63 antibody and generated using a non-viral Sleeping Beauty transposon system. Two humanized scFv variants, H1 and H2, sharing the same humanized light chain but distinct heavy chain frameworks, were evaluated for binding affinity, structural stability, and functional performance.
    Results: Although both humanized variants displayed reduced affinity relative to FMC63, they retained specific CD19 binding and supported robust CAR expression, activation, and memory differentiation in primary human T cells. In vitro cytotoxicity assays demonstrated comparable tumor cell killing and cytokine secretion across all constructs, including against CD19low leukemia targets. In vivo xenograft models of standard and advanced B-cell acute lymphoblastic leukemia revealed that the H1 CAR-T cells achieved durable tumor control and overall survival comparable to FMC63, whereas the lower-affinity H2 construct showed reduced persistence and increased exhaustion marker expression.
    Conclusions: Collectively, these results demonstrate that rational humanization and harmonization of anti-CD19 scFvs can preserve antitumor efficacy, while mitigating functional exhaustion. This work supports the H1 construct as a promising candidate for further clinical development and highlights a scalable, cost-effective strategy for advancing locally manufactured CAR-T therapies in resource-limited settings.
    Keywords:  CAR-T cell therapy; CD19; antibody humanization; exhaustion markers; non-viral gene delivery; sleeping beauty
    DOI:  https://doi.org/10.3389/fimmu.2026.1798748
  31. J Extracell Vesicles. 2026 Jun;15(6): e70310
    Heparanase-Loaded CAR T Extracellular Vesicles Remodel the Colorectal Tumour Microenvironment and Boost T Cell Antitumor Immunity.
    Songshan Zhu, Jun Yin, Weiqiang Yang, Xin Fu, Yiwei Zeng, Na Huang, Ling Zhang, Cong Yu, Ping Ouyang, Kaisong Huang, Rui Chen, Xiaolei Zhao, Dan Jiang, Guangxian Xu.
      Chimeric antigen receptor (CAR) T cell therapy has shown promise in solid tumours, but its efficacy is limited by dense extracellular matrix (ECM) that blocks T cell entry. We engineered mesothelin-targeted CAR T cells to express heparanase (HPSE) fused to the truncated hepatitis A virus pX domain (pX-Δ1-30), enabling surface display of HPSE on extracellular vesicles for localized, pH-dependent ECM degradation within the acidic tumour microenvironment while limiting systemic exposure. HPSE-pX-Δ1-30 CAR T (referred to as HPSE CAR T) cells penetrated ECM mimics nearly fourfold more effectively than standard CAR T cells. They also expressed more TNF-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), and perforin, leading to stronger tumour killing in 2D and 3D colorectal cancer models. HPSE-pX-Δ1-30 CAR T-derived extracellular vesicles (EVs) retained CAR and chemokine receptors (CCR5/CCR7), carried apoptotic ligands, and were efficiently taken up by tumour cells and T cells. EV exposure promoted T cell proliferation, CCR5 expression, and central/stem-like memory formation while lowering PD-1 and CD57. In HCT116 xenografts, HPSE CAR T cells showed increased intratumoral infiltration, and EVs from these cells promoted infiltration of host T cells. Treatment reduced tumour burden, extended survival beyond 70 days, and did not cause systemic toxicity. These results highlight a dual strategy of ECM remodelling and immune modulation, offering a translational approach to overcome barriers to CAR T therapy in colorectal cancer.
    Keywords:  CAR T extracellular vesicles; colorectal cancer; extracellular matrix; heparanase; tumour microenvironment
    DOI:  https://doi.org/10.1002/jev2.70310
  32. Cancers (Basel). 2026 Jun 01. pii: 1803. [Epub ahead of print]18(11):
    Longitudinal Cognitive Assessment After CAR-T Cell Immunotherapy: A Prospective Cohort Study.
    Evlampia Strongyli, Anna Papakonstantinou, Christos Demosthenous, Zoi Bousiou, Anna Vardi, Despina Mallouri, Panagiotis Dolgyras, Ioannis Batsis, Paschalis Evangelidis, Ioannis Kyriakou, Marianna Masmanidou, Ioannis Giokaris, Maria Gavriilaki, Asimina Bouinta, Evangelia Yannaki, Damianos Sotiropoulos, Sotirios Papagiannopoulos, Dimitrios Kazis, Vasilios Kimiskidis, Ioanna Sakellari, Eleni Gavriilaki.
      (1) Background: Cognitive dysfunction represents an emerging concern in chimeric antigen receptor T-cell (CAR-T) therapy recipients, yet longitudinal data using simple, clinically applicable tools are lacking. (2) Methods: We conducted a single-center prospective cohort study of consecutive adults with hematologic malignancies treated with commercially available CAR-T cell products between May 2023 and November 2025 at our center. Cognitive function was evaluated with the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) at baseline (before the administration of lymphodepleting chemotherapy) (T1), 6 h after infusion (T2), at 3 months (T3), and at 6 months (T4). MoCA scores ≤ 25 and/or MMSE scores ≤ 23 were considered indicative of impaired cognitive function. (3) Results: Thirty-six patients were enrolled in the present study, while cytokine release syndrome occurred in 33/36 patients (91.7%), and immune effector cell-associated neurotoxicity syndrome of any grade occurred in 23/36 (63.9%). At baseline (T1), cognitive impairment was identified in 12/36 patients (33.3%) by MoCA. Following infusion (T2), 11/35 (31.4%) exhibited cognitive impairment, while baseline cognitive impairment and older age were associated with early post-infusion cognitive dysfunction. Across follow-up (T3 and T4), no significant overall changes were observed in MoCA- or MMSE-defined cognitive status or in total test scores. However, abstraction in MoCA and attention/calculation in MMSE showed time-dependent variation. (4) Conclusions: These findings support the use of simple longitudinal cognitive assessment in CAR-T recipients.
    Keywords:  CAR-T cell therapy; Montreal cognitive assessment; cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome; mini-mental state examination; neurotoxicity
    DOI:  https://doi.org/10.3390/cancers18111803
  33. Int J Mol Sci. 2026 Jun 02. pii: 5026. [Epub ahead of print]27(11):
    Molecular Insights and Novel Therapies for Lymphoproliferative Disorders.
    Shucen Wan, Seema Naik.
      Hematological malignancies encompass a broad spectrum of relatively rare cancers with diverse biological and clinical characteristics that are capable of affecting individuals across all age groups, though certain subtypes show a predilection for specific age ranges. Advances in next-generation sequencing have greatly enhanced our understanding of the molecular and genetic basis of these diseases, while epigenetic, transcriptional, and proteomic analyses have further clarified their pathogenesis. These developments have shaped the classification and treatment of lymphoma. Updated classification frameworks which include the identification of clinically relevant molecular targets have opened the door to a number of targeted agents, each designed to exploit specific vulnerabilities within malignant cells, while stem cell transplantation continues to offer curative potential for eligible patients, with improving safety profiles over time. CAR-T-cell therapy has been extended to multiple blood cancer indications, achieving lasting remissions in patients with previously exhausted treatment options. Bispecific antibodies have further broadened the immunotherapy landscape by redirecting the body's own T cells against tumor cells, offering a readily available alternative that overcomes many of the practical limitations associated with CAR-T-cell production. The ability to combine these strategies has fundamentally changed what is achievable in blood cancer treatment, with long-term remission now a realistic goal for many patients. This review seeks to outline the core molecular mechanisms underlying lymphoma and leukemia, evaluate currently approved treatment options, discuss significant ongoing clinical trials with practice-changing potential, and explore the prospect of chemotherapy-free approaches in carefully selected patient groups.
    Keywords:  chimeric antigen receptor T cell therapy (CART); diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL); hematological malignancies; mantle cell lymphoma (MCL); molecular mechanisms; targeted therapies
    DOI:  https://doi.org/10.3390/ijms27115026
  34. Front Immunol. 2026 ;17 1761834
    Microbiome-orchestrated cross-organ immunity in autoimmunity: from metabolites to therapeutic targets.
    Xianlin Rao, Li Zou, Xiaoyu Cai, Yao Yao, Lingling Zhong.
      Autoimmune diseases are systemic disorders in which barrier-site immune activation, especially in the gut, can reshape inflammatory programs in distant organs. This review advances a metabolite-centered, cross-organ framework for understanding how gut microbial ecology influences autoimmunity beyond individual gut-organ axes. We synthesize evidence that short-chain fatty acids, bile acid derivatives, tryptophan catabolites, polyamines and related microbial products act as mobile biochemical checkpoints linking intestinal barrier integrity, pattern-recognition signaling, immune-cell metabolism and tissue-specific inflammation in joints, kidneys, skin, lungs and the central nervous system. Across these axes, shared mechanisms include barrier failure, altered microbial metabolite pools, dysregulated MAMP sensing, trafficking or systemic conditioning of lymphoid and myeloid cells, and local stromal imprinting in target organs. We also discuss sex-dependent microbiome-immune interactions, including the microgenderome concept, as a framework for explaining why microbiome composition, hormone metabolism and immune responses may shape autoimmune risk and treatment response differently in females and males. Finally, we evaluate multi-omics, single-cell and spatial profiling, organ-on-chip platforms and causal computational tools, and we outline translational strategies ranging from diet, probiotics, fecal microbiota transplantation and engineered consortia to pharmacologic targeting of metabolite receptors. By treating microbial metabolites as actionable cross-organ immune checkpoints, this review highlights opportunities and limitations for biomarker-guided, metabolite-focused precision therapy in autoimmunity.
    Keywords:  autoimmunity; cross-organ immunity; gut microbiota; gut–organ axis; microbial metabolites; precision therapeutics
    DOI:  https://doi.org/10.3389/fimmu.2026.1761834
  35. Mol Immunol. 2026 Jun 08. pii: S0161-5890(26)00129-X. [Epub ahead of print]196 35-43
    Combined targeting of mesothelin and tenascin-C enhances CAR-T cell function and tumor microenvironment modulation in ovarian cancer.
    Xiaoqin Wang, Duoyi Zhang, Tingting Wang, Xin Li, Jing Zhang.
       BACKGROUND: The efficacy of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors is limited by dense extracellular matrix deposition and an immunosuppressive tumor microenvironment. Tenascin-C (TNC), an extracellular matrix protein enriched in ovarian cancer stroma, may provide a stromal cue that restricts T-cell engagement while offering a complementary target to mesothelin (MSLN). This study evaluated whether combined targeting of MSLN and TNC could enhance CAR-T-cell function and remodel the ovarian cancer microenvironment.
    METHODS: CAR-T cells targeting MSLN and/or TNC were generated using single lentiviral vectors encoding second-generation CAR constructs, including tandem dual-target CARs and MSLN-directed CAR-T cells secreting an anti-TNC single-chain variable fragment with or without a membrane-tethered PD-L1-binding module. CAR expression and function were evaluated across three healthy-donor batches. Target expression on SKOV3 cells and ovarian cancer-associated fibroblasts (CAFs) was validated by flow cytometry and qPCR. Functional studies included NFAT reporter assays, cytokine release, cytotoxicity, immune synapse quantification, adhesion assays, CAF co-culture, and xenograft studies with randomized treatment allocation and blinded tumor measurements.
    RESULTS: Dual-target TNC+MSLN CAR-T cells demonstrated reproducible CAR expression across donors, enhanced NFAT activation in TNC-rich conditions, increased CD69/CD25 upregulation, and greater IFN-γ, TNF-α, and IL-2 secretion than single-target controls. Compared with MSLN-CAR-T cells, dual-target CAR-T cells showed improved tumor-cell killing, larger and more polarized immune synapses, and stronger tumor-cell adhesion. In CAF co-culture, anti-TNC-secreting CAR-T cells partially reversed suppression, reduced PD-1 and Tim-3 expression, and showed concordant reductions in LAG-3 and TIGIT in exploratory analyses. In vivo, combination stromal targeting delayed tumor growth, increased intratumoral CD4 + and CD8 + infiltration, improved CAR-T persistence, and reduced extracellular matrix deposition and CAF-associated markers.
    CONCLUSIONS: Combined targeting of MSLN and TNC was associated with improved CAR-T-cell activation and broader microenvironmental remodeling in ovarian cancer models. These data support further evaluation of stromal co-targeting as an adjunct strategy for CAR-T therapy in ovarian cancer, while additional validation of target dependence, safety, and long-term persistence remains necessary.
    Keywords:  CAR-T; Mesothelin; Ovarian cancer; Tenascin-C; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.molimm.2026.05.010
  36. Mol Ther. 2026 Jun 10. pii: S1525-0016(26)00494-6. [Epub ahead of print]
    Antibody Format Matters: A Comparative Analysis of VHH and scFv Domains Reveals Superior In Vivo CAR T Cell Function with VHH Domains.
    Alexander Kinna, Preeta Datta, Reyisa Bughda, Farhaan Parekh, Mathew Robson, Ram Jha, Phillip Wu, Ian Scott, Elizabeth Hogben, Oliver Amin, Gordon Weng-Kit Cheung, Warren Hazelton, Zulaikha Akbar, Katarina Lamb, Emily Macken, Chris Allen, Sofi Panovska, Lisa Hogan, Mohamed El-Kholy, Reevesh Shrestha, Jonathan Popplewell, Evangelia Kokalaki, James Sillibourne, Simon Thomas, Shimobi Onuoha, Mathieu Ferrari, Martin Pule.
      Chimeric antigen receptor (CAR) T cells require an extracellular targeting domain for antigen specificity, typically a scFv. VHH antibodies are emerging as alternative CAR binding regions due to their reduced size, improved stability and CDR3 loop architecture. Herein, we generated and compared VHH and scFv antibodies targeting CD123, via immunised phage display libraries, selecting ten antibody pairs based on comparable domain targeting and kinetic profiles (KD range M 10-9-10-11). The VHH antibody fragments showed improved stability (Tm50 Δ7.85°C), reduced aggregation and a favourable surface charge. CARs incorporating a VHH demonstrated higher IL2 and IFNγ secretion than scFv derived CARs during in vitro analysis and substantially enhanced survival and decreased tumour burden in a xenograft murine model of acute myeloid leukaemia. This comprehensive comparison of the two most adopted antibody classes provides a rationale for the selection of VHH as preferred CAR binding domains.
    DOI:  https://doi.org/10.1016/j.ymthe.2026.06.017
  37. Ann Pharm Fr. 2026 Jun 10. pii: S0003-4509(26)00101-X. [Epub ahead of print]
    Future trends and the role of artificial intelligence in pharmaceutical project management.
    Gaurav Gujral, Rama Rajesh, Nidhi Jain Singhai, Hindu Marla, Kirankumar Hunashimarad, Rahul Maheshwari.
      The pharmaceutical industry is undergoing rapid change, driven by increasing scientific complexity, stringent regulatory requirements, rising development costs, and shorter time to market. Conventional project management techniques, although foundational, are not sufficient for managing the uncertainty and scale of modern drug development. Artificial intelligence (AI), together with digital platforms, advanced analytics, and automation, is growing as a critical enabler of adaptive, data-driven pharmaceutical project management. This review critically examines current and emerging applications of AI across pharmaceutical project management, spanning R&D, clinical development, CMC, manufacturing, quality, and regulatory affairs. It also evaluates challenges related to data integrity, regulatory acceptance, ethics, and organizational readiness, and highlights future trends such as agile AI-driven management, digital twins, and generative AI. The article provides a future perspective relevant to industry professionals, academics, and policymakers.
    Keywords:  Artificial Intelligence; Digital Transformation; Intelligence artificielle; Pharmaceutical Project Management; Predictive Analytics; Regulatory Compliance (ICH Q9/Q10); analytique prédictive; conformité réglementaire (ICH Q9/Q10); gestion de projet pharmaceutique; transformation numérique
    DOI:  https://doi.org/10.1016/j.pharma.2026.06.005
  38. Transplant Cell Ther. 2026 Jun 10. pii: S2666-6367(26)00430-6. [Epub ahead of print]
    Neighborhood socioeconomic disadvantage and distance from treatment center do not impact survival outcomes of patients with non-Hodgkin lymphoma and multiple myeloma treated with CAR T-cell therapies.
    Agrima Mian, Rafaella Litvin, Danai Dima, Betty K Hamilton, Allison Winter, Jack Khouri, Louis Williams, Shahzad Raza, Deepa Jagadeesh, Aaron T Gerds, Robert M Dean, Ronald M Sobecks, Faiz Anwer, Matt E Kalaycio, Claudio G Brunstein, Craig S Sauter, Marcelo Pasquini, Brian T Hill, Paolo F Caimi.
       BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapies have transformed the treatment of relapsed/refractory (r/r) hematologic malignancies but are largely delivered at specialized academic centers. Socioeconomic and geographic factors may influence access to these therapies and potentially impact outcomes. While neighborhood disadvantage has been associated with worse health outcomes, its impact on survival following CAR T-cell therapy remains unclear.
    METHODS: We conducted a retrospective study of adult patients with r/r B-cell non-Hodgkin lymphoma (B-NHL) and multiple myeloma (MM) treated with CAR T-cell therapy at a single academic center. Neighborhood socioeconomic disadvantage was assessed using the Area Deprivation Index (ADI), with higher scores indicating greater disadvantage. Distance to treatment center (DTC) was calculated from patient residence. Overall survival (OS) and progression-free survival (PFS) were compared by ADI and DTC using Kaplan-Meier estimates and Cox proportional hazards models.
    RESULTS: A total of 124 B-NHL and 45 MM patients received CAR T-cell therapy between 2018 and 2023. Median ADI was 62.5 and median DTC was 42.5 miles. Longer DTC was associated with higher ADI (p<0.001). No significant differences in OS, PFS, or response rates were observed between high- and low-ADI groups for either B-NHL (median OS: 19 vs. 14 months; p=0.5) or MM (median OS: 14 vs. 18 months; p=0.6). Similarly, survival did not differ between patients with long versus short DTC for B-NHL (median OS: 19 vs. 14 months; p=0.4) or MM (median OS: 14 vs. 20 months; p=0.9). Dichotomizing ADI into the highest 15% versus lower 85% also showed no impact on outcomes.
    CONCLUSIONS: In this single-center cohort of patients who received CAR T-cell therapy, neighborhood disadvantage and distance to the treatment center were not associated with differences in survival outcomes. Although selection and referral biases likely influence which patients ultimately receive therapy, these findings suggest that once access to CAR T-cell therapy is achieved, outcomes may be comparable across socioeconomic and geographic groups. Improving equitable referral pathways and access to specialized centers remains essential.
    Keywords:  CAR-T; area deprivation index; cellular immunotherapies; chimeric antigen receptor T-cell therapy; healthcare disparities; large B-cell lymphoma
    DOI:  https://doi.org/10.1016/j.jtct.2026.05.039
  39. J Clin Med. 2026 May 26. pii: 4104. [Epub ahead of print]15(11):
    Experimental Therapies in Multiple Sclerosis: Epstein-Barr Virus and Potential EBV-Related Therapeutic Strategies-A Systematic Review.
    Julia Bartczak, Piotr Gronowski, Martyna Małek, Aleksandra Denkiewicz, Olga Grodzka, Piotr Chądzyński, Izabela Domitrz.
      Background/Objectives: Multiple sclerosis (MS) constitutes a chronic autoimmune, inflammatory, and neurodegenerative disease, with dissemination in space and time, warranting diagnosis. Epstein-Barr virus (EBV) is increasingly recognized as a key contributor to MS pathogenesis. This review summarizes evidence on EBV-related mechanisms of currently approved disease-modifying therapies (DMTs) and emerging EBV-directed therapeutic strategies in MS. Methods: A systematic search of PubMed, Embase, Cochrane, and Web of Science was performed. Original English-language studies addressing EBV-related therapeutic mechanisms or EBV-targeted interventions in MS were included; 23 studies met the inclusion criteria. Results: Current DMTs may influence EBV-related immunity through diverse mechanisms, including modulation of B-cell subsets, altered lymphocyte trafficking, reduction in EBV-specific humoral responses, and restoration of T-cell surveillance. Monoclonal antibody-based therapies, particularly anti-CD20 agents and natalizumab, appear to affect the EBV-B-cell-immune axis through distinct but complementary mechanisms. Other interventions, including interferons, glatiramer acetate, dimethyl fumarate, autologous hematopoietic stem cell transplantation, and vitamin D supplementation, may also modulate EBV-specific cellular or humoral responses, although the magnitude and durability of these effects vary. Emerging EBV-directed approaches, including EBV-specific T-cell therapy, inhibition of specific proteins, modulation of autophagy, and cholesterol-dependent viral latency, provide additional support for targeting EBV-related pathways in MS. Conclusions: The therapeutic efficacy of DMTs in MS may extend beyond nonspecific immunomodulation and involve partial disruption of EBV-driven immune persistence. Further controlled studies are required to validate EBV-related biomarkers and determine whether direct EBV-targeted therapies can provide sustained clinical benefit.
    Keywords:  EBV; EBV-transformed cells; Epstein–Barr virus; MS; experimental therapy; immunotherapy; multiple sclerosis; targeted therapy
    DOI:  https://doi.org/10.3390/jcm15114104
  40. Biomed Pharmacother. 2026 Jun 08. pii: S0753-3322(26)00673-6. [Epub ahead of print]200 119637
    NKG2D-based CAR-T cells for synovial sarcoma: A preclinical proof-of-concept study.
    Tomohiro Miyazaki, Yudai Murayama, Naoki Oike, Minori Baba, Yasushi Kasahara, Chansu Shin, Nobuhiro Kubo, Takashi Ariizumi, Yuko Suzuki, Keichiro Mihara, Yiwei Ling, Shujiro Okuda, Akihiko Saitoh, Masaru Imamura, Akira Ogose, Hiroyuki Kawashima, Chihaya Imai.
      The prognosis for advanced synovial sarcoma remains poor, with limited therapeutic options. Recently, cloned T cell receptor (TCR)-engineered T cell therapy has shown promising results in patients with advanced synovial sarcoma; however, the number of patients eligible for this therapy is limited owing to human leukocyte antigen (HLA) restriction. To solve this problem, we focused on chimeric antigen receptor (CAR)-T cells that target ligands of NKG2D, an activating receptor of natural killer cells. Because NKG2D recognizes a family of eight ligands, we hypothesized that NKG2D-based CARs could function as an intrinsic multi-antigen targeting platform, potentially mitigating antigen heterogeneity and antigen escape, which are key barriers in CAR-T therapy for solid tumors. We first evaluated the surface expression of NKG2D ligands (NKG2DLs) in synovial sarcoma cell lines and examined their transcript levels in public bulk RNA-seq datasets from synovial sarcoma tissues. We then constructed NKG2D-based, 4-1BB-co-stimulated CAR-T cells. These CAR-T cells showed effector responses and antitumor effects against synovial sarcoma cells in vitro, as demonstrated by the results of the intracellular cytokine production, cytokine secretion, CD107a degranulation assay, WST-8 assay, and real-time cell analysis, and in vivo in an NSG mouse xenograft model of synovial sarcoma. Although further mechanistic, translational, and safety validation studies are required, these findings provide a preliminary disease-specific preclinical proof of concept for HLA-independent NKG2D-based CAR-T cell therapy in synovial sarcoma, particularly in patients who are ineligible for or have not responded to TCR-T therapy.
    Keywords:  CAR-T cell therapy; Chimeric antigen receptor; Immunotherapy; Natural killer group 2 member D; Synovial sarcoma
    DOI:  https://doi.org/10.1016/j.biopha.2026.119637
  41. Ann Allergy Asthma Immunol. 2026 Jun 12. pii: S1081-1206(26)00269-3. [Epub ahead of print]
    Reductions in Immunoglobulin Levels, Atopic Disease, and Asthma Following CAR T-Cell Therapy.
    Ahmed Elmoursi, Lingxiao Zhang, Marcela V Maus, Sara Barmettler.
      
    Keywords:  Chimeric Antigen Receptor (CAR) T-Cell Therapy CD19 CAR T Cells BCMA CAR T Cells B-Cell Depletion Immunoglobulins Atopic Disease Asthma Allergic Inflammation Hypogammaglobulinemia Immune Resetting
    DOI:  https://doi.org/10.1016/j.anai.2026.06.008
  42. Glob Reg Health Technol Assess. 2026 Jan-Dec;13:13 133-145
    Optimizing CAR-T therapy delivery in the Italian healthcare system: economic and organizational insights in follicular lymphoma.
    Andrea Vitagliano, Marzia Bonfanti, Emanuele Angelucci, Alice Di Rocco, Maria Paola Martelli, Elena Del Sarto, Marianna Morani, Chiara Lucchetti, Simona Palladino.
       Introduction: Follicular Lymphoma (FL) is the second most common lymphoid malignancy, with 20% of patients progressing within 24 months of first-line therapy. Chimeric antigen receptor T-cell (CAR-T) therapies have improved outcomes in relapsed or refractory FL, yet their use requires significant resources and complex care pathways. Although outpatient CAR-T programs have shown promising safety and feasibility, limited evidence exists on their organizational, economic, and ethical implications in the Italian healthcare setting. This study compares the current CAR-T pathway for FL patients with a virtual optimized scenario incorporating outpatient management in selected phases.
    Methods: A multidimensional framework was applied to assess differences between standard in-hospital care (Standard Pathway) across three Italian public hospitals (Genoa, Rome, Perugia) and a partially outpatient model (Efficient Pathway). Literature review and expert consultations validated existing practices and informed optimization criteria. Structured surveys provided quantitative and qualitative inputs. Economic modelling estimated three-year full costs using patient-level data, while organizational and ethical aspects were evaluated through Likert scales.
    Results: Efficient Pathway shifted bridging therapy, post-infusion monitoring, and follow-up to outpatient settings, reducing total costs from € 611,070 (As-Is) to € 497,421 (To-Be). Organizational benefits included increased bed capacity (average score: 4.9/6) and consumable utilization (average score: 4.3/6), while ethical gains were observed in treatment accessibility (average score: 4.3/6).
    Conclusions: Introducing outpatient management into CAR-T phases may provide economic, organizational, and ethical advantages when supported by clear eligibility criteria and structured monitoring. As CAR-T indications expand, pathway redesign will be essential to ensure equitable access and sustain healthcare system resources.
    Keywords:  CAR-T; Economic impact; Follicular Lymphoma; Organizational impact; Outpatient
    DOI:  https://doi.org/10.33393/grhta.2026.3722
  43. Discov Oncol. 2026 Jun 10. pii: 896. [Epub ahead of print]17(1):
    A bibliometric analysis of global research trends in adoptive cell therapy for triple negative breast cancer over the past 15 years.
    Wesam Ibrahim Abo Elenien, Nada Ashraf Ibrahim, Mariam Mohamed, Youssef Abo Elenien, Momen Heiba, Osama Abouelenin, Dunya Abbas Mahmood, Farhan Khaleel Hussein.
       BACKGROUND: The aggressive and diverse subtype of breast cancer known as triple-negative breast cancer (TNBC) has poor clinical outcomes and few specific therapeutic choices. Tumor-infiltrating lymphocytes (TILs), T-cell receptor-engineered T cells, and chimeric antigen receptor T (CAR-T) cells are examples of adoptive cell therapy (ACT), which has become a promising immunotherapeutic approach. Its clinical application in TNBC is still difficult, nevertheless. This study used bibliometric techniques to thoroughly assess growing hotspots, intellectual structure, and worldwide research trends pertaining to ACT in TNBC.
    METHODS: The Scopus database was searched for publications related to ACT in TNBC from 2011 to 2025. There were only original articles and reviews written in English. VOSviewer (version 1.6.20) and Microsoft Excel 2021 were used to analyse bibliometric indicators, such as annual publication output, country and institutional contributions, authorship patterns, citation characteristics, and keyword co-occurrence. To investigate thematic evolution and collaboration patterns, network visualisation and clustering analysis were carried out.
    RESULTS: With a compound annual growth rate of more than 60%, a total of 8,496 publications were found, indicating an exponential rise in research output, especially beyond 2020. Together, China and the US accounted for over 60% of all publications, dominating the world's research output. The core research network was made up of a few institutions and very productive writers. CAR-T cell therapy, tumor microenvironment manipulation, immunological checkpoint inhibition, metabolic reprogramming, and biomarker-driven methods were among the clinically orientated themes that emerged from foundational and preclinical investigations, according to keyword analysis. The literature shows ongoing translational difficulties with regard to tumor heterogeneity, antigen instability, immunosuppressive microenvironments, and safety concerns in solid tumors, despite increased research activity.
    CONCLUSION: Over the past ten years, research on ACT in TNBC has grown significantly, reflecting both unmet clinical need and growing scientific interest. However, continuous efforts to overcome biological and translational constraints are highlighted by the concentration of scientific leadership and the conceptual move towards combination methods and next-generation engineering approaches. This bibliometric analysis offers a thorough picture of the state of the field and could direct future research, teamwork, and the creation of more potent ACT tactics for TNBC.
    Keywords:  Adoptive cell therapy; Bibliometric analysis; CAR-T cells; Immunotherapy; Triple-negative breast cancer; Tumor microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1007/s12672-026-05277-6
  44. Data Brief. 2026 Jun;66 112839
    Building a single market for data: Data spaces as pro-competitive infrastructure.
    Effimia Styliani Konstantopoulou.
      European data spaces constitute pro-competitive infrastructures deliberately designed to align with EU competition law objectives. Unlike proprietary ecosystems that risk entrenching market dominance, data spaces embed neutrality, openness, and non-discrimination into their architectural design, thereby addressing market contestability through governance frameworks rather than ex post regulatory intervention. The main argument advances that data spaces represent a transformative "soft-market intervention" that shifts competitive dynamics from exclusive data hoarding to innovation-based rivalry on shared datasets. The paper demonstrates how data spaces extend the principle of free movement to data as a potential "fifth freedom" within the EU internal market, while their federated governance structure prevents any single participant from monopolizing data access or determining participation terms. Through ex ante pro-competitive design, data spaces reconcile the need for large-scale data aggregation with competition law safeguards, enabling economies of scale and scope without creating dominance risks. The technical infrastructure emphasizes interoperability by design, federated cloud architecture, and open standards that prevent vendor lock-in and foreclosure effects. By providing structured alternatives to proprietary data marketplaces controlled by dominant gatekeepers, European data spaces demonstrate how institutional architecture can embed pro-competitive safeguards into market design itself, while fostering digital sovereignty and sustainable competitive advantage within the EU's evolving data economy.
    Keywords:  Competition law; Data governance; Data sovereignty; Data spaces; EU internal market; Federated infrastructure; Market design
    DOI:  https://doi.org/10.1016/j.dib.2026.112839
  45. J Neuroimmune Pharmacol. 2026 Jun 10. pii: 28. [Epub ahead of print]21(1):
    Natural Killer Cells: Dual Regulators and Therapeutic Targets in Multiple Sclerosis Immunopathogenesis.
    Maryam Vahdat Lasemi, Maryam Mehravar, Amirhossein Izadpanah, Dorsa Halvachi, Sahar Parkhideh, Hoda Hasheminasab, Abbas Hajifathali, Elham Roshandel.
      Multiple sclerosis is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, axonal injury, and neurodegeneration. Natural killer cells participate in MS through context-dependent regulatory and cytotoxic functions, yet their precise contribution to disease remains incompletely defined. This review summarizes current knowledge on NK cell development, receptor-mediated activation and inhibition, and mechanisms shaping NK cell responses in the inflamed central nervous system. We examine evidence from experimental autoimmune encephalomyelitis and clinical studies describing how distinct NK subsets may exert protective or pathogenic effects depending on disease stage and microenvironment. Emerging strategies to modulate NK cell function, including cytokine-based stimulation, metabolic and epigenetic regulation, and engineered NK platforms, are also discussed. These approaches have been primarily developed in oncology, and their relevance to MS currently remains preclinical, with only early exploratory efforts reported in autoimmune contexts. Overall, we aim to provide a clear and updated assessment of NK cell biology in MS and to outline the opportunities and limitations of NK-targeted interventions. Further mechanistic and translational studies are required before NK-focused strategies can be reliably considered for therapeutic development in MS.
    Keywords:  Immunotherapy; Multiple sclerosis (MS); Natural killer (NK) cells; Precision medicine; Reprogramming
    DOI:  https://doi.org/10.1007/s11481-026-10296-9
  46. Front Oncol. 2026 ;16 1811170
    Advancing CAR-T therapy in multiple myeloma: a critical appraisal of CARTITUDE-4 and the path toward earlier lines.
    Chao-Qun Zhou, Shi-Qiong Zhou, Qing-Hua Ke.
      
    Keywords:  CAR T-cell therapy; CARTITUDE-4 trial; cilta-cel; health equity; multiple myeloma; overall survival
    DOI:  https://doi.org/10.3389/fonc.2026.1811170
  47. J Immunother Cancer. 2026 Jun 08. pii: e015727. [Epub ahead of print]14(6):
    From viral drift to tumor drift: why cancer immunotherapy needs B cells and dynamic adaptation.
    Zheng Liu.
      Current T-cell-based immunotherapies-chimeric antigen receptor T (CAR-T) cells, checkpoint inhibitors, and neoantigen vaccines-share a fundamental vulnerability: they target fixed antigens while tumors continuously evolve. Like influenza viruses, cancer cells undergo antigenic drift, remodeling their surface antigen landscape and rendering static therapies eventually ineffective. Drawing on our recent proof-of-concept study and establishing the foundation in a mouse model of cutaneous squamous cell carcinoma, we propose a paradigm shift: treat cancer as a moving target. By periodically harvesting tumor cells, immunizing healthy donors, and returning the resulting antibody-rich serum, this approach generates polyclonal antibodies that dynamically match the tumor's evolving antigenic profile. We articulate three interconnected principles underlying this strategy: the threshold principle (immune control operates below a critical tumor burden), the drift principle (antigen change renders fixed targeting futile), and the B-cell advantage (healthy donors generate antibodies that tolerant hosts cannot). We outline key experiments to test these principles directly and discuss translational paths, including off-the-shelf antibody banks and combination with T-cell therapies. This article argues that borrowing adaptive strategies from infectious disease epidemiology could establish a new framework for cancer immunotherapy-one built on B-cell responses, dynamic matching, and continuous adaptation.
    Keywords:  Antibody; B cell; Immunotherapy
    DOI:  https://doi.org/10.1136/jitc-2026-015727
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