bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–11–30
fifty-five papers selected by
Luca Bolliger, lxBio
  1. CAR-T Cell Therapy for Central Nervous System Tumors.
  2. State of the Art of CAR-NK Cell Therapy in Multiple Myeloma: A Comprehensive Review of Cell Sources and Target Antigens.
  3. Precision Reprogramming in CAR-T Cell Therapy: Innovations, Challenges, and Future Directions of Advanced Gene Editing.
  4. Advances and prospects of CAR-T cell therapy in autoimmune disease treatment.
  5. [Basic Principle and Pharmacological Mechanism of the Chimeric Antigen Receptor (CAR)-T Cell].
  6. Harnessing the potential of gene editing technology for CAR-T cell therapy of solid tumors.
  7. Chimeric Antigen Receptors Transmit Co-stimulatory Domain Dependent Piconewton Forces to their Target.
  8. Chimeric Antigen Receptor T Cell Therapy in Systemic Lupus Erythematosus: Mechanisms, Clinical Advances, and Future Directions a Comprehensive Review.
  9. Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.
  10. Special Issue "Targeting CAR T-Cell Therapy: Molecular Research and Its Future Implication".
  11. Advancing CAR-T Cell Manufacturing in Latin America: Current Landscape, Future Directions, and Challenges.
  12. CAR-T cell therapy for the treatment of lung cancer: Current challenges and emerging therapeutic strategies.
  13. [The Role of Nurses in Chimeric Antigen Receptor T-Cell Therapy].
  14. Reshaping CAR-T cells through overexpression of T cell factor 1.
  15. Chimeric Antigen Receptor-Based Cellular Therapy for T-Cell Malignancies.
  16. Mechanisms and Applications of γδ T Cells in Anti-Tumor Immunity.
  17. Managing Treatment-Emergent Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome Following CAR-T Cell Therapy: A Case-Based Review of the use of Emapalumab.
  18. Landscape assessment to characterize baseline access and multilevel barriers to IMProve Access to CAR-T CD19 therapy (IMPACT study) across Europe.
  19. Precision medicine with car cells in acute myeloid leukemia: where are we?
  20. Mitochondrial priming in therapy-induced senescence: implications for CAR-T/NK immunosenolytic therapy.
  21. Emerging strategies in CAR-T cell therapy for acute myeloid leukemia: overcoming heterogeneity and improving safety through dual-antigen targeting.
  22. Emerging therapeutic strategies for CD30-positive lymphomas.
  23. Chimeric Antigen Receptors Transmit Piconewton Forces that are Coupled with T Cell Function.
  24. IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy.
  25. Editorial: Future directions and current trends in cellular therapies.
  26. Crowdfunding for cellular and gene therapy products.
  27. A Guide for Initiating and Managing Chimeric Antigen Receptor T Cell Therapy Clinical Trials in Autoimmune Rheumatic Diseases.
  28. Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
  29. Position statement from the British Society of Blood and Marrow Transplantation and Cellular Therapy on insertional oncogenesis in gene-engineered advanced cell therapy products for treatment of haematological disorders.
  30. Scaffold-free cell sheet therapies: clinical advances, global approval landscapes, and strategic directions to address regenerative medicine barriers.
  31. Genetic findings of potential donor origin in cells used for cell and gene therapy: Recommendations from the World Marrow Donor Association (WMDA).
  32. Autologous, allogeneic, in vivo CAR for autoimmune diseases.
  33. Stem cell revolution: bridging the gap between research and clinical application.
  34. Single-Cell Transcriptomics Reveals CCL3+ Classical Monocyte Subset Linked to Autoimmune Pathogenesis.
  35. Peptide-Drug Conjugates in Tumor Therapy: Current Advances and Future Perspectives.
  36. Hematopoietic cell transplantation after CD19-directed CAR T-cell therapy for remission consolidation or relapse treatment in pediatric acute lymphoblastic leukemia.
  37. Energy-based generative models for monoclonal antibodies.
  38. Smart Biomaterials as Immunomodulators in Cancer Therapy.
  39. Anionic lipids modulate mRNA-lipid nanoparticle immunogenicity and confer protection in a mouse model of multiple sclerosis.
  40. Precision Delivery of Active Compounds from Edible and Medicinal Plants via Gut Microbiota Targeting: A New Paradigm for Cancer Immunotherapy.
  41. Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
  42. Prevalence and predictive factors associated with sustained remission in SLE: a systematic review.
  43. Optimization of velocity receptor transduction in CAR T cells.
  44. Joint Clinical Assessments in Europe: Implications for Market Access, Reimbursement, and National HTA Alignment.
  45. Single-cell transcriptomics reveals dynamics of natural killer cell expansion in a feeder cell-free culture of peripheral blood mononuclear cells-implications for immunotherapy.
  46. Digital Twins in Pediatric Infectious Diseases: Virtual Models for Personalized Management.
  47. Newborn Screening for Metachromatic Leukodystrophy: A Systematic Literature Review.
  48. How the First Medical Imaging Cancer Atlas EUCAIM Was Populated: The Experience of a Reference Hospital.
  49. Value-based health care frameworks for the health technology assessments of "omics" technologies: an international survey.
  50. Customizable mRNA Lipid Nanoparticles for Transfection of Primary Human T Cells.
  51. 'They don't have symptoms': CAR-T therapies send autoimmune diseases into remission.
  52. Innovative Contracting for Gene Therapies: Current Landscape and Perspectives on the Future of Gene Therapy Financing in the USA.
  53. Pneumonia in Immunocompromised Patients.
  54. Flavonoids in Autoimmune Diseases: Mechanisms, Clinical Evidence, and Future Directions.
  55. M-DODII: Bayesian dose optimization design for randomized phase II study with multiple indications.
  1. Methods Mol Biol. 2026 ;2974 249-268
    CAR-T Cell Therapy for Central Nervous System Tumors.
    Masasuke Ohno, Mitsugu Fujita.
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising immunotherapy for central nervous system (CNS) tumors, despite the unique biological barriers posed by the blood-brain barrier (BBB) and immunosuppressive tumor microenvironment (TME). This chapter comprehensively reviews the evolution of CAR designs, gene delivery methods using lentiviral vectors (LVVs), and clinical applications for CNS tumors. We discuss current issues in CAR-T cell therapy for CNS tumors, while highlighting the strategies about new CAR designs and novel delivery methods to overcome these issues.
    Keywords:  Blood–brain barrier; Central nervous system tumors; Chimeric antigen receptor T cell therapy; Glioblastoma; Lentiviral vectors; Tumor microenvironment
    DOI:  https://doi.org/10.1007/978-1-0716-4807-0_21
  2. Int J Mol Sci. 2025 Nov 20. pii: 11224. [Epub ahead of print]26(22):
    State of the Art of CAR-NK Cell Therapy in Multiple Myeloma: A Comprehensive Review of Cell Sources and Target Antigens.
    Asya Bastrich, Kamilla Vinogradova, Diana Mokrousova, Anna Efremova, Oleg Makhnach, Dmitry Goldshtein.
      Multiple myeloma (MM) is a clonal malignancy of plasma cells that remains largely incurable despite major advances in proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Chimeric antigen receptor (CAR)-engineered immune cells have transformed the therapeutic landscape, but CAR-T cell therapy faces challenges such as severe cytokine release syndrome (CRS), neurotoxicity, limited persistence, and logistical complexity. In recent years, natural killer (NK) cells have emerged as a promising platform for next-generation cellular immunotherapy, offering innate antitumor activity, a reduced risk of graft-versus-host disease (GvHD), and the feasibility of "off-the-shelf" allogeneic production. This review summarizes current advances in CAR-NK cell therapy for MM, focusing on two major aspects: the diversity of cell sources-including NK-92, peripheral (PB) and cord blood (CB), and induced pluripotent stem cell (iPSC)-derived NK cells-and the expanding repertoire of target antigens such as BCMA (B-cell maturation antigen), NKG2D, CD38, CD70, SLAMF7, CD138, and GPRC5D. We highlight preclinical and early clinical studies demonstrating potent cytotoxicity, favorable safety profiles, and innovative multi-targeting strategies designed to overcome antigen escape and enhance persistence. Emerging clinical data suggest that CAR-NK cell therapy may combine the specificity of CAR recognition with the inherent safety and versatility of NK biology, offering a potential paradigm shift in the treatment of relapsed or refractory MM. Further clinical validation will determine whether CAR-NK cell therapy can achieve durable remission and complement or surpass current CAR-T modalities.
    Keywords:  BCMA; CAR-NK cells; CD138; CD38; GPRC5D; NKG2D; SLAMF7; allogeneic cell therapy; iPSC-derived NK cells; immunotherapy; multiple myeloma
    DOI:  https://doi.org/10.3390/ijms262211224
  3. Int J Biol Sci. 2025 ;21(15): 6884-6906
    Precision Reprogramming in CAR-T Cell Therapy: Innovations, Challenges, and Future Directions of Advanced Gene Editing.
    Zimo Jia, Jiajin Wu, Jiyue Zhang, Peixian Zheng, Haoxuan Zhang, Yiqin Lin, Tao Pan, Meng Wu, Yuqin Song.
      Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in cancer immunotherapy, demonstrating impressive clinical outcomes, particularly for hematologic malignancies. However, its broader therapeutic application, especially against solid tumors, remains limited. Key challenges include T cell exhaustion, limited persistence, cytokine-mediated toxicities, and logistical hurdles associated with manufacturing autologous products. Emerging gene editing technologies, such as CRISPR/Cas systems, base editing, and prime editing, offer novel approaches to optimize CAR-T cells, aiming to enhance efficacy while managing toxicity and improving accessibility. This review comprehensively examines the current landscape of these gene editing tools in CAR-T cell therapy, highlighting the latest advancements, persisting challenges, and future directions. Leveraging gene editing holds the potential to transform CAR-T therapy into a more potent, safer, and broadly applicable modality for cancer and beyond.
    Keywords:  CAR-T; CRISPR/Cas9; gene editing; immunotherapy
    DOI:  https://doi.org/10.7150/ijbs.124144
  4. Medicine (Baltimore). 2025 Nov 21. 104(47): e45698
    Advances and prospects of CAR-T cell therapy in autoimmune disease treatment.
    Tong Wang, Tong Fu, Guoli Xing, Hongbo Cai, Ying Tong.
      Autoimmune diseases, owing to their chronic onset and immune imbalance, seriously affect the quality of life of patients. Existing treatment methods have limited efficacy and significant side effects. Chimeric antigen receptor (CAR)-based cell therapy strategies, particularly CAR-T cell therapy, are emerging as a promising approach for treating autoimmune diseases. Therefore, this study systematically evaluated the application progress, safety, and target selection of CAR-T therapy in autoimmune diseases and clarified its clinical potential. Through a systematic review and analysis of clinical trial data on CAR-T cell therapy for autoimmune diseases worldwide, combined with target types, research stages, and trial status, a systematic analysis was conducted to explore the efficacy and safety of different targets and summarize the results of existing research. Early-stage studies account for the vast majority of relevant trials registered globally. CD19-targeting CAR-T cells have exhibited significant therapeutic effects in various autoimmune diseases, especially in difficult-to-treat cases. The research on new targets such as B cell maturation antigen and CD20 has also made positive progress. CAR-T cell therapy provides a potential new treatment option for autoimmune diseases, and the trend of diversified targets provides a new path for precision treatment, warranting further in-depth research and clinical translation.
    Keywords:  CAR-T cell therapy; autoimmune diseases; clinical trials; immunotherapy; targets
    DOI:  https://doi.org/10.1097/MD.0000000000045698
  5. Hu Li Za Zhi. 2025 Dec;pii: JN.202512_72(6).05. [Epub ahead of print]72(6): 25-30
    [Basic Principle and Pharmacological Mechanism of the Chimeric Antigen Receptor (CAR)-T Cell].
    Yu-Wen Wang.
      Chimeric antigen receptor T-cell (CAR-T) therapy is an advanced immunotherapy designed for the effective treatment of patients with refractory or relapsed hematologic malignancies. In recent years, CAR-T therapy has demonstrated remarkable therapeutic efficacy in applications on diseases such as acute lymphoblastic leukemia and diffuse large B-cell lymphoma. The treatment approach involves collecting a patient's own T cells and genetically engineering them to express a CAR structure, enabling specific recognition of tumor-associated antigens. Reinfused into the patient, these modified T cells undergo robust expansion, secrete cytokines, and directly induce apoptosis in tumor cells. CAR-T cells typically comprise three domains, namely antigen-recognition, signaling, and co-stimulatory, each of which influences the activity and toxicity profile of these cells. The CAR-T cell therapy process includes patient evaluation, leukapheresis, gene transduction and cell expansion, lymphodepleting chemotherapy, and CAR-T infusion, all of which require multidisciplinary collaboration. The common adverse effects of CAR-T therapy, including cytokine release syndrome and neurotoxicity, must be closely monitored for and graded by nursing staff for early intervention. In addition, delayed toxicities such as pancytopenia or hypogammaglobulinemia may occur, necessitating long-term follow-up and supportive care. Nurses play a pivotal role throughout the CAR-T treatment process in terms of providing clinical monitoring, patient education, and psychological support; ensuring treatment safety; and optimizing overall patient care quality.
    Keywords:  chimeric antigen receptor T cells; mechanism of action; nursing care
    DOI:  https://doi.org/10.6224/JN.202512_72(6).05
  6. Inflamm Regen. 2025 Nov 24. 45(1): 34
    Harnessing the potential of gene editing technology for CAR-T cell therapy of solid tumors.
    Elnaz Khodabandehloo, Mohammad Rayati, Ehsan Ahmadi, Mohammadjavad Naghdibadi, Vahid Moradi, Naser Ahmadbeigi.
      Chimeric antigen receptor (CAR)-T cell therapy is now considered a mainstay treatment for certain hematologic malignancies, as evidenced by several products that have gained marketing authorization from regulatory authorities worldwide. Despite the undeniable successes of this treatment in certain blood cancers, its effectiveness in solid tumors remains unsatisfactory. This limited efficacy is attributed to several factors, including low trafficking and poor infiltration of CAR-T cells into the tumor bed, antigen heterogeneity, the risk of on-target off-tumor toxicities, immunosuppressive tumor microenvironment, and intrinsic resistance mechanisms in tumor cells. Advances in gene editing platforms, notably CRISPR/Cas9 and its derivative novel technologies, have created opportunities to overcome the existing hurdles of CAR-T cell therapy in solid tumors. Gene editing can be harnessed to disrupt, correct, activate, repress intended genes, and precisely integrate transgenes at predefined loci. Multiplex genome editing using the CRISPR system enables the simultaneous targeting of multiple genes to induce desired changes in cellular behavior, aiming to improve the efficacy and safety profile of CAR-T cell therapy. This review comprehensively examines how gene editing technology is leveraged to enhance CAR-T cell therapy against solid tumors. In this regard, after an overview of various applications of gene editing in CAR-T cell therapy of solid tumors, clinical trials of genome-edited CAR-T cells in solid tumors are discussed to provide a comprehensive perspective regarding the current state of genome-edited CAR-T cell therapy in solid tumors.
    Keywords:  CAR-T; CRISPR; Chimeric antigen receptor (CAR); Gene editing; Solid tumors
    DOI:  https://doi.org/10.1186/s41232-025-00398-x
  7. bioRxiv. 2025 Oct 23. pii: 2025.10.22.683904. [Epub ahead of print]
    Chimeric Antigen Receptors Transmit Co-stimulatory Domain Dependent Piconewton Forces to their Target.
    Hemakshi J Mishra, Lauren Mahoney, Dominique R Smith, Luke Kalcheim, Kartikey Kansal, Nat Murren, Myrna Chang, Rebecca M Richards, Joshua M Brockman.
      Chimeric antigen receptor (CAR) T cells promote tumor-specific cytotoxicity through engagement of a recombinant, synthetic receptor with target ligands expressed on cancer cells. Native T cells are mechanically active, both transmitting and sensing forces exceeding 19 piconewtons (pN) via transmembrane receptors, including the T cell receptor (TCR). Emerging evidence implicates mechanoactivity in CAR T cell biology, but CAR-transmitted T cell forces have not been directly measured. Here, we utilize DNA-based molecular tension probes (MTPs) conjugated to CAR target ligands, providing evidence of actin-polymerization dependent forces exceeding 4.7-19 pN borne by the CAR. We demonstrate force transmission by three clinically relevant CARs (CD123, CD33, and CD19), suggesting that these forces are generalizable across CAR targets and constructs. Additionally, we identify intracellular co-stimulatory domains as the main determinants of CAR-mediated forces, because first-generation CARs lacking co-stimulatory domains do not transmit measurable forces to their ligand. Finally, we demonstrate that CAR forces temporally precede Ca 2+ signaling and are spatially correlated with phosphorylation of classical TCR-signaling machinery, indicating a link between CAR T cell forces and early biochemical signaling. Our study introduces CAR-mediated mechanobiology as a key correlate of early CAR T cell activation events.
    Significance Statement: Chimeric antigen receptor (CAR) T cell therapies have revolutionized treatment for several hematological malignancies. CARs are recombinant receptors containing domains derived from the T cell receptor complex machinery and other co-stimulatory proteins. Mechanical forces are believed to be important in T cell activation and antigen recognition. The role of mechanobiology in CAR T cell immunotherapy remains poorly understood. Here, using DNA-based molecular tension probes conjugated to CAR ligands, we provide direct evidence that CARs bear actin polymerization-dependent piconewton forces during antigen engagement that precede early signaling events. These forces depend on CAR co-stimulatory domains, and first-generation CARs lacking these domains fail to transmit detectable force. These findings suggest mechanobiology may be a key, tunable parameter for next-generation CAR T cells.
    DOI:  https://doi.org/10.1101/2025.10.22.683904
  8. Clin Rev Allergy Immunol. 2025 Nov 27. 68(1): 103
    Chimeric Antigen Receptor T Cell Therapy in Systemic Lupus Erythematosus: Mechanisms, Clinical Advances, and Future Directions a Comprehensive Review.
    Ahmad Matarneh, Bayan Matarneh, Omar Salameh, Abdelrauof Akkari, Nasrollah Ghahramani, Naman Trivedi.
      Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder characterized by loss of self-tolerance, immune complex deposition, and progressive organ damage. Despite advances in immunosuppressive therapy, a subset of patients develops treatment-resistant or refractory manifestations; terms used variably in the literature to describe inadequate response to multiple standard immunosuppressants. Chimeric antigen receptor T cell (CAR-T) therapy, a revolutionary modality in oncology, is now emerging as a promising approach in severe autoimmune diseases including SLE. By redirecting autologous T cells to target B cell antigens such as CD19 or BCMA, CAR-T therapy enables deep and sustained B cell depletion, potentially resetting immune tolerance.Early case series have reported encouraging remission rates and serologic improvements in refractory SLE; however, these observations derive from small, uncontrolled studies. The long-term durability, relapse risk, safety profile, and cost-effectiveness of CAR-T therapy in autoimmune disease remain uncertain and require confirmation in larger, controlled trials. This narrative review synthesizes the current understanding of CAR-T therapy in SLE, covering immunopathogenesis, rationale for B cell targeting, CAR-T mechanisms, preclinical evidence, clinical outcomes, safety considerations, and future directions. We integrate data from peer-reviewed studies, conference abstracts, and preprints up to August 2025, and propose a framework for integrating CAR-T into the treatment paradigm for refractory SLE.
    Keywords:  Autoimmunity; B cell depletion; BCMA; CAR-T; CD19; Chimeric antigen receptor T cells; Immunotherapy; Systemic lupus erythematosus
    DOI:  https://doi.org/10.1007/s12016-025-09114-6
  9. J Hematol Oncol. 2025 Nov 28.
    Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.
    Xiaomei Chen, Kaifan Liu, Bowen Liu, Shiyin Li, Yulian Wang, Xin Du, Jianyu Weng, Bing Song, Kongming Wu, Peilong Lai.
      Chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial efficacy against various hematological malignancies. The remarkable success of CAR-T cell therapy in targeting B-cell malignancies has generated significant interest in its potential application for treating autoimmune diseases (ADs). By engineering T cells to express CARs that specifically recognize B-cell antigens, researchers aim to selectively eliminate or modulate the dysregulated autoimmune responses underlying disease pathology. Early clinical trials targeting the B-cell marker CD19 have shown promising results, including clinical remission in patients with B-cell-mediated ADs. To broaden therapeutic potential and improve the safety profile of CAR-T cell therapy in autoimmunity, innovative strategies are under investigation. These include the development of chimeric autoantibody receptors (CAARs) for the precise depletion of autoantigen-specific B cells, and the engineering of regulatory T cells (Tregs) expressing antigen-specific CARs to achieve targeted immune modulation. Critical considerations for the safe and effective translation of CAR-T therapy to ADs include optimal target cell identification, CAR construct design, toxicity management, and the capacity to induce durable immune tolerance. This review explores strategies to optimize CAR-T cell therapies for ADs, focusing on enhancing efficacy and addressing current limitations. We summarize recent advances in alternative cell sources, CAR structural modifications, genetic and metabolic interventions, clinical translation, and the integration of novel technologies, presenting approaches poised to improve the efficacy and applicability of CAR-T cell therapy in ADs.
    Keywords:  Autoimmune diseases; CAR-T cell therapy; Clinical translation; Novel technologies
    DOI:  https://doi.org/10.1186/s13045-025-01769-0
  10. Int J Mol Sci. 2025 Nov 09. pii: 10868. [Epub ahead of print]26(22):
    Special Issue "Targeting CAR T-Cell Therapy: Molecular Research and Its Future Implication".
    Stella Bouziana.
      The emergence of chimeric antigen receptor (CAR) T-cell therapy represents a significant milestone in the cellular treatment of cancer [...].
    DOI:  https://doi.org/10.3390/ijms262210868
  11. Crit Rev Oncol Hematol. 2025 Nov 20. pii: S1040-8428(25)00429-9. [Epub ahead of print] 105041
    Advancing CAR-T Cell Manufacturing in Latin America: Current Landscape, Future Directions, and Challenges.
    Alejandro Toro-Pedroza, Juan Sebastián Victoria, Miguel Cardona-Sepúlveda, Juan Esteban García-Robledo, Lady J Rios-Serna, Alexandre Loukanov, Joshua Ortiz-Guzman, Valentina Hoyos, Jackelin E Mainguez-Rodriguez, Carlos Alberto Cañas, Francisco J Jaramillo, William Franco, Beatriz Wills, Juan Guillermo Restrepo, Juan C Baena.
      Chimeric antigen receptor T cell therapy has transformed outcomes in hematologic malignancies, yet access in Latin America remains limited by high costs, fragmented regulation, constrained manufacturing capacity, and uneven clinical readiness. This review synthesizes the regional landscape and distills practical strategies to advance sustainable manufacturing and delivery. We map the full value chain from discovery to routine care, highlighting instructive examples. India's talicabtagene autoleucel program built domestic vector and cell production to lower cost and shorten timelines, Brazil coupled a mature regulatory pathway with accredited centers and an emerging national platform for vectors and plasmids, Mexico demonstrated feasibility of hospital based closed system production under national oversight; Colombia and Chile are developing academic pipelines and locally relevant targets. From these experiences we propose a staged roadmap for Latin America that prioritizes domestic capability in vectors and cell processing, regulatory alignment to trusted standards, and workforce development anchored in manufacturing standards and consensus. Network models that combine reference centers with point of care manufacture can reduce logistics burden. Enabling systems are essential, reliable cold chain, precleared customs lanes for critical inputs, pharmacovigilance, and shared minimum datasets for outcomes and safety. Emerging technologies, including non viral nanoparticle transfection and artificial intelligence for construct selection and process control, can reduce costs and improve consistency if advanced through careful, stepwise evaluation. Finally, coordinated alliances among hospitals, professional societies, patient groups, academia, and industry are needed to secure policy support and public investment. Together, these measures provide with a realistic path to safe, equitable, and affordable access to CAR T therapy in Latin America.
    Keywords:  Adoptive; Chimeric Antigen Receptor Therapy; Immunotherapy; Latin America; Manufacturing Industry
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105041
  12. Lung Cancer. 2025 Nov 21. pii: S0169-5002(25)00741-X. [Epub ahead of print]210 108849
    CAR-T cell therapy for the treatment of lung cancer: Current challenges and emerging therapeutic strategies.
    Dongxue Shi, Xin Yan, Jianwei Liu, Hongmei Chen, Xiuqin Wang, Rongjun Li, Xuan Tian, Xiaoyan Lin, Yunshan Wang.
      Lung carcinoma has consistently ranked as the most prevalent malignancy and foremost contributor to cancer-related mortality in global epidemiology. Despite the paradigm-shifting advancements in molecularly targeted therapies and immune checkpoint inhibitors (ICIs) for advanced-stage non-small cell lung cancer (NSCLC), clinical outcomes remain constrained by tumor recurrence and treatment resistance. Chimeric antigen receptor (CAR) T cell therapy, a revolutionary cellular immunotherapy modality, has demonstrated unprecedented clinical efficacy in hematological malignancies. Nevertheless, its clinical implementation in solid malignancies, particularly non-small cell lung cancer (NSCLC), remains hindered by some cardinal biological barriers including spatial heterogeneity of tumor-associated antigens, on-target/off-tumor toxicity risks, immunosuppressive tumor microenvironment (TME), inefficient T-cell trafficking, and T-cell dysfunction hallmarked by exhaustion and poor persistence signatures. This review aims to discuss the development of CAR-T cells for lung cancer from preclinical studies to ongoing clinical trials. Specifically, we summarize tumor-associated antigens in lung cancer, ongoing clinical trials, barriers to CAR-T cell therapy in lung cancer, and discuss potential strategies to improve therapeutic efficacy. We, therefore outline the trajectory of CAR-T cells that may evolve from promising experimental approaches to a standard modality for lung cancer therapy.
    Keywords:  Chimeric antigen receptor; Clinical trials; Immunotherapy; Lung cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.lungcan.2025.108849
  13. Hu Li Za Zhi. 2025 Dec;pii: JN.202512_72(6).03. [Epub ahead of print]72(6): 12-17
    [The Role of Nurses in Chimeric Antigen Receptor T-Cell Therapy].
    Pei-Yu Tsai.
      Chimeric antigen receptor T-cell (CAR-T) therapy represents a significant breakthrough in contemporary oncology. By engineering patients' autologous T cells to precisely target tumor cells, CAR-T offers new treatment opportunities for individuals with refractory hematologic malignancies. However, the therapeutic process is complex and accompanied by high-risk adverse effects, including cytokine release syndrome, immune effector cell-associated neurotoxicity, and infections, all of which pose major challenges to clinical nursing. Nurses play a pivotal role across the CAR-T care continuum in terms of providing pre-treatment education and health assessments, vigilant monitoring and complication management during therapy, and post-discharge follow-up and self-care guidance. Clinical nurses must demonstrate acute clinical sensitivity to identify the early warning signs of adverse events and collaborate closely with multidisciplinary teams to ensure timely intervention. Moreover, nurses serve as essential communicators between patients and families, coordinating interdisciplinary care to ensure treatment plans are implemented accurately as well as providing psychological support to reduce anxiety and uncertainty. In the post-discharge phase, ongoing education and follow-up further empower patients and caregivers to strengthen self-management skills, thereby enhancing treatment safety and quality of life. In conclusion, the success of CAR-T therapy depends not only on advances in medical technology but also on the comprehensive professional care and humanistic support delivered by nurses.
    Keywords:  CAR-T; chimeric antigen receptor T cell; nursing role
    DOI:  https://doi.org/10.6224/JN.202512_72(6).03
  14. Front Immunol. 2025 ;16 1623869
    Reshaping CAR-T cells through overexpression of T cell factor 1.
    Hao Yao, Yuntian Ding, Qian Chen, Huixiu Han, David Sedloev, Carsten Müller-Tidow, Tim Sauer, Anita Schmitt, Michael Schmitt, Lei Wang.
       Introduction: Although chimeric antigen receptor (CAR) T cell therapy has revolutionized treatment for hematologic malignancies, insufficient CAR-T cell persistence remains a major limitation. T cell factor 1 (TCF-1) is a transcription factor crucial for T cell development, self-renewal, and memory formation. However, CAR-T cells typically exhibit low TCF-1 expression. This study investigated whether restoring TCF-1 expression could enhance CAR-T cell persistence and functionality.
    Methods: Human peripheral blood T cells were transduced with third-generation CD19 or CD33 CAR retroviral vectors, with or without a TCF-1 (Tcf7.NGFR) construct. Phenotypic, functional, and transcriptional analyses were performed using flow cytometry, cytokine profiling, long-term killing assays, and RNA sequencing. Data mining and machine learning were applied for high-dimensional immunophenotyping.
    Results: TCF-1 overexpression generated CAR-T cells with reduced apoptosis, lower activation marker expression, and an increased proportion of naïve and stem cell-like subsets. These modified cells displayed a higher CD4⁺/CD8⁺ ratio, preserved proliferative capacity, and maintained cytotoxicity with attenuated cytokine release. Long-term co-culture assays demonstrated superior persistence and sustained tumor-killing activity in TCF-1-overexpressing CAR-T cells. Transcriptomic profiling revealed downregulation of apoptotic and cytokine release pathways, and enrichment of cell cycle and metabolic pathways supporting T cell longevity.
    Discussion: Overexpression of TCF-1 confers resistance to apoptosis, limits excessive activation, and promotes a less differentiated phenotype, collectively enhancing CAR-T cell persistence and long-term efficacy. These findings suggest that TCF-1 modulation represents a promising strategy to improve durability and safety of CAR-T cell therapy in relapsed or refractory hematologic malignancies.
    Keywords:  CAR (chimeric antigen receptor) T cells; CRS - cytokine release syndrome; T cell persistence; TCF (T-cell factor); immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1623869
  15. Crit Rev Oncol Hematol. 2025 Nov 22. pii: S1040-8428(25)00432-9. [Epub ahead of print] 105044
    Chimeric Antigen Receptor-Based Cellular Therapy for T-Cell Malignancies.
    Sile Li, Yuanxin Li, Man Yan Hui, Asif Rashid, Hong Kee Tan, Shing Chan, Wilson Yau Ki Chan, Kee See Lam, Wenwei Tu, Wing Leung.
      Chimeric antigen receptor (CAR) T-cell therapy utilizes synthetic biology techniques to engineer T cells to specifically target tumor cells using most commonly single-chain variable fragments (scFvs) to recognize tumor-associated antigens, which has been successfully applied to patients with B-lineage hematologic malignancies including leukemia, lymphoma and multiple myeloma. However, treatment outcomes for relapsed or refractory (R/R) T-cell malignancies remain suboptimal. A significant challenge is the shared antigens between malignant and normal T cells, leading to fratricide among CAR T cells. Moreover, the presence of malignant T cells in patients' leukapheresis may increase risk of relapse. Post-infusion, patients may experience severe T-cell aplasia, rendering the cancer patients who are generally immunocompromised even more immunodeficient. This review article explores CAR-based cellular therapy, including immune effector cells (IECs) such as conventional T cell subsets, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, and γδ T cells for T-cell malignancies. We discuss multiple antigen-targeting, emerging technologies, and the latest clinical trials in attempt to improve CAR-based therapy for T-lineage neoplasms.
    Keywords:  Adoptive cell therapy; CAR T-cell therapy; Cancer immunotherapy; Clinical trial; Hematological disease; T-cell malignancies
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105044
  16. Cancer Control. 2025 Jan-Dec;32:32 10732748251399242
    Mechanisms and Applications of γδ T Cells in Anti-Tumor Immunity.
    Yu Zhang, Jiawang Liu, Junwen Yao, Nanhai Yuan, Ruiquan Xu.
      γδ T cells represent a distinctive subset of immune cells with considerable promise in cancer immunotherapy. They recognize a broad spectrum of tumor-associated antigens via non-major histocompatibility complex (non-MHC) pathways and exert antitumor effects by inducing apoptosis, directly lysing tumor cells, and modulating other immune components. This unique antigen-recognition capacity has spurred extensive efforts to harness γδ T cells for innovative immunotherapeutic applications. Consequently, their use in cancer treatment is gaining increasing traction. Researchers have employed genetic engineering and other strategies to enhance γδ T cell anti-tumor efficacy and have begun evaluating their potential in clinical trials. However, this therapeutic approach faces notable challenges, including interindividual variability in response and risk of adverse effects. Future research should aim to achieve a more comprehensive understanding of the mechanisms of γδ T cells across different tumor types and improve their safety and efficacy in clinical settings. This review synthesizes recent advances in γδ T cell research, examining their roles in tumor recognition, cytotoxicity, immunoregulation, and anti-tumor immunity. It further evaluates preclinical and clinical evidence to assess the therapeutic potential of γδ T cell-based cancer immunotherapies.
    Keywords:  anti-tumor; immunotherapy; tumor immunity; tumor microenvironment; γδ T cells
    DOI:  https://doi.org/10.1177/10732748251399242
  17. Hematol Oncol. 2026 Jan;44(1): e70157
    Managing Treatment-Emergent Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome Following CAR-T Cell Therapy: A Case-Based Review of the use of Emapalumab.
    Livia Donzelli, Veronica Zullino, Giovanni Fernando Torelli, Maria Stefania De Propris, Mario Piazzolla, Franco Ruberto, Maurizio Martelli, Alice Di Rocco.
      Chimeric antigen receptor T (CAR-T) cell therapies have revolutionized the treatment of hematological malignancies, achieving high response rates in patients with relapsed or refractory disease. Despite these benefits, CAR-T cell therapies are associated with unique toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), immune cell-associated hematotoxicity (ICAHT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which is characterized by a rare and life-threatening hyperinflammatory response. This paper presents a case of a 56-year-old woman with relapsed mantle cell lymphoma (MCL) treated with the CAR-T cell therapy, brexucabtagene autoleucel, who had subsequently developed CRS and later IEC-HS. Initial management included tocilizumab, corticosteroids, and anakinra, followed by the compassionate use of emapalumab, an interferon-γ blocker. To provide broader context, we conducted a literature review of CAR-T cell-related toxicities, focusing on IEC-HS and its management with emapalumab. Clinical and laboratory manifestations, such as elevated ferritin levels, cytopenias, and organ dysfunction, underpin the diagnostic criteria for IEC-HS. Vigilant monitoring and tailored therapeutic approaches are required to effectively manage toxicities associated with CAR-T cell therapy, to maximize its benefits and minimize adverse effects. In more severe IEC-HS cases, emapalumab may be used as an effective targeted therapy.
    Keywords:  CAR‐T cell therapy; IEC‐HS; brexucabtagene autoleucel; emapalumab; interferon‐γ; mantle cell lymphoma
    DOI:  https://doi.org/10.1002/hon.70157
  18. medRxiv. 2025 Nov 06. pii: 2025.11.04.25339516. [Epub ahead of print]
    Landscape assessment to characterize baseline access and multilevel barriers to IMProve Access to CAR-T CD19 therapy (IMPACT study) across Europe.
    St. Jude Global, the European Group for Blood and Marrow Transplantation (EBMT) PDWP and the International BFM Study Group (I-BFM)
       Background/Purpose: Chimeric Antigen Receptor-T Cell Therapy (CAR-T) has revolutionized the treatment of B-cell precursor acute lymphoblastic leukemia (B-ALL), but its global availability is limited. This study assessed current access and barriers to CAR-T CD19 cell therapy for children across Europe.
    Methods: A country questionnaire developed by the EBMT PDWP, St. Jude Children's Research Hospital, and IBFM assessed current access to advanced therapies for B-ALL in Europe using Qualtrics software.
    Results: Data from 35 WHO-defined European countries (26 high-income, 9 upper middle-income) revealed a median of 5 pediatric hematology-oncology (PHO) centers per country (0.55 PHO centers/1 million inhabitants, range: 0.05-1.83). Hematopoietic stem cell transplantation (HSCT) facilities were available in 89% of countries (31/35). Sixty B-ALL cases were diagnosed annually per country (4 B-ALL children/100,000 children, range: 0.4-8.4). CAR-T CD19 therapy was available in 71% of countries; however, more than 50% of countries lacked clinical trials or international collaborations for pediatric CAR-T CD19 therapy. Most countries accepted foreign patients, but referrals remained limited, with 1-2 foreign patients treated annually per country. Seventeen countries expressed interest in a referral network, but only six had established mechanisms for domestic or international referrals.
    Conclusion: Substantial disparities exist in access to advanced therapies for pediatric B-ALL across Europe. Although CAR-T CD19 therapy is available in most countries, gaps in clinical trials, collaborations, and referral systems limit equitable access. Efforts to improve infrastructure and establish referral networks are essential to enhance care for pediatric B-ALL patients.
    DOI:  https://doi.org/10.1101/2025.11.04.25339516
  19. Front Immunol. 2025 ;16 1653350
    Precision medicine with car cells in acute myeloid leukemia: where are we?
    Larissa C Zanetti, Victoria Tomaz, Ingrid Ferreira de Souza, Paulo V Campregher, Nelson Hamerschlak, Lucila N Kerbauy.
      The integration of chimeric antigen receptor (CAR) therapies with precision medicine holds potential to impact the treatment landscape for acute myeloid leukemia (AML). Genetic mutations play a role in the efficacy of CAR-T and CAR-NK cells, influencing their crucial role in determining the effectiveness of these cells, as well as their proliferation, persistence, resistance, and safety. This review examines how mutations in FLT3, DNMT3A, NPM1, TP53, TET2, gene fusions involving RUNX1 and KMT2A and other key genes modulate CAR-based immunotherapies, highlighting both vulnerabilities and resistance mechanisms. Recent findings demonstrate that mutations in genes such as DNMT3A and NPM1 enhance antigen expression, thereby improving CAR targeting. In contrast, mutations in TP53 drive immune escape and resistance to therapy. Understanding these mutation-specific effects is essential for tailoring CAR therapies to individual patients, optimizing efficacy while minimizing toxicity. By leveraging genomic profiling and personalized engineering approaches, CAR therapies can be refined to overcome resistance and enhance precision in AML treatment. Future research should focus on integrating multiomic data to develop mutation-adapted CAR strategies, ensuring that patients receive the most effective and personalized immunotherapy.
    Keywords:  AML; CAR-T; genetic mutations; immunotherapy; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2025.1653350
  20. Front Immunol. 2025 ;16 1695244
    Mitochondrial priming in therapy-induced senescence: implications for CAR-T/NK immunosenolytic therapy.
    Javier A Menendez, Ruth Lupu, Begoña Martin-Castillo, Josep Sardanyés, Tomás Alarcón, Sara Verdura, Elisabet Cuyàs.
      Therapy-induced senescence (TIS) generates an immunogenic state in cancer cells by altering how they present antigens, produce cytokines, and organize their surfaceome. TIS can be exploited for therapeutic purposes using "immunosenolytic" strategies, including adoptive cellular therapies such as chimeric antigen receptor (CAR)-engineered T and natural killer (NK) cells. A frequently overlooked barrier may limit the success of these living drugs: mitochondrial apoptotic priming in the target TIS cancer cells. Contrary to the prevailing dogma, recent assessments of mitochondrial apoptotic signaling via BH3 profiling (a functional assay measuring proximity to the mitochondrial apoptotic threshold and identifying BCL-2 family dependencies) have revealed that TIS cancer cells are globally less primed for apoptosis than their proliferating precursors. TIS cancer cells exhibit a conserved, druggable dependence on specific members of the BCL-2 family for survival. Interestingly, the pre-existing priming and anti-apoptotic addictions of parental, non-senescent cells, are retained upon induction of senescence. This suggests an "inherited" mitochondrial memory that may predict the (immuno)senolytic responsiveness of TIS cancer cells. BH3 profiling could help to personalize CAR-based immunosenolytic therapy according to apoptotic readiness across pre- and post-TIS states. This companion diagnostic could inform the rational use of BH3 mimetics in combination with CARs and guide the engineering of precision immunosenolytic interventions such as "armored" CAR-T/NK cells neutralizing specific anti-apoptotic dependencies at the effector-target interface. This perspective reframes mitochondria as predictive checkpoints that can be monitored and targeted to enable TIS cancer cells to respond precisely and durably to adoptive CAR-T/NK immunotherapy within "one-two punch" senogenic-immunosenolytic designs.
    Keywords:  BH3 mimetics; BH3 profiling; CAR-NK cells; CAR-T cells; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1695244
  21. Exp Hematol Oncol. 2025 Nov 27. 14(1): 135
    Emerging strategies in CAR-T cell therapy for acute myeloid leukemia: overcoming heterogeneity and improving safety through dual-antigen targeting.
    Ángeles Ocaña-Cara, Tuna Mutis, Jort J van der Schans.
      While CAR-T cell therapy has been very successful for treating B cell malignancies, and more recently multiple myeloma, achieving clinical success for acute myeloid leukemia (AML) remains a significant challenge. The examination of current single-antigen targeting CAR-T cell studies for AML illustrates the challenges faced by this therapy: efficacy limitations arise from the heterogeneity of the disease, which often results in antigen escape and subsequent circumvention of single-antigen targeting CAR-T cells, while safety limitations are mainly due to undesired hematological toxicity stemming from the absence of an antigen specifically expressed on AML tumor cells and not on normal hematopoietic cells. This study offers a comprehensive analysis of the most relevant AML surface antigenic markers -CD123, CD33, ADGRE2, CLL-1, TIM-3, CD70, among others- along with their expression patterns across key cell types, including leukemic blasts, leukemic stem cells, hematopoietic stem cells and progenitors, adult blood cells, and other tissues. Additionally, a variety of strategies for developing CAR-T therapies with improved efficacy and specificity are explored, with dual-antigen targeting CAR-T cell therapies emerging as the most promising approach to overcome the major hurdles observed in single-antigen targeting CAR-T cell therapies. Overall, this review identifies dual-antigen targeting as a therapy holding great prospects in the search of an effective and safe therapeutic approach for AML patients.
    Keywords:  Acute myeloid leukemia; Antigen expression; Chimeric antigen receptor T cell; Dual-antigen targeting; Immunotherapy
    DOI:  https://doi.org/10.1186/s40164-025-00726-4
  22. Clin Transl Oncol. 2025 Nov 28.
    Emerging therapeutic strategies for CD30-positive lymphomas.
    Alberto Boretti.
      The antibody-drug conjugate brentuximab vedotin (BV) has significantly improved outcomes for CD30-expressing lymphomas. The ECHELON-2 trial established BV combined with cyclophosphamide, doxorubicin, and prednisone (CHP) as a frontline standard for systemic anaplastic large cell lymphoma, demonstrating superior survival over the traditional CHOP regimen. Despite this progress, the limitations of a universal BV + CHP standard are increasingly apparent, and the therapeutic landscape is rapidly diversifying. This review critically evaluates the evidence supporting BV + CHP, including methodological considerations of the ECHELON-2 trial, and explores the expanding arsenal of novel therapies. We assess alternative strategies, such as BV-based combinations with immunotherapies or alternative chemotherapies, the integration of other targeted agents, and the transformative potential of advanced cellular treatments like anti-CD30 chimeric antigen receptor (CAR)-T cell therapy for relapsed/refractory disease. The collective evidence signals a paradigm shift from a one-size-fits-all approach toward personalized, precision-driven strategies aimed at maximizing efficacy, minimizing toxicity, and improving long-term quality of life for patients with CD30-positive lymphomas.
    Keywords:  Brentuximab vedotin; CAR-T cell therapy; CD30+ lymphomas; CHOP; CHP regimen; ECHELON-2 trial; Financial conflicts in research; Immunotherapy; Political influence in medicine; Targeted therapies
    DOI:  https://doi.org/10.1007/s12094-025-04151-1
  23. bioRxiv. 2025 Oct 24. pii: 2025.10.23.684052. [Epub ahead of print]
    Chimeric Antigen Receptors Transmit Piconewton Forces that are Coupled with T Cell Function.
    Rachel M Fitzgerald, Areeba A Hashmi, Anna M Davis, Alexander K Foote, Gianna M Branella, Jhordan Rogers, Emily C Sullivan, Mohamed Husaini Bin Abdul Rahman, Sunil S Raikar, Khalid Salaita.
      Chimeric antigen receptor (CAR) T cells are engineered to display a receptor that binds antigens expressed on the surface of cancerous cells, which leads to cancer cytotoxicity. Recently, the T cell field has come to recognize the role of small, piconewton level forces in establishing specificity and cytotoxicity in naïve T cells with the αβ TCR, raising the possibility that these forces could be present in CAR T cells. Using DNA-based tension probes, we reveal 8-19 pN mechanical forces with ∼1 sec timescales transmitted by CAR T cells to their target antigens. CAR-antigen force magnitude is independent of CAR expression level and shows heterogeneity across different T cell donors, suggesting utility as a biomarker of T cell fitness. Using an established exhaustion model, we show strong correlation between CAR exhaustion, cytotoxic capacity, and CAR-antigen force, suggesting that CAR mechanics provide a biomarker of CAR potency complementary to functional assays. Pharmacological inhibition studies demonstrate that CAR forces are driven by actin, Zap70 and Src family proximal kinases. Titration of dasatinib, a clinically used tyrosine kinase inhibitor also dampens both CAR-antigen tension and CAR function in a dose-dependent manner. Structural engineering of the CAR confirms that force levels are modulated by the scFv receptor and co-stimulatory domains, but force transmission requires CD3ζ ITAMs. Taken together, this work shows that CAR T cells transmit pN force to their cognate antigens which holds potential significance in the design and screening of CAR therapeutic candidates and for predicting treatment outcomes in a personalized fashion.
    DOI:  https://doi.org/10.1101/2025.10.23.684052
  24. Immunity. 2025 Nov 21. pii: S1074-7613(25)00475-3. [Epub ahead of print]
    IL-9 signaling redirects CAR T cell fate toward CD8+ memory and CD4+ cycling states, enhancing antitumor efficacy.
    Sofía Castelli, Wesley V Wilson, Ugur Uslu, Amanda V Finck, Philipp C Rommel, Charles-Antoine Assenmacher, Sebastian J Atoche, Mikko Siurala, M Angela Aznar, Regina M Young, Carl H June.
      The success of chimeric antigen receptor (CAR) T cell therapies targeting solid tumors is limited by the immunosuppressive tumor microenvironment. We demonstrate that endowing CAR T cells with ectopic interleukin (IL)-9 signaling by co-expressing an IL-9 receptor rewires CAR T cell fate under antigen stress to enhance antitumor efficacy. In preclinical solid tumor models, IL-9-signaling CAR T cells exhibit increased expansion, persistence, and tumor infiltration, resulting in superior tumor control at substantially lower doses than conventional products. Trajectory and RNA velocity analyses of single-cell RNA sequencing data reveal that IL-9 signaling alters CAR T cell differentiation under antigen stress away from dysfunction, favoring a multipotent transition toward CD8+ T cell memory and effector states and promoting a CD4+ cell proliferative state. Interrogation of transcription factor pathways indicates that IL-9-mediated activation of STAT1 and STAT4 may contribute to the superior phenotype of IL-9-signaling CAR T cells, providing a promising therapeutic strategy for targeting solid cancers.
    Keywords:  CAR T cells; IL-9; IL-9R; T cell dysfunction; T cell memory; cancer immunotherapy; cytokine receptors; cytokines; solid tumors
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.021
  25. Front Med (Lausanne). 2025 ;12 1732925
    Editorial: Future directions and current trends in cellular therapies.
    Ruxandra Irimia, Eleni Gavriilaki.
      
    Keywords:  CAR-T cell therapy; allogeneic stem cell transplantation; autologous stem cell transplantation; engineered immunity; stem cell transplant
    DOI:  https://doi.org/10.3389/fmed.2025.1732925
  26. Cytotherapy. 2025 Nov 01. pii: S1465-3249(25)00871-0. [Epub ahead of print]28(1): 101995
    Crowdfunding for cellular and gene therapy products.
    Jeremy Snyder.
       BACKGROUND AIMS: Cellular and gene therapy products provide hope to people experiencing debilitating diseases. Many people seek to access these products ahead of regulatory approval through clinical trials, exceptional access programs, and direct to consumer purchases. Even when regulatory approval has been given, these products can cost millions of dollars in direct and indirect expenses. This study examines how crowdfunding campaigns are being used to pay for United States Federal Drug Administration (FDA) approved cellular and gene therapy products.
    METHODS: The author searched the GoFundMe crowdfunding platform for 43 FDA-approved cellular and gene therapy products. The campaign title, campaign text, funding requested, funding pledged, number of donations, campaign start date, and campaign location was collected for each campaign. Total 529 campaigns were identified and 322 included for content analysis as seeking funding to pay for the direct or indirect costs of accessing FDA-approved cellular or gene therapy products.
    RESULTS: Crowdfunding campaigns for 17 FDA-approved cellular and gene therapy products were identified. Total 322 campaigns raised $8,997,107.19 (median $3675.04) from 154,230 (72.5) donations out of $334,723,452.76 ($184,250) requested. Two campaigns raised 39.2% of all funds and 10 raised 64.8% of all funds. Fundraising goals ranged from $1.11-$12,000,000. The 4th and 5th largest quintiles of fundraising requests were over $1,200,000.
    CONCLUSIONS: The median fundraising goal and funding received were larger than has been found in other studies of medical crowdfunding. Differences in fundraising goals and donations suggest inequities in insurance coverage and the ability to access cellular and gene therapy products.
    Keywords:  access; affordability; cell therapies; crowdfunding; equity; gene therapies
    DOI:  https://doi.org/10.1016/j.jcyt.2025.10.005
  27. ACR Open Rheumatol. 2025 Dec;7(12): e70139
    A Guide for Initiating and Managing Chimeric Antigen Receptor T Cell Therapy Clinical Trials in Autoimmune Rheumatic Diseases.
    Lupus Clinical Investigators Network
      Chimeric antigen receptor (CAR) T-cell therapy, long transformative in oncology, is now rapidly emerging as a frontier in autoimmune rheumatic diseases, particularly systemic lupus erythematosus (SLE), driven by accumulating evidence of deep B-cell depletion, immune "resetting," and durable drug-free remission in early studies, yet its translation into rheumatology demands mastery of formidable logistical, regulatory, clinical, and ethical complexities that span institutional readiness, multidisciplinary team formation, stringent regulatory compliance, sophisticated operational workflows, comprehensive patient selection and education, meticulous clinical management of both classical toxicities (CRS, ICANS, ICAHT) and autoimmune-specific reactions such as LICATS, robust financial and resource planning, and long-term follow-up extending 15 years or more; successful implementation requires coordinated expertise among rheumatologists, hematologist-oncologists, cellular therapy units, pharmacists, research coordinators, and ICU-capable teams, all embedded within disciplined communication structures, harmonized SOPs, validated PROs, biorepository governance frameworks, and adherence to national and international cellular therapy standards; in parallel, investigators must anticipate bottlenecks such as apheresis access, manufacturing slot scarcity, competing trial enrollment, fluctuating SLE phenotypes, and heterogeneity-driven signal variability, while sustaining patient engagement over years through education, navigation support, and transparent risk/benefit communication; finally, collaboration with industry partners, clinical trial networks, and patient-advocacy organizations is essential for overcoming operational barriers, securing financial sustainability, and ensuring ethical stewardship, so that CAR T-cell clinical trials in autoimmunity can be executed safely, rigorously, and with maximal therapeutic promise for patients.
    DOI:  https://doi.org/10.1002/acr2.70139
  28. bioRxiv. 2025 Oct 24. pii: 2025.10.23.684261. [Epub ahead of print]
    Immunometabolic determinants of long-term response in leukemia patients receiving CD19 CAR T cell therapy.
    Lior Goldberg, Eric R Haas, Jiaqi Wu, Bryan Garcia, Ryan Urak, Vibhuti Vyas, Ruby Espinosa, Tamara Munoz, Shirley Bierkatz, Khyatiben V Pathak, Nathaniel P Hansen, Patrick Pirrotte, Jyotsana Singhal, James L Figarola, Ricardo Zerda Noriega, Zhuo Li, Dasol Wi, Erin Tanaka, Ramon Klein Geltink, Min-Hsuan Chen, Xiwei Wu, Jamie R Wagner, Jinny Paul, Mary C Clark, Dat Ngo, Ibrahim Aldoss, Stephen J Forman, Xiuli Wang.
      Although most patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) receiving CD19-targeted chimeric antigen receptor (CAR) T cell therapy achieve remission, loss of CAR T cell functionality and subsequent relapse remains an unmet therapeutic need. We applied an integrative approach to study the immunometabolism of pre- and post-infusion CD19-CAR T cells of patients with relapsed/refractory B-ALL. Pre-infusion CAR T cells of long-term responders (LTR) had increased oxidative phosphorylation, fatty acid oxidation, and pentose phosphate pathway activities, higher mitochondrial mass, tighter cristae, and lower mTOR expression compared to products of short-term responders. Post-infusion CAR T cells in bone marrow (BM) of LTR had high immunometabolic plasticity and mTOR-pS6 expression supported by the BM microenvironment. Transient inhibition of mTOR during manufacture induced metabolic reprogramming and enhanced anti-tumor activity of CAR T cells. Our findings provide insight into immunometabolic determinants of long-term response and suggest a therapeutic strategy to improve long-term remission.
    DOI:  https://doi.org/10.1101/2025.10.23.684261
  29. Br J Haematol. 2025 Nov 25.
    Position statement from the British Society of Blood and Marrow Transplantation and Cellular Therapy on insertional oncogenesis in gene-engineered advanced cell therapy products for treatment of haematological disorders.
    S Ghorashian, R Sanderson, J Lee, A Black, M A O'Reilly, D I Marks, J Snowden, D Richardson, E Olavarria.
      
    Keywords:  CAR T cell therapy; cell therapy; gene therapy
    DOI:  https://doi.org/10.1111/bjh.70247
  30. Stem Cell Res Ther. 2025 Nov 29.
    Scaffold-free cell sheet therapies: clinical advances, global approval landscapes, and strategic directions to address regenerative medicine barriers.
    An Lin, Shengmeng Yuan, Cheng Liang, Fangjun Huo, Chao Yang, Weidong Tian.
      Cell sheet therapy has emerged as a transformative technology in regenerative medicine, providing scaffold-free constructs that preserve cell-cell junctions and extracellular matrix components. Compared with traditional cell delivery methods, cell sheets enable improved engraftment, survival, and integration after transplantation. Recent years have witnessed remarkable progress in clinical translation, with several products approved in Japan, the United States, and South Korea. This review summarizes the current landscape of cell sheet therapies approved worldwide, focusing on their fabrication technologies, cell sources, and clinical indications. We highlight representative products such as JACE®, Nepic®, Ocural®, JACEMIN®, HeartSheet®, Epicel®, Holoderm®, Kaloderm®, and ZEVASKYN™, emphasizing their technological foundations and regulatory trajectories. Advances in temperature-responsive culture surfaces, closed culture devices, and automated sheet manipulation have facilitated large-scale and standardized manufacturing. Furthermore, the establishment of cell banks, donor eligibility screening, and Good Manufacturing Practice (GMP)-compliant processes ensure product consistency and safety. In parallel, regulatory frameworks in Japan, the United States, and South Korea have shaped the development paths of autologous and allogeneic products, with different strategies for approval, reimbursement, and long-term monitoring. Cell sheet-based regenerative therapies have already demonstrated clinical and commercial viability, offering novel treatment options for burns, ocular diseases, vitiligo, and cardiac conditions. Despite encouraging outcomes, challenges remain in vascularization, large-scale production, cost-effectiveness, and equitable patient access. Continued progress will depend on addressing biological limitations, optimizing manufacturing logistics, and harmonizing international regulations. Collectively, cell sheet therapies represent a pivotal step toward broader adoption of regenerative medicine in routine clinical practice.
    Keywords:  Cell sheet therapy; Clinical translation; Global landscape; Regenerative medicine; Regulatory approval; Tissue engineering
    DOI:  https://doi.org/10.1186/s13287-025-04818-0
  31. Transplant Cell Ther. 2025 Nov 26. pii: S2666-6367(25)01591-X. [Epub ahead of print]
    Genetic findings of potential donor origin in cells used for cell and gene therapy: Recommendations from the World Marrow Donor Association (WMDA).
    Angharad Pryce, Meghann Cody, Abeer Madbouly, Eefke van Eerden, Laura L Machin, Heather E Stefanski, Darren Hatton, Chloe Anthias, Diana Hernandez, Sarah Bannon, Thilo Mengling, David S Allan.
      Manufacturing cell and gene therapy products derived from donor cells may involve genetic and other testing that identifies unexpected findings of potential donor origin. Testing may be done to assess the safety of the product or manufacturing process, assess gene transduction efficiency or aspects of cell expansion, and may also be performed in recipients of cell and gene therapy products following infusion to monitor the effects of treatment. Tests that could identify unexpected findings in donor cells include chromosomal karyotyping, targeted tests for specific gene mutations or rearrangements, large gene panels or whole genome sequencing which could detect mutations or cytogenetic abnormalities of relevance to donors. Deciphering whether variants are of donor origin as opposed to introduced via manufacturing processes is key, as is having a framework for protecting donors that includes procedures for ensuring robust donor consent and appropriate pathways for disclosure of clinically relevant and actionable results. Building upon recent recommendations from the World Marrow Donor Association (WMDA) regarding unexpected findings of potential donor origin following allogeneic hematopoietic cell transplantation, an expert group was assembled to review available evidence and develop a framework to apply to healthy volunteer donors who provide cells for manufacturing of allogeneic cell and gene therapy products. These guidelines aim to provide recommendations for pre-donation consenting, and a framework for informing and managing care of donors when findings of potential donor origin are identified. Since many cellular therapies remain under development, donors who provide cells for any aspect of research and development of CGT products require special consideration. Realizing that cellular therapy may involve commercial entities and donors that are recruited within conventional stem cell registries or through other mechanisms, we have made suggestions on how recommendations can be adapted.
    Keywords:  cell and gene therapy; ethics; genetic findings; stem cell donor; transplant
    DOI:  https://doi.org/10.1016/j.jtct.2025.11.016
  32. Trends Pharmacol Sci. 2025 Nov 25. pii: S0165-6147(25)00241-X. [Epub ahead of print]
    Autologous, allogeneic, in vivo CAR for autoimmune diseases.
    Yan-Ruide Li, Lili Yang.
      Chimeric antigen receptor (CAR)-based therapies are emerging for autoimmune diseases (ADs). Early-phase clinical studies in systemic lupus erythematosus (SLE) show encouraging results using autologous, allogeneic, and in vivo CAR T-cell (CAR-T) strategies. This forum compares these three strategies, highlighting clinical design, safety, and efficacy, and explores the translational challenges of in vivo CAR engineering in ADs.
    Keywords:  CAR-T cell therapy; allogeneic; autoimmune disease; autologous; clinical landscape; in vivo CAR engineering
    DOI:  https://doi.org/10.1016/j.tips.2025.11.001
  33. Stem Cell Res Ther. 2025 Nov 26. 16(1): 661
    Stem cell revolution: bridging the gap between research and clinical application.
    Fengfeng Li, Chen Fu.
      Stem cells are characterized by their capacity for self-renewal and their potential for multi-directional differentiation, enabling them to develop into various functional tissues and organs under specific conditions. Their applications hold considerable promise, and the market for stem cell products is progressively expanding. Internationally, several stem cell products have received approval for market release; however, in China, the field remains largely undeveloped, presenting substantial opportunities for growth. Recent years have witnessed significant advancements in stem cell research, driven by improvements in national policies, regulatory frameworks, and ongoing technological innovations. This progress has resulted in notable breakthroughs in basic science, as well as substantial advancements in clinical trials and industrial applications. Compared to previous decades, stem cell therapies in China have experienced remarkable progress, with numerous companies advancing to the clinical research phase, indicating a robust overall development trajectory. Nonetheless, the considerable variability in the sources, types, and preparation processes of stem cell products contributes to the complexity of their therapeutic mechanisms and in vivo activities, which are more intricate than those of traditional pharmaceuticals. Consequently, stem cell therapies encounter several challenges in drug development, including issues related to safety, induction efficiency, the exploration of clinical translation processes, and elevated research and development costs, all of which may hinder the advancement of stem cell therapies. Nevertheless, numerous companies and research institutions are actively engaged in promoting progress within the stem cell domain. It is anticipated that, as the stem cell sector continues to evolve, these challenges will be addressed, ultimately serving as a crucial catalyst for meeting various unmet clinical needs and effecting transformative changes in human healthcare and other sectors.
    Keywords:  Clinical application; Development; Stem cells; Therapy
    DOI:  https://doi.org/10.1186/s13287-025-04784-7
  34. J Inflamm Res. 2025 ;18 16273-16291
    Single-Cell Transcriptomics Reveals CCL3+ Classical Monocyte Subset Linked to Autoimmune Pathogenesis.
    Heng Xu, Kai Yuan, Guangyao Chen, Jing Luo, Aimin Yan, Huaijuan Huang, Xinbo Yu, Qingwen Tao, Guangrui Huang, Anlong Xu.
       Objective: The diverse differentiation states of mononuclear macrophages are closely associated with the pathogenesis of autoimmune diseases. This study integrates single-cell RNA sequencing data from six autoimmune diseases to characterize shared and disease-specific alterations in mononuclear macrophages, with the aim of enhancing our understanding of the immune landscape in autoimmune diseases and refining clinical treatment strategies.
    Methods: We collected single-cell RNA-sequencing data of autoimmune diseases including primary Sjogren's syndrome (pSS), Behçet's disease (BD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), relapsing-remitting multiple sclerosis (RRMS), and systemic lupus erythematosus (SLE). We performed scRNA-seq analysis on 350,043 peripheral blood immune cells from autoimmune diseases patients and healthy controls, followed by validations with flow cytometry, immunohistochemical staining, and immunofluorescence.
    Results: Fifteen mononuclear phagocyte subpopulations were clustered from peripheral blood mononuclear cells (PBMCs), we identified a new subpopulation named CCL3+ classical monocytes (cMo) that is co-amplified in multiple autoimmune diseases (BD, JDM, pSS, RRMS, SLE). The CCL3+ cMo cells are characterized by high M1-like score, exhibiting strong inflammatory characteristics and high chemotaxis toward other monocytes. In addition, CCL3+ cMo cells upregulated antigen presentation-related signaling pathways, and the cytotoxic CD8+ T or memory CD8+ T cells were strongly perturbed by their signaling crosstalk.
    Conclusion: This study delineates a comprehensive landscape of mononuclear phagocyte heterogeneity in autoimmune diseases and reveals CCL3+ cMo as a commonly amplified immune subset associated with multiple autoimmune diseases. These findings highlight its potential role in disease mechanisms and nominate CCL3+ cMo as a candidate therapeutic target.
    Keywords:  CCL3+ classical monocytes; autoimmune diseases; mononuclear phagocytes; primary Sjogren’s syndrome; single-cell RNA sequencing
    DOI:  https://doi.org/10.2147/JIR.S547283
  35. Cancer Lett. 2025 Nov 25. pii: S0304-3835(25)00746-3. [Epub ahead of print] 218174
    Peptide-Drug Conjugates in Tumor Therapy: Current Advances and Future Perspectives.
    Huiyuan Jin, Peizhen Yang, Huan Min, Jian Song, Yingqiu Qi.
      As a novel targeted therapeutic approach, peptide-drug conjugates (PDCs) integrate peptides, drug payloads, and linkers to establish an efficient drug delivery system. In addition to retaining the selective advantage inherent in targeted therapy, this modular approach confers a spectrum of therapeutic capabilities, such as enhanced drug targeting, controlled drug release, improved bioavailability, and reduced systemic toxicity and immunogenicity. Moreover, by leveraging their active tumor-targeting capacity and stimulus-responsive drug release properties, PDCs could induce immunogenic cell death and synergistically reprogram the immunosuppressive tumor microenvironment, thereby enabling precise intervention in tumors. This strategy exhibits a favorable efficacy-to-toxicity profile and remarkable potential in immunotherapy, ultimately leading to an improved therapeutic index against tumors. Currently, the PDC Lutathera has been approved by the U.S. FDA for the treatment of cancer, and several other PDCs candidates are currently under investigation in clinical trials. This review provides a systematic summary of the recent research progress in PDCs for cancer treatment over the past five years, focusing on the molecular design strategies based on peptides, linkers, and drugs, as well as recent technological breakthroughs, such as PDCs constructed using nano-strategies, and the applications of PDCs in monotherapy and combination therapy. Additionally, the therapeutic advantages, existing challenges and future clinical applications of PDCs are also discussed. This review tries to offer critical insights into PDCs and provides new perspectives for the future development of antitumor therapies.
    Keywords:  Antitumor Therapy; Drugs; Linker; Nano-strategy; PDCs; Peptide
    DOI:  https://doi.org/10.1016/j.canlet.2025.218174
  36. Haematologica. 2025 Nov 27.
    Hematopoietic cell transplantation after CD19-directed CAR T-cell therapy for remission consolidation or relapse treatment in pediatric acute lymphoblastic leukemia.
    Regina M Myers, Yimei Li, Hongyan Liu, Sarah Mumanachit, Lei Wang, Allison Barz Leahy, Lucy E Cain, Amanda M DiNofia, Caroline Diorio, Jason L Freedman, Stephen P Hunger, Shannon L Maude, Susan E McClory, Susan R Rheingold, Sarah K Tasian, Lisa Wray, Timothy S Olson, Stephan A Grupp, Nancy J Bunin, Alix E Seif, Caitlin W Elgarten.
      Relapse of B-cell acute lymphoblastic leukemia (B-ALL) after CD19-targeted chimeric antigen receptor T-cell therapy (CAR19) remains a substantial challenge. Allogeneic hematopoietic cell transplant (HCT) represents an approach for both post-CAR19 relapse prevention and relapse therapy. However, a paucity of detailed HCT safety and outcome data exists in this population. We conducted a retrospective review of 47 children and young adults with B-ALL who underwent first HCT for post-CAR19 remission consolidation (preemptive cohort, n=26) or relapse therapy (relapse cohort, n=21). With a median follow-up of 4.1 years, 3-year disease-free survival was 90% in the preemptive cohort and 64% in the relapse cohort. Overall survival, cumulative incidence of relapse, and non-relapse mortality at 3 years were 95%, 5%, and 5% in the preemptive cohort, respectively, and 67%, 20%, and 15% in the relapse cohort, respectively. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) was 14% in the preemptive and 19% in the relapse cohort. Chronic GVHD developed in 24% and 14% of patients alive at 100 days in the preemptive and relapse cohorts, respectively. Veno-occlusive disease/sinusoidal obstruction syndrome was the most common non-GVHD severe organ toxicity, with a cumulative incidence of 10% in the preemptive and 31% in the relapse cohort. In appropriate patients, HCT can be an effective strategy for attaining durable B-ALL remission when used preemptively post-CAR19 or as part of post-CAR19 relapse salvage therapy.
    DOI:  https://doi.org/10.3324/haematol.2025.288303
  37. MAbs. 2025 Dec;17(1): 2584935
    Energy-based generative models for monoclonal antibodies.
    Paul Pereira, Hervé Minoux, Aleksandra M Walczak, Thierry Mora.
      Since the approval of the first antibody drug in 1986, a total of 162 antibodies have been approved for a wide range of therapeutic areas, including cancer, autoimmune, infectious, or cardiovascular diseases. Despite advances in biotechnology that accelerated the development of antibody drugs, the drug discovery process for this modality remains lengthy and costly, requiring multiple rounds of optimizations before a drug candidate can progress to preclinical and clinical trials. This multi-optimization problem involves increasing the affinity of the antibody to the target antigen while refining additional biophysical properties that are essential to drug development such as solubility, thermostability or aggregation propensity. Additionally, antibodies that resemble natural human antibodies are particularly desirable, as they are likely to offer improved profiles in terms of safety, efficacy, and reduced immunogenicity, further supporting their therapeutic potential. In this article, we explore the use of energy-based generative models to optimize a candidate monoclonal antibody. We identify tradeoffs when optimizing for multiple properties, focusing on solubility, humanness and affinity and use the generative model we develop to generate candidate antibodies that lie on optimal Pareto fronts with respect to these properties.
    Keywords:  AI models; Computational design; multi-objective optimization
    DOI:  https://doi.org/10.1080/19420862.2025.2584935
  38. Immunology. 2025 Nov 25.
    Smart Biomaterials as Immunomodulators in Cancer Therapy.
    Amit Sharma, Bhavin Parekh, Vinay Patil, Renuka Jyothi S, Priya Priyadarshini Nayak, Bethanney Janney J, Gurjant Singh, Hasnaawei Al-Shaker.
      The integration of immunotherapy into oncology has transformed cancer treatment by harnessing the immune system to selectively eliminate malignant cells. Despite remarkable advances, conventional immunotherapies remain constrained by limited response rates, tumour heterogeneity and severe systemic toxicities, including cytokine release syndrome and autoimmunity. To address these challenges, smart biomaterials have emerged as next-generation platforms capable of modulating immune responses with high precision. By enabling localised and controlled release of therapeutic agents, these systems enhance drug retention at tumour sites, reduce systemic exposure and minimise off-target effects. Engineered biomaterials, including liposomes, polymeric nanoparticles, hydrogels, microneedle arrays and implantable scaffolds, provide spatial and temporal control over the delivery of cytokines, checkpoint inhibitors, engineered T cells and cancer vaccines. These platforms improve pharmacokinetics and biodistribution while also facilitating crosstalk with the tumour microenvironment, thereby enhancing therapeutic potency and reducing adverse effects. Recent innovations such as lipid nanoparticles for mRNA-based vaccines and reactive oxygen species-responsive hydrogels highlight the translational potential of these materials, with several formulations now advancing into clinical trials. This review synthesises current progress in the design and application of smart biomaterials as immunomodulators, emphasising their capacity to overcome major clinical barriers in cancer immunotherapy. Key areas of focus include strategies to improve immune cell recruitment, enhance antigen presentation and integrate multimodal therapies. By bridging materials science and immuno-oncology, smart biomaterials represent a transformative approach to achieving safer, more durable and personalised cancer treatments. Continued innovation in this field is poised to reshape the therapeutic landscape and accelerate clinical translation.
    Keywords:  cancer immunotherapy; immune modulation; localised drug delivery; smart biomaterials; tumour microenvironment
    DOI:  https://doi.org/10.1111/imm.70068
  39. bioRxiv. 2025 Oct 17. pii: 2025.10.17.683125. [Epub ahead of print]
    Anionic lipids modulate mRNA-lipid nanoparticle immunogenicity and confer protection in a mouse model of multiple sclerosis.
    Jilian R Melamed, Jenna Muscat-Rivera, Michael Kegel, Lesley S Chaboub, Roxanne Perez-Tremble, Navdeep S Bhalla, Houping Ni, Honghong Sun, Drew Weissman.
      The modularity of mRNA-lipid nanoparticle (mRNA-LNP) platforms has enabled their rapid adaptation from infectious disease vaccines to emerging applications in immune-mediated disorders. However, extending mRNA-LNPs to autoimmune and inflammatory diseases requires precise control over immune cell targeting and immunogenicity. Here, we systematically investigate how incorporating anionic lipids into LNPs modulates both immune cell tropism and innate immune activation. Using a library of 40 distinct LNP formulations, we demonstrate that anionic lipids enhance mRNA delivery to splenic dendritic cells, reduce early cellular markers of adjuvant activity and tune cytokine responses in a lipid-dependent manner. We identify formulations that retain pro-inflammatory adjuvant activity and others that promote tolerogenic responses. A lead formulation containing the anionic lipid DOPG selectively dampens innate activation and induces IL-10 production. When encoding the myelin antigen MOG35-55, this LNP suppresses disease in a mouse model of multiple sclerosis, reducing neuroinflammation, T cell infiltration, and maintaining myelin morphology. These findings establish a framework for designing immune-targeted mRNA-LNPs with tunable immunogenicity and promote the development of antigen-specific tolerizing immunotherapies for autoimmune disease.
    DOI:  https://doi.org/10.1101/2025.10.17.683125
  40. Nutrients. 2025 Nov 17. pii: 3591. [Epub ahead of print]17(22):
    Precision Delivery of Active Compounds from Edible and Medicinal Plants via Gut Microbiota Targeting: A New Paradigm for Cancer Immunotherapy.
    Lu Peng, Long Wang, Yingtong Zhao, Peng Yu, Hongmei Yang.
      The immune system plays a pivotal role in the progression of tumors. Recent advancements in immunotherapies, notably CAR-T cell therapy and checkpoint inhibitors, have markedly improved clinical outcomes. However, a significant proportion of patients continue to experience treatment resistance, posing a persistent and formidable challenge. The gut microbiota has been established as a critical determinant of responses to immunotherapy. Enriched with bioactive components such as polysaccharides, (poly)phenols, and flavonoids, edible and medicinal plants (EMPs) exhibit significant potential to enhance host immunity by reshaping the gut microbiota, increasing the production of microbiota-derived metabolites (e.g., short-chain fatty acids), strengthening the intestinal barrier, and reducing intestinal inflammation. The bioactive components derived from EMPs not only demonstrate substantial pharmacological activities but also serve dual roles: functioning either as inherent drug carriers or as effective modifiers for existing carrier systems, which facilitates targeted drug delivery to specific sites such as the liver and intestinal, enhancing therapeutic efficacy. In summary, this review highlights that bioactive components from EMPs hold significant promise for enhancing cancer immunotherapy by modulating complex interactions with the gut microbiota.
    Keywords:  bioactive components; cancer immunotherapy; drug carriers; edible and medicinal plants; gut microbiota
    DOI:  https://doi.org/10.3390/nu17223591
  41. Front Immunol. 2025 ;16 1710733
    Gut microbiota-derived metabolites modulate Treg/Th17 balance: novel therapeutic targets in autoimmune diseases.
    Guolin Li, Yu Xiong, Zhimin Li, Qin Yu, Shiran Li, Jingxian Xie, Siyu Zeng, Dongke Yu, Yong Yang, Jiangping Yu.
      Dysregulation of the homeostasis between regulatory T cell (Treg) and T helper 17 cell (Th17) is increasingly recognized as a pivotal mechanism in the pathogenesis of autoimmune diseases. Emerging evidence indicates that gut microbiota-derived metabolites, including short-chain fatty acids, secondary bile acids, and aromatic metabolites, modulate Treg/Th17 balance by shaping immune cell differentiation and function, thereby revealing novel therapeutic opportunities. This Review synthesizes recent clinical and preclinical findings on the influence of microbial communities and their metabolites on Treg/Th17 dynamics and examines the underlying mechanisms in representative autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, Graves' disease, autoimmune hepatitis, and myasthenia gravis. We critically evaluate current microbiome-targeted interventions and discuss their translational potential, highlighting both promises and challenges. Finally, we outline priorities for future research, focusing on multi-omic integration, the development of individualized therapeutic strategies, and rigorous clinical evaluation, to facilitate the development of safe and effective microbiota-based therapies for autoimmune diseases.
    Keywords:  Treg/Th17 balance; autoimmune diseases; gut microbiota; immune regulation; microbial metabolites; therapeutic targets
    DOI:  https://doi.org/10.3389/fimmu.2025.1710733
  42. Lupus Sci Med. 2025 Nov 28. pii: e001765. [Epub ahead of print]12(2):
    Prevalence and predictive factors associated with sustained remission in SLE: a systematic review.
    Rym Abida, Anisur Rahman.
       OBJECTIVE: The question of sustained remission in SLE has been highlighted recently following data published on the use of chimeric antigen receptor-T cell therapy in SLE. With the review, we wanted to investigate the prevalence of sustained remission of 2 years or more in SLE with the current available treatments and to assess the predictive factors associated with this state.
    METHODS: A systematic review of Embase via Ovid and Medline via Ovid was performed. We considered articles of adult patients with SLE that report the prevalence and/or the predictive factors of sustained remission in SLE. We considered that the latter state is sustained if it was for 2 years or more.
    RESULTS: 20 studies were included for final review. The definition of remission was different between studies, and most authors considered different types of remission based on the serological activity and the current therapy. The prevalence of long-term remission was different across studies depending on the definition used. It ranged from 0.3% to 63%. Older age at diagnosis, lower disease activity at baseline and the absence of renal disease involvement were the most commonly found factors likely associated with sustained remission.
    CONCLUSION: Long-term remission is an achievable state in SLE with current treatment. Studies report a striking heterogeneity in the current prevalences. This is likely to be caused by the lack of objective measures to confirm the state of sustained remission in SLE.
    Keywords:  Lupus Erythematosus, Systemic; Prevalence; Risk Factors
    DOI:  https://doi.org/10.1136/lupus-2025-001765
  43. bioRxiv. 2025 Oct 06. pii: 2025.10.05.680548. [Epub ahead of print]
    Optimization of velocity receptor transduction in CAR T cells.
    Xinyun Jiang, Vasco Queiroga, Eban A Hanna, Denis Wirtz.
      Limited infiltration capacity significantly limits the effectiveness of chimeric antigen receptor (CAR) T cells for solid tumors. We have recently developed a large family of highly modular synthetic cytokine receptors termed velocity receptors (VRs), capable of binding key inflammatory cytokines, such as IL5, IL8, and TNFα, which drive CAR T cells into an elevated motility state. These new CAR T cells sense and amplify these autocrine secreted cytokines, thereby maintaining a self-propelled, high migratory state, facilitating penetration into dense tumor cores. In this study, we systematically evaluated key factors influencing VR transduction in order to improve their stable integration and expression. We established a dual-fluorescence reporter system to allow simultaneous monitoring of both VR and CAR constructs, and while evaluating modifications to the vector construct and generating standardized infectious unit (IFU) curves under various conditions. Our results demonstrate that the attempt to reduce overall lentiviral vector size by eliminating non coding sections upstream of the central polypurine tract (cPPT) do not yield better transduction efficiency, though it is unclear if the effect is due to viral production or integration impairment. We also observed a log-linear relationship between viral dose and transduction efficiency for a subset of VRs previously tested in various mouse models of human cancer, with VR5αIL8 and VR5αTNFα VRs consistently outperforming VR5αIL5 and V5 (full length native IL5 receptor). Overall, these findings establish an optimized and reproducible framework that offers valuable guidance for the future development and functional study of VR-CAR T cells in cellular therapies for solid tumors.
    DOI:  https://doi.org/10.1101/2025.10.05.680548
  44. Pharmaceut Med. 2025 Nov 26.
    Joint Clinical Assessments in Europe: Implications for Market Access, Reimbursement, and National HTA Alignment.
    Amit Dang, Sameera Tak.
      The Joint Clinical Assessment is a crucial development under the European Union Health Technology Assessment Regulation (EU HTAR, 2021/2282), aimed at standardizing clinical assessments across the Member States. This review explores the opportunities, challenges, and future actions for Joint Clinical Assessment implementation, particularly emphasizing methodological, regulatory, and stakeholder considerations. With the evolution of the European healthcare landscape from decentralized health technology assessment processes to a more streamlined framework, the Joint Clinical Assessment aims to enhance efficiency, reduce duplication, and expedite patient access to novel therapies while maintaining national reimbursement autonomy. Central to the Joint Clinical Assessment is the Patients, Interventions, Comparator, Outcomes (PICO) framework, which guides evidence generation but varies across countries, creating uncertainty and requiring early transparent agreement. Challenges to Joint Clinical Assessment implementation include tight timelines, misalignment with national processes, autonomy of national health technology assessment agencies over reimbursement, and the uncertainty about real-world evidence, specifically for oncology and rare diseases. Orphan drugs, gene therapies, and vaccines present unique concerns owing to smaller patient populations, limited data from clinical trials, or ethical restrictions in conducting randomized controlled trials. These concerns can be overcome with scientifically robust alternatives, such as adaptive assessment approaches enabling staged assessments and updates with evolving data. Early patient involvement through advisory panels, surveys, and feedback loops in processes, such as scoping, assessment, and evidence-generation phases can improve transparency and integration of patient preferences while reflecting real-world treatment needs in clinical evaluations. The long-term success of the Joint Clinical Assessment will depend on both standardisation and flexibility, supported by stakeholder collaboration and robust methodological guidance.
    DOI:  https://doi.org/10.1007/s40290-025-00594-7
  45. Cytotherapy. 2025 Oct 25. pii: S1465-3249(25)00872-2. [Epub ahead of print]28(1): 101994
    Single-cell transcriptomics reveals dynamics of natural killer cell expansion in a feeder cell-free culture of peripheral blood mononuclear cells-implications for immunotherapy.
    Brian Ladd, Markella Zacharouli, Per-Henrik Holmqvist, Stefanie Renken, Pontus Blomberg, Véronique Chotteau.
      Natural killer (NK) cell therapies hold great promise for cancer treatment; however, donor-to-donor heterogeneity in the ex vivo expansion process remains a critical bottleneck in their supply. This study aimed to identify factors influencing donor variability in a 2-week-long ex vivo NK cell expansion from peripheral blood mononuclear cells, analyzed across three donors. Single-cell transcriptomics was applied to investigate the distribution of cell types and phenotypes, as well as trajectory inference and differential gene expression. Our results identified that several factors were associated with the variability in the final NK cell fraction and expansion, and that their influence was prevalent between culture days 3 and 8. Compared to a high final NK cell expansion, a culture with a low final NK cell expansion exhibited an upregulation of some stress and inflammatory genes and an increase in one specific subcluster of NK cells already on culture day 3. It showed a low score of CD56Bright CD16- phenotype and a high score of CD56Dim CD16+ phenotype. It also had a decreased presence of cytotoxic CD8+ Tm cells. Among the observed subclusters of CD8+ Tm cells, it exhibited a higher presence of a subcluster associated with a less differentiated and less cytotoxic phenotype, as well as a lower prevalence of a subcluster associated with chemokine and cytotoxic genes. Finally, it had a major expansion of one of the CD8+ Tm cells subclusters annotated as NK-like T cell and characterized by a high CCR5 mRNA expression, while the levels of CCL3, CCL4 and CCL5 mRNA were downregulated. The present findings point toward a potential link between CCL signaling and improved NK cell expansion performance, including possible markers for further investigations, and suggest future strategies to increase the final NK cell fraction and expansion based on donor-specific markers.
    Keywords:  NK cell culture; cell therapy; donor-to-donor heterogeneity; ex vivo expansion; scRNA-seq; single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.jcyt.2025.10.004
  46. J Pers Med. 2025 Oct 30. pii: 514. [Epub ahead of print]15(11):
    Digital Twins in Pediatric Infectious Diseases: Virtual Models for Personalized Management.
    Susanna Esposito, Beatrice Rita Campana, Hajrie Seferi, Elena Cinti, Alberto Argentiero.
      Digital twins (DTs), virtual replicas that integrate mechanistic modeling with real-time clinical data, are emerging as powerful tools in healthcare with particular promise in pediatrics, where age-dependent physiology and ethical considerations complicate infectious disease management. This narrative review examines current and potential applications of DTs across antimicrobial stewardship (AMS), diagnostics, vaccine personalization, respiratory support, and system-level preparedness. Evidence indicates that DTs can optimize antimicrobial therapy by simulating pharmacokinetics and pharmacodynamics to support individualized dosing, enable Bayesian therapeutic drug monitoring, and facilitate timely de-escalation. They also help guide intravenous-to-oral switches and treatment durations by integrating host-response markers and microbiological data, reducing unnecessary antibiotic exposure. Diagnostic applications include simulating host-pathogen interactions to improve accuracy, forecasting clinical deterioration to aid in early sepsis recognition, and differentiating between viral and bacterial illness. Immune DTs hold potential for tailoring vaccination schedules and prophylaxis to a child's unique immune profile, while hospital- and system-level DTs can simulate outbreaks, optimize patient flow, and strengthen surge preparedness. Despite these advances, implementation in routine pediatric care remains limited by challenges such as scarce pediatric datasets, fragmented data infrastructures, complex developmental physiology, ethical concerns, and uncertain regulatory frameworks. Addressing these barriers will require prospective validation, interoperable data systems, and equitable design to ensure fairness and inclusivity. If developed responsibly, DTs could redefine pediatric infectious disease management by shifting practice from reactive and population-based toward proactive, predictive, and personalized care, ultimately improving outcomes while supporting AMS and health system resilience.
    Keywords:  antimicrobial stewardship; diagnostic innovation; digital twin; pediatric infectious diseases; precision medicine
    DOI:  https://doi.org/10.3390/jpm15110514
  47. Int J Neonatal Screen. 2025 Nov 05. pii: 103. [Epub ahead of print]11(4):
    Newborn Screening for Metachromatic Leukodystrophy: A Systematic Literature Review.
    Lucia Laugwitz, Andrew Shenker, Erica F Sluys, Stéphane Pintat, David Whiteman, Charlotte Chanson.
      A systematic literature review was conducted to evaluate the emerging evidence on newborn screening (NBS) for metachromatic leukodystrophy (MLD; MIM #250100). The review focuses on (1) screening assay performance, (2) diagnostic confirmation methods and care pathways, (3) feasibility of population-based identification, and (4) the impact of early diagnosis and treatment on health outcomes. Electronic databases were searched in February 2025, and supplementary searches were performed up to 17 June 2025, for articles referencing NBS for MLD and treatments for MLD; 52 publications were eligible for inclusion. Nationwide NBS for MLD is currently carried out in Norway and large prospective pilots are running in Germany, Austria, Italy and the US. MLD meets established Wilson and Jungner criteria, with a reliable screening algorithm, established confirmatory diagnostics, and actionable care pathways. There is ongoing work to develop tools to predict disease severity and subtype. Early intervention-via gene therapy for early-onset MLD and hematopoietic stem cell transplantation (HSCT) for late-onset forms-significantly improves outcomes when initiated before symptom onset. This review provides the first comprehensive synthesis of the evidence supporting MLD for inclusion in NBS programs, underscoring the public health value of early identification and intervention.
    Keywords:  metachromatic leukodystrophy; newborn screening; systematic literature review
    DOI:  https://doi.org/10.3390/ijns11040103
  48. Open Res Eur. 2025 ;5 310
    How the First Medical Imaging Cancer Atlas EUCAIM Was Populated: The Experience of a Reference Hospital.
    Ana Penadés Blasco, Leonor Cerdá Alberich, Ana de Marco García, Carina Soler Pons, Irene Marín Radoszynski, Ricard Martínez, Damián Segrelles-Quilis, Ignacio Blanquer, Luis Martí-Bonmatí.
      The fragmentation and decentralization of medical data, including radiological imaging, continue to challenge large-scale observational research across Europe. Artificial Intelligence (AI) applied to big datasets is transforming diagnosis and treatments towards precision medicine across many diseases, yet the lack of findable, accessible, and interoperable datasets still limits model development, validation, and final clinical translation. The European Federation for Cancer Images (EUCAIM) project was launched in 2023 to address these challenges by establishing a secure centralized and federated infrastructure for the secondary use of large-scale oncological imaging and related clinical data. By consolidating fragmented datasets, EUCAIM lays the groundwork for harmonized data governance and trusted cross-border sharing. Implementing a robust documentation framework is essential to ensure regulatory compliance, safeguard data integrity, and support secure data flows across institutional and national boundaries, fully aligned with European regulations and ethical standards. EUCAIM builds on the AI for Health Imaging (AI4HI) initiative (Predictive In-silico Multiscale Analytics to support cancer personalized diagnosis and prognosis, empowered by imaging biomarkers - PRIMAGE, Accelerating the lab to market transition of AI tools for cancer management - CHAIMELEON, Novel pan-European imaging platform for artificial intelligence advances in oncology - EuCanImage, An AI Platform integrating imaging data and models, supporting precision care through prostate cancer's continuum - ProCancer-I, A multimodal AI-based toolbox and an interoperable health imaging repository for the empowerment of imaging analysis related to the diagnosis, prediction and follow-up of cancer - INCISIVE and integrates over 94 partners and more than 180 stakeholders spanning medical imaging, high performance computing, data standardization, innovation, and legal compliance. This large collaborative ecosystem reinforces EUCAIM's role as a reference for General Data Protection Regulation (GDPR) and European Health Data Space Regulation (EHDSR) adherence. This publication presents the real-world experience of integrating imaging and clinical data from a reference university hospital into the EUCAIM infrastructure. It outlines the procedural, ethical, and legal challenges encountered, and details the strategies implemented to ensure compliance with data protection regulations, including privacy, security, and ethical standards. These insights offer a practical framework for future large-scale oncological imaging datasets harmonization and AI development, contributing to scalable, reproducible, and legally compliant research that strengthens Europe's capacity for trustworthy AI-driven oncology solutions.
    Keywords:  Artificial Intelligence; cancer research; data governance; federated infrastructures; innovation; medical imaging; sustainability
    DOI:  https://doi.org/10.12688/openreseurope.21016.2
  49. Int J Technol Assess Health Care. 2025 Nov 28. 41(1): e80
    Value-based health care frameworks for the health technology assessments of "omics" technologies: an international survey.
    Tommaso Osti, Abdelrahman Taha, Eva Reviriego-Rodrigo, Roberta Pastorino, Stefania Boccia, Iñaki Gutierrez-Ibarluzea.
       BACKGROUND: Despite omics technologies gaining traction in clinical settings, particularly in oncology, challenges persist in their widespread adoption due to the pre-requisite robust evidence supporting efficacy and cost-effectiveness. This study aims to explore the experiences of organizations working in the health technology assessment (HTA) field in evaluating omics technologies, with a particular focus on the adoption and application of specific assessment frameworks.
    METHODS: We conducted a global survey to gather insights into current practices and frameworks used in HTA evaluations of omics technologies.
    RESULTS: We gathered responses from thirty-nine participants representing organizations across twenty-nine countries and five continents. Among them, 51 percent (n = 20) reported experience in evaluating omics technologies, including multi-omics tests for early disease detection, biomarker-based cancer diagnostics, and advanced genomic sequencing techniques. Only three organizations employed specific assessment frameworks: the Adelaide Health Technology Assessment Agency in Australia, the Netherlands Cancer Institute, and the Andalusian HTA Agency in Spain. These frameworks address key evaluation aspects such as analytical and clinical validity, clinical and personal utility, organizational impact, and ethical, legal, and social implications of omics technologies.
    DISCUSSION: Despite their relevance, the limited adoption of tailored frameworks highlights the need for more structured and context-specific approaches to facilitate the integration of omics technologies into healthcare systems. Collaborative efforts among stakeholders, including patients, healthcare providers, policymakers, and industry representatives, are crucial for devising robust evaluation strategies addressing the complexities of omics technologies comprehensively.
    Keywords:  assessment framework; genomics; health technology assessment; personalised medicine; precision medicine; value-based healthcare
    DOI:  https://doi.org/10.1017/S0266462325103279
  50. ACS Nano. 2025 Nov 25.
    Customizable mRNA Lipid Nanoparticles for Transfection of Primary Human T Cells.
    Rachel VanKeulen-Miller, Julia Huff, Eshan A Narasipura, Edward P Browne, Owen S Fenton.
      A central goal of genetic therapies, including RNA-based medicines, is to develop vectors that enable clinical translation for the treatment of specific cell types. T cells provide a unique opportunity for genetic medicines, particularly in their relevance to CAR-T cell therapies, autoimmune diseases, and vaccines. However, T cells are notoriously difficult to transfect, and many RNA delivery vectors are designed with model systems that may not reflect true T cell morphology, compounding the difficulty in isolating trends in particle properties that promote efficacy. Here, we use primary human T cell populations and leverage design of experiment to optimize a lipid nanoparticle (LNP)-based delivery vector for genetic therapies in T cells. In doing so, we discern key trends in LNP composition that promote better efficacy in both the uptake and expression of mRNA, namely, that high cholesterol and low polyethylene glycol (PEG) compositions aid in the efficacy of the LNPs. Informed by these trends, our novel T cell RNA Expression and Activity (TEA) LNP platform represents a strategy for transfection of primary human T cells. These TEA LNPs are investigated for their mechanism of efficacy, synergy with clinically relevant latency reversal agents, and T cell subtype affinity. Taken collectively, we not only highlight key trends in formulation design for T cells and provide a platform optimized for human T cells, but also more broadly highlight the value in leveraging genetic therapies for the treatment of disease.
    Keywords:  CD4+ T cell; design of experiment; lipid nanoparticles; mRNA; primary human T cell
    DOI:  https://doi.org/10.1021/acsnano.5c15903
  51. Nature. 2025 Nov 26.
    'They don't have symptoms': CAR-T therapies send autoimmune diseases into remission.
    Rachel Fieldhouse.
      
    Keywords:  Cancer; Diseases
    DOI:  https://doi.org/10.1038/d41586-025-03885-w
  52. Pharmacoeconomics. 2025 Nov 27.
    Innovative Contracting for Gene Therapies: Current Landscape and Perspectives on the Future of Gene Therapy Financing in the USA.
    Tyler D Wagner, Jacqlyn W Riposo, Kendra M Gould, Jonathan D Campbell, James T Kenney, Claire M Csenge, Theresa Schmidt.
       BACKGROUND AND OBJECTIVE: Over the last decade, payers in the USA have been exploring novel financing mechanisms for gene therapies (GTs). Our research objective was to assess the landscape of innovative contracts (ICs) between payers and manufacturers for GTs and identify barriers and opportunities for future contract development and implementation.
    METHODS: We used a multi-method approach including a targeted literature review and interviews. We developed a framework defining 'innovative contracts' as agreements using real-world outcomes that link to the total price paid for gene therapy, encompassing value-based pricing, outcome-based payments, and performance-based models between payers and manufacturers. We searched for published information about implementation of ICs for GTs in PubMed and government, industry, and research institutions from January 2014 to January 2025. We excluded any insights specific to ICs for non-GTs as well as those relevant to ex-US markets. We supplemented these findings with bibliographic searches. Semi-structured interviews with payers, manufacturers, and other diverse representatives from the GT financing ecosystem were conducted to validate and enrich the literature findings.
    RESULTS: The PubMed search yielded ten studies relevant to implementation of ICs. Gray literature included over 50 publications referencing active contracts, policy solutions, payer budget impact, and state Medicaid programs' innovative GT contracting. Information on manufacturer and payer contracts was publicly available for 10 of 14 gene therapies (71%). Of 16 identified GT contracts, eight used upfront payments with milestone-based rebates, two used performance-based installment payments, one offered upfront payment with a rebate or payment over 5 years, and five do not have publicly available details on the type of financial arrangement. Interviews (N = 15) suggested that barriers to ICs include a lack of mutual trust between payers and manufacturers, lack of data conveying the return on investment for innovative contracts, lack of a sufficient incentive for stakeholders to engage in contracting, perceived regulatory limitations (e.g., implications of Medicaid Best Price), and patient portability challenges. Some interviewees believed that ICs should be the standard for GTs, while others stated that ICs should only be pursued when they are expected to have a significant impact on timely patient access in the early launch period when payers are considering limited or no coverage. Interviewees indicated that policy changes may encourage future contracting negotiation and implementation.
    CONCLUSIONS: Widespread uptake of ICs will require a multi-stakeholder collaboration to overcome common barriers, as a one-size-fits-all approach is insufficient for diverse stakeholder needs. Establishing industry-wide contracting principles and practices may help bridge differences in opinions and build trust between contracting parties, allow stakeholders to share lessons from early adopters, and support efficient contracting processes that promote consistent and equitable patient access to GTs while ensuring healthcare system sustainability.
    DOI:  https://doi.org/10.1007/s40273-025-01563-3
  53. Radiographics. 2025 Dec;45(12): e250021
    Pneumonia in Immunocompromised Patients.
    Silvia Arora, Stephanie M Walker, Kristopher W Cummings, Mark M Hammer.
      Due to longer survival of patients with cancer, better recognition and understanding of immunocompromising conditions, and emerging immune-modulating therapies for malignant and nonmalignant diseases, the number of immunocompromised individuals has increased. Immunocompromised patients require complex, often individualized, evaluation and treatment of an expanded spectrum of pathogens. Pneumonia is a leading cause of death due to infectious disease in these patients, and identification of the pathogen is key to providing appropriate therapy. One important factor in evaluating an immunocompromised patient with pneumonia is the type of immunocompromise, because this will help determine the potential opportunistic agents that should be included in the differential diagnosis. Radiologists can play a vital role in the diagnosis of a wide range of pulmonary diseases associated with immunocompromise, including many opportunistic pulmonary infections, by recognizing key imaging features. The authors summarize the types of immunocompromise encountered in different clinical settings and associate these with specific opportunistic organisms, describe patterns of disease seen in patients with HIV infection with different CD4 cell counts, and describe the imaging appearance of viral and fungal infections in patients with neutropenia. ©RSNA, 2025.
    DOI:  https://doi.org/10.1148/rg.250021
  54. Curr Pharm Biotechnol. 2025 Nov 25.
    Flavonoids in Autoimmune Diseases: Mechanisms, Clinical Evidence, and Future Directions.
    Wong Simone, Shamala Salvamani, Rhun Yian Koh, Baskaran Gunasekaran.
      Autoimmune diseases remain one of the top leading causes of morbidity and mortality globally. While several first-line therapies like corticosteroids, immunosuppressants, and DMARDs are proven effective, their prolonged use often leads to drug-induced complications. Researchers are increasingly drawn to natural compounds, which are more accessible, inexpensive, and safer. Among these interventions are flavonoids, which are natural polyphenols derived from plants. The goal of autoimmune disease treatment is to. Flavonoids such as quercetin, EGCG balance effector and regulatory immune function to prevent autoimmunity. Flavonoids such as quercetin, EGCG, and silymarin exert immunomodulatory, anti-inflammatory, and antioxidant activities in this context by inhibiting NF-κB signaling and downregulating proinflammatory cytokines such as IL-6 and TNF-α. For this reason, flavonoids have gained attention as promising adjuvants to conventional therapies, especially in preclinical studies. However, robust clinical evidence remains limited, and further trials are necessary to validate these therapeutic claims. In this review, we summarize the newest research on the specific molecular mechanisms underlying flavonoids' therapeutic effects and their clinical use in certain autoimmune diseases.
    Keywords:  Autoimmune diseases; autoimmunity; flavonoids; molecular mechanisms; polyphenols; therapeutic effects.
    DOI:  https://doi.org/10.2174/0113892010399864251028081855
  55. J Biopharm Stat. 2025 Nov 27. 1-14
    M-DODII: Bayesian dose optimization design for randomized phase II study with multiple indications.
    Sasha Amdur Kravets, Ziji Yu, Rachael Liu, Jianchang Lin.
      The landscape of oncology drug development is transitioning from traditional cytotoxic chemotherapy drugs to novel agents, such as molecularly targeted therapies (MTA) or immunotherapies. Conventional dose optimization methods based on chemotherapy that assume a monotone dose-response relationship might not be ideal for the development of these novel therapies. Recognizing these limitations, the US FDA has introduced Project Optimus, an initiative aimed to reform the current paradigm of dose optimization. In addition to dose optimization, another critical objective for early phase proof-of-concept clinical trials is indication selection. However, there are limited methodologies that can address dose optimization and indication selection simultaneously. In this paper, we propose a Bayesian Dose Optimization Design for Randomized Phase II trials with Multiple Indications (M-DODII) that integrates Bayesian continuous monitoring and Bayesian pick-the-winner approach, utilizing efficacy and toxicity endpoints to inform dose selection for multiple indications simultaneously. Through simulation studies, we demonstrate that M-DODII has favorable operating characteristics with controlled selection error. Compared to other adaptive designs, M-DODII shows a lower probability of choosing a suboptimal dose, a higher probability of selecting the optimal dose, and reduced total sample size.
    Keywords:  Bayesian adaptive design; Dose optimization; Project Optimus; master protocol; phase II trial
    DOI:  https://doi.org/10.1080/10543406.2025.2589731
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