bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–12–28
67 papers selected by
Luca Bolliger, lxBio
  1. Genetic engineering and allogeneic optimization of Vδ1 γδ CAR-T cells (ADI-270) for cancer immunotherapy.
  2. Breakthrough for Anticancer Immunotherapy: Current Advances in Manufacturing Protocols of Chimeric Antigen Receptor-Based Therapies.
  3. GPCRs in CAR-T Cell Immunotherapy: Expanding the Target Landscape and Enhancing Therapeutic Efficacy.
  4. Integrating CAR-T cells with other immunotherapies for improved efficacy in cancer patients.
  5. Chimeric antigen receptor T-cell and bispecific antibody therapies for follicular lymphoma: Recent advances and future prospects.
  6. [Establishment of hPSC derived CAR-macrophage and its application in solid tumors].
  7. CAR-NK cell for gynecological cancers: immune microenvironment remodeling and immunotherapeutic strategies.
  8. Efficient and Rapid Generation of CAR-T and Cytokine-Induced Killer Cells in GMP-scalable Devices.
  9. CRS and ICANS in CAR T-cell therapy for large B-cell lymphoma.
  10. [Expert consensus on the management practice of CD19 CAR-T cell therapy for B-cell lymphoma in China (2025 edition)].
  11. Integration of a novel anti-PD-1 antibody with chimeric antigen receptor-T engineered to express interleukin-7 enhances targeting efficacy against lung cancer.
  12. A novel case of presumed immunotherapy related inflammatory orbitopathy.
  13. CAR-T for all? Barriers, facilitators, and interventions to commercial CAR T-cell therapy access.
  14. Lipid nanoparticle mediated delivery of Anti-CD19 CAR mRNA to umbilical blood cord NK cells for targeting CD19⁺ primary B-ALL cells.
  15. Synthesis of mRNA lipid nanoparticles for engineering GD2 CAR T and CAR NK cells against neuroblastoma.
  16. Personalised Rational Drug Monitoring Combined with KABP Model Health Education to Improve Adherence and Prognosis of CAR-T Cell Therapy.
  17. Adverse events and recent advances in CAR-T-cell therapy.
  18. Nanoparticle-Based Tolerogenic Vaccines: Next-Generation Strategies for Autoimmune and Allergic Disease Therapies.
  19. Scarless circular mRNA-based CAR-T cell therapy elicits superior antitumor efficacy.
  20. The race between 4-1BB- and CD28-based CD19 CAR-T products in the therapy of B-cell malignancies.
  21. Is a Functional Cure Possible in Autoimmune Diseases? Evidence from Trigger Eradication, Transplantation, and Cellular Therapies.
  22. Neural control of Immunotherapy: how Tumor-innervation shapes Anti-Tumor immune responses.
  23. Multi-omics-driven biomarker discovery in autoimmune diseases: a comprehensive review.
  24. Sequential pseudoallogeneic CAR20/22/19 T-cell therapy in patient with diffuse large B-cell lymphoma relapse after allo-HSCT: a case report.
  25. Self-Assembled Nanoparticles: Overcoming Limitations of Conventional Nanomedicines for Enhanced Tumor Therapy.
  26. Hematologic malignancies and an overview of emerging therapies for hematologic malignancies: a systematic review.
  27. Precise Control of Switchable Chimeric Antigen Receptor T Cells Allows Enhanced Safety and Less T Cell Exhaustion.
  28. Editorial: Enhancing CAR T-cell therapy with imaging.
  29. Immunotherapy-Mediated Cancer Reversion: Possibilities and Prospects.
  30. JAK/STAT in human diseases: a common axis in immunodeficiencies and hematological disorders.
  31. "Live" cell shipment-a forward-looking transport option for cryo-sensitive cell-based therapies.
  32. Reshaping multiple myeloma treatment: recent breakthroughs.
  33. Immune checkpoint TIM-3 in tumor immunotherapy.
  34. Clinical Pharmacology Perspective on Direct-To-Subcutaneous Dosing of T Cell Engagers in Oncology First-In-Human Studies.
  35. Recent Advances in Theranostic-based Extracellular Vesicles in Cancer Stem Cell Diagnosis and Therapy.
  36. Advances in lipid nanoparticle delivery systems for targeted cytokine immunotherapy in autoimmune disorders.
  37. Recent Advances in Plant-Derived Extracellular Vesicles as Nanoparticles for Cancer Drug Delivery.
  38. What to Do When Medical Evidence Can Only Be Generated Through Routine Data: An Example From Pediatric Oncology.
  39. Chemical evolution of antibody-drug conjugates focused on linker design and conjugation strategies in hematology.
  40. How Patients Can Contribute to the Assessments of Health Technologies.
  41. [Estimating the real price of CAR-T cells in France: From list price to net price].
  42. The Role of Macrophages in Cancer: From Basic Research to Clinical Applications.
  43. Anti-BCMA-CAR-IL15 natural killer cells prevent multiple myeloma growth in the bone marrow but allow subsequent emergence of extramedullary disease.
  44. Bridging the rural cancer gap: why clinical trials must include rural patients.
  45. Translating neurophysiological biomarkers into clinical tools: A psychometric blueprint illustrated with the error-related negativity.
  46. Training in cell and gene therapy manufacturing: Unmet needs and arguments for graduate medical education.
  47. Cre-dependent gene expression enables thymic development of autoreactive tumor associated antigen targeting chimeric antigen receptor T cells.
  48. AI-powered in silico twins: redefining precision medicine through simulation, personalization, and predictive healthcare.
  49. Significance and challenges of immunopharmacogenomics.
  50. Engineering Anti-Tumor Immunity: An Immunological Framework for mRNA Cancer Vaccines.
  51. Current Status of Colorectal Cancer Screenings: Tailoring Them to Mississippi's Rural Geography, Demographics, Infrastructure and Community Needs.
  52. Charters in Patient-Engaged Research: A Scoping Review of Current Evidence.
  53. [Innovation-driven pharmaceutical development and clinical advancement].
  54. Comparative Study of Regulatory Frameworks for Medicinal Products in Eurasian Economic Union and European Union.
  55. [Expert consensus on clinical application of whole nutritional oncology foods for special medical purposes (2025 edition)].
  56. From immune suppression to immunotherapy sensitization: the dual roles of circRNAs in cancer progression.
  57. CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.
  58. TCR Repertoire Analysis Quantifies Effect of Irradiation on Homeostasis of iNKT Cell Development in the Thymus of Mice.
  59. Nanovaccines in hepatocellular carcinoma: a new frontier in cancer immunotherapy.
  60. Nanocarrier-based delivery of siRNA therapeutics in rheumatoid arthritis: immune mechanisms and translational perspectives.
  61. Improving transfusion access through improved policy: a call for a less fragmented blood supply.
  62. Progression-free survival is strongly associated with overall survival in relapsed/refractory diffuse large B-cell lymphoma in the CAR T-cell era.
  63. Clinical Manifestations.
  64. The roles and clinical applications of mesenchymal stem cells and their exosomes in hematologic diseases.
  65. Mapping the Landscape: A Systematic Review of Technology Trends in Medical Education and Competency Development.
  66. Physical Inactivity Syndrome: A Risk Factor and Target for Intervention-A Narrative Review.
  67. Preferences for Non-Pharmacological Traditional Chinese Medicine in Cancer Care: A Mixed-Methods Systematic Review.
  1. J Immunother Cancer. 2025 Dec 25. pii: e013537. [Epub ahead of print]13(12):
    Genetic engineering and allogeneic optimization of Vδ1 γδ CAR-T cells (ADI-270) for cancer immunotherapy.
    Wenlong Liu, Branden S Moriarity, Beau R Webber.
      Genetic engineering has fundamentally transformed T cell-based therapies by enabling tumor targeting capability, improving their functionality, and facilitating allogeneic use. These strategies-originally developed in αβ chimeric antigen receptor (CAR)-T cells-have become increasingly established as blueprints for enhancing the function of other immune effector cells, including gamma delta (γδ) T cells. A recent study by Nishimoto et al showcased the adaptation of these engineering approaches to Vδ1 γδ T cells (ADI-270) by coexpressing a CD70-targeted CAR and a dominant-negative TGFβRII receptor (dnTGFβRII) to target CD70+ malignancies, addressing immunosuppression and host-versus-graft rejection. This commentary explores αβ T cell-derived engineering strategies applicable to γδ T cells, while also highlighting genome-editing innovations poised to advance next-generation γδ CAR-T development.
    Keywords:  Adoptive cell therapy - ACT; Chimeric antigen receptor - CAR; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-013537
  2. Antibodies (Basel). 2025 Dec 08. pii: 105. [Epub ahead of print]14(4):
    Breakthrough for Anticancer Immunotherapy: Current Advances in Manufacturing Protocols of Chimeric Antigen Receptor-Based Therapies.
    Yuxin Qian, Weiwei Ma, Xiao-Ning Xu.
      Chimeric antigen receptor (CAR)-based immunotherapy has emerged as a transformative strategy in anticancer treatment, driven by advances in CAR construct design, manufacturing platforms, and expansion to diverse immune cell types. The landmark success of CD19-targeted CAR-T cell therapy in B cell malignancies has paved the way for broader clinical applications. As of 2025, the U.S. FDA has approved multiple autologous CAR-T products, underscoring their therapeutic promise. However, challenges persist, including cytokine release syndrome (CRS), neurotoxicity, product inconsistency, and the high cost and complexity of cell manufacturing. Variations in cell source, gene delivery methods, expansion protocols, and CAR design significantly influence the safety, efficacy, and scalability of these therapies. In this review, we comprehensively examine the current advances in manufacturing protocols for CAR-modified T cells, natural killer (NK) cells, and unconventional T cell subsets, including γδ T, invariant natural killer T (iNKT), and mucosal-associated invariant T (MAIT) cells. We also highlight emerging innovations such as in vivo CAR-T generation and off-the-shelf allogeneic approaches. By integrating updated strategies with a critical evaluation of current limitations, this review aims to support the development of standardized, robust, and accessible CAR-based immunotherapies.
    Keywords:  antibody-derived scFv; cancer immunotherapy; cell manufacturing; chimeric antigen receptor (CAR)
    DOI:  https://doi.org/10.3390/antib14040105
  3. Adv Sci (Weinh). 2025 Dec 23. e17188
    GPCRs in CAR-T Cell Immunotherapy: Expanding the Target Landscape and Enhancing Therapeutic Efficacy.
    Zhuoqun Liu, Yuchen Xiao, Yamin Zhao, Lihe Dai, David J H Shih, Shikang Liang, Honglei Tian, Liu Liu, Feng Tian, Bing Liu, Lei Chang, Chao Zhang.
      Chimeric Antigen Receptor T cell (CAR-T) therapy has shown significant efficacy in treating hematologic malignancies. However, its application in solid tumors is still challenged by a scarcity of specific targets and the immunosuppressive tumor microenvironment. G protein-coupled receptors (GPCRs), due to their wide distribution and diverse signaling cascades in tumorigenesis, have emerged as promising targets for CAR-T therapy. This review systematically integrates recent advances of GPCR CAR-T therapy for cancer immunotherapy, with a particular emphasis on current targeting strategies and optimization approaches. This includes the identification of GPCRs as novel tumor-associated antigens to expand CAR-T therapeutic applications, co-expressi on of chemokine receptors to enhance tumor infiltration, and utilization ofGPCR signaling pathways to improve CAR-T cell persistence and cytotoxic efficacy. Potential future research directions include application of AI(Artificial Intelligence) to expedite the development of GPCR antibodies, creation of precision therapies targeting GPCR complexes, modulation of GPCR dimerization networks to maintain homeostasis of membrane antigen expression, employment of nanobody platform to enhance targeting specificity, and design of GPCR allosteric modulators as molecular switches for CAR-T cells. Additionally, this review also examines the application of specific antibodies and other immunotherapeutic approaches of GPCRs in oncology. Overall, this review aims to provide novel scientific and therapeutic perspectives for CAR-T cell therapy in treating mutiple types of human cancers.
    Keywords:  (GPCRs, antibody); CAR‐T therapy; cancer; immunotherapy
    DOI:  https://doi.org/10.1002/advs.202517188
  4. Curr Res Transl Med. 2025 Dec 16. pii: S2452-3186(25)00071-6. [Epub ahead of print]74(1): 103562
    Integrating CAR-T cells with other immunotherapies for improved efficacy in cancer patients.
    Gagandeep Singh, Lata Kumari, Dipansh Katoch, Arshiya Sood, Neelam Thakur, Kaalindi Singh, Umesh Kumar.
      Chimeric Antigen Receptor (CAR) T cell therapy is a novel cum innovative treatment for cancer patients, especially the ones dealing with blood cancers. However, solid tumours remain an area where this therapy is not so effective. The challenges are antigen heterogeneity, immunosuppressive tumour microenvironment, and some unaddressed serious side effects. This study details how different immunotherapeutic approaches can be used in synergy with each other to augment efficacy of CAR-T cell-based therapy and to minimize its limitations as a standalone therapy. Our review looks at how immune checkpoint inhibitors (ICIs), cytokine-based approaches, hematopoietic stem cell transplantation (HSCT), cancer vaccines, oncolytic viruses, monoclonal antibodies, NK cell therapy, tumour-infiltrating lymphocytes, bispecific T-cell engagers (BiTEs), and oncolytic viruses (OVs) could be utilized together with CAR-T cell therapy. Reducing repressive cell populations and improving antigen presentation helps OVs modify the TME, enabling better CAR-T cell penetration and persistence. Similar to this, BiTEs deal with issues of antigen loss and relapse by increasing the number of cells that target antigens and bringing in bystander T-cells. Moreover, cytokine co-delivery and changes inside cells show promise in lowering systemic toxicity and increasing continuous CAR-T activation. Early-stage clinical trials and preclinical studies show that these combinatorial strategies may work, but there are still issues like dose-dependent toxicity, exact treatment timing, and delivery restrictions. This review highlights generally the possibilities of combinational techniques to greatly increase the efficacy and safety profile of CAR-T cell treatments, thus providing insightful information for next studies and clinical uses in cancer immunotherapy.
    Keywords:  Antibodies; Cytokines; Hematopoietic stem cell transplantation; Immune checkpoint inhibitors; Oncolytic viruses
    DOI:  https://doi.org/10.1016/j.retram.2025.103562
  5. J Clin Exp Hematop. 2025 ;65(4): 253-258
    Chimeric antigen receptor T-cell and bispecific antibody therapies for follicular lymphoma: Recent advances and future prospects.
    Tsutomu Kobayashi.
      Patients with follicular lymphoma are expected to have relatively long survival due to slow disease progression, but the disease generally relapses repeatedly and remains incurable. Therefore, development of treatments for relapsed or refractory follicular lymphoma is an urgent issue. The recent introduction of cellular immunotherapy has significantly changed treatment of B-cell malignancies. Clinical development of anti-CD19 chimeric antigen receptor (CAR)-T cell therapy and CD20×CD3 bispecific antibody therapy for follicular lymphoma is underway. Multiple studies have also reported the effectiveness of CAR-T cell and bispecific antibody therapies for relapsed or refractory follicular lymphoma, and some cellular immunotherapies have already been approved in Japan. While CAR-T therapy is highly effective and may offer a functional cure in some patients, it faces challenges such as limited access, high cost, and high toxicities. Bispecific antibodies, in contrast, have relatively mild toxicities and can be widely used in patients with poor general conditions, including elderly patients, but have problems such as the burden of long-term administration. Optimal patient selection, management of unique toxicities, and high costs remain issues to be resolved for cellular immunotherapy. This review summarizes the recent clinical data on cellular immunotherapy for follicular lymphoma.
    Keywords:  bispecific antibody; chimeric antigen receptor T cell therapy; follicular lymphoma; immune therapy
    DOI:  https://doi.org/10.3960/jslrt.25050
  6. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2025 Dec;41(12): 1136-1145
    [Establishment of hPSC derived CAR-macrophage and its application in solid tumors].
    Zhangbing Liu, Xiafei Pan, Meng Ji, Minxia Ke, Yuehong Wu.
      Immunotherapy, in particular, chimeric antigen receptor T cells (CAR-T), is known as a critical approach for the treatment of patients with hematological malignancies. However, there are still huge challenges in the treatment of solid tumors. Therefore, further studies are required to the application of CAR technology to other types of immune cells, for example, CAR-macrophages (Mϕ). Human pluripotent stem cells (hPSC) can be genetically modified either by viral and non-viral methods at clonal level and efficiently differentiate into Mϕ. Therefore, hPSC provide an important platform to produce large scale of genetically engineered Mϕ. CAR engineering Mϕ can enhance the targeted recognition ability, antigen presentation function, cytokine secretion and immune cell recruitment, thereby improving its anti-tumor activity. In the current review, we summarize the current methods for differentiating hPSC into Mϕ, the engineering strategies of CAR-Mϕ, and the current antitumor applications to treat solid tumors. Meanwhile, we focus on the application prospects and challenges of hPSC-derived CAR-Mϕ in solid tumors. Furthermore, we comprehensively analyze the potential of CAR-Mϕ in the field of cell therapy, and deeply explore the unique advantages of Mϕ. This review might provide the potential ideas and new directions for future research and application.
  7. Front Immunol. 2025 ;16 1705354
    CAR-NK cell for gynecological cancers: immune microenvironment remodeling and immunotherapeutic strategies.
    Mingyao Huang, Siyang Wang, Huiyan Huang, Linze Li, Tian Wang.
      Gynecological malignancies, including ovarian, cervical, and endometrial cancers, represent a substantial global health burden, contributing significantly to morbidity and mortality among women. Despite advancements in therapeutic strategies, outcomes for many patients remain suboptimal due to challenges such as late-stage detection and resistance to standard treatments. The advent of chimeric antigen receptor (CAR)-engineered natural killer (NK) cells has introduced a cutting-edge immunotherapy option. This review provides an in-depth exploration of the development of CAR-NK cells, emphasizing their sources, design methodologies, and applications in managing gynecological cancers. It also examines current obstacles and outlines innovative strategies to improve the effectiveness and safety of CAR-NK cell-based therapies. Furthermore, we discuss prospective advancements, highlighting the importance of ongoing research and technological innovation to unlock the full potential of CAR-NK cells in the fight against gynecological cancers.
    Keywords:  CAR-NK cells; gynecological cancers; immunomodulation; immunotherapy; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1705354
  8. J Vis Exp. 2025 Dec 05.
    Efficient and Rapid Generation of CAR-T and Cytokine-Induced Killer Cells in GMP-scalable Devices.
    Giulia D'Accardio, Hieu Trong Ngo, Emilia Vigolo, Roberta Sommaggio, Pierangela Palmerini, Sara Boscarato, Elisa Cappuzzello, Antonio Rosato.
      Adoptive cell therapies (ACT) have progressed rapidly in recent years, playing a pivotal role in cancer immunotherapy and significantly influencing treatment outcomes. A critical step in cell therapy development, at both preclinical and clinical stages, is the manufacturing process. Conventional static culture methods require frequent cell manipulation and are often limited by reduced gas exchange and nutrient supply, which can compromise cell yield and phenotype. Here, we present a step-by-step, reproducible, and scalable protocol for the ex vivo expansion of two ACT products, namely Chimeric Antigen Receptor (CAR)-T and Cytokine-Induced Killer (CIK) cells, using Gas-permeable Rapid expansion (G-Rex) devices. G-Rex devices are specifically designed to enhance nutrient exchange and support high-density cultures with minimal user intervention. Among various ACT approaches, CAR-T cells have demonstrated remarkable success in treating hematological malignancies, facilitating a rapid advance from experimental research into clinical applications. In addition to CAR-T cells, CIK cells have also been widely applied in clinical trials due to their characteristic phenotype and the absence of treatment-related adverse events and Graft-versus-Host Disease (GvHD). This protocol outlines the key technical steps for both cell types, starting with the isolation and seeding of peripheral blood mononuclear cells (PBMCs). Briefly, PBMCs are stimulated with anti-CD3/CD28 antibodies, followed by lentiviral transduction to expand CAR-T cells, or with Interferon-γ (IFN-γ), anti-CD3 antibody, and Interleukin 2 (IL-2) to obtain CIK cells. Flow cytometry is employed to monitor the viability and phenotype of the cells, and functional assays are performed to confirm the therapeutic potential of the cell product and to validate the scalability of the approach. Overall, this protocol provides a practical solution for producing large numbers of effector cells in a preclinical setting, facilitating clinical application with several immune cell populations. Finally, it offers a scalable solution for high-yield effector cell manufacturing.
    DOI:  https://doi.org/10.3791/69369
  9. J Clin Exp Hematop. 2025 ;65(4): 268-275
    CRS and ICANS in CAR T-cell therapy for large B-cell lymphoma.
    Hideki Goto.
      Chimeric antigen receptor T-cell (CAR T-cell) therapy has become an established treatment option for relapsed or refractory large B-cell lymphoma, offering durable remission in some previously incurable cases. However, the effective management of immune-mediated toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remains critical to ensure safety. Treatment algorithms have been proposed based on the American Society for Transplantation and Cellular Therapy consensus grading system by the Joint Accreditation Committee of the International Society for Cellular Therapy and the European Group for Blood and Marrow Transplantation, as well as the National Comprehensive Cancer Network guidelines. Recently, early intervention to ensure that CAR T-cell therapy is performed safely has also been proposed. This review provides an update and overview of the treatment strategies for CRS and ICANS in CAR T-cell therapy for malignant lymphoma.
    Keywords:  CAR-T; chimeric antigen receptor T-cell; cytokine; cytokine release syndrome; immune effector cell-associated neurotoxicity syndrome
    DOI:  https://doi.org/10.3960/jslrt.25072
  10. Zhonghua Zhong Liu Za Zhi. 2025 Dec 23. 47(12): 1166-1178
    [Expert consensus on the management practice of CD19 CAR-T cell therapy for B-cell lymphoma in China (2025 edition)].
    National Cancer Center
      In recent years, the incidence of B-cell non-Hodgkin lymphoma (B-NHL) in China has shown a steady increase, accounting for approximately 85%-90% of all lymphomas. Although standard immunochemotherapy regimens such as R-CHOP have led to long-term remission in some patients, approximately 30%-40% still experience relapse or refractory disease, with dismal prognosis and a median survival of less than one year. For patients who fail multiple lines of therapy, conventional options such as chemotherapy, radiotherapy, or hematopoietic stem cell transplantation offer limited benefits, highlighting an urgent need for innovative treatments. Chimeric antigen receptor T-cell (CAR-T) therapy, a breakthrough form of adoptive cellular immunotherapy, modifies autologous T cells to specifically recognize and eliminate malignant B cells, thereby achieving significant survival improvement in patients with relapse or refractory B-NHL. The clinical research and clinical application of CAR-T in the treatment of hematological tumors in China are in a state of rapid development. At present, there are two targeting CD19 CAR-T cells for the treatment of B-cell lymphoma, which gradually changed the diagnosis and treatment practice of lymphoma in China. At the same time, the clinic is actively exploring and improving the whole-process management experience of CAR-T therapy in lymphoma patients. So the Lymphoma Quality Control Expert Committee of the National Cancer Quality Control Center organized experts to form the consensus through discussion and revision many times, aiming to provide better guidance for clinicians to standardize the whole-process management of CAR-T cell therapy for B-cell Lymphoma, and further improve the survival benefits of patients.
    DOI:  https://doi.org/10.3760/cma.j.cn112152-20250626-00296
  11. Life Med. 2025 Dec;4(6): lnaf035
    Integration of a novel anti-PD-1 antibody with chimeric antigen receptor-T engineered to express interleukin-7 enhances targeting efficacy against lung cancer.
    Chenxi Cheng, Lin Zhang, Jiani Cao, Xiaoyan Li, Ya Wen, Kun Liu, Tongbiao Zhao.
      Chimeric antigen receptor (CAR) T cell therapy has emerged as a promising approach for hematological malignancies, yet its efficacy in solid tumors is hindered by limited persistence. To address this, immune checkpoint inhibitors (ICIs) and cytokines have been explored as potential solutions. In this study, we developed a novel monoclonal antibody (mAb), m8A8, which exhibits high specificity for human PD-1 and effectively disrupts its ligand interactions. Furthermore, we engineered CAR-T cells to express human IL-7, resulting in enhanced anti-tumor efficacy in xenograft models. Additionally, the human-mouse chimeric antibody C8A8, derived from m8A8, was found to significantly amplify the anti-tumor activity of IL-7-engineered CAR-T cells. Our findings provide compelling evidence and a robust rationale for the synergistic integration of ICIs, cytokines, and CAR-T cell therapy in the treatment of solid tumors.
    Keywords:  chimeric antigen receptor T (CAR-T); interleukin-7 (IL-7); monoclonal antibody (MAb); programmed cell death protein 1 (PD-1)
    DOI:  https://doi.org/10.1093/lifemedi/lnaf035
  12. Orbit. 2025 Dec 22. 1-5
    A novel case of presumed immunotherapy related inflammatory orbitopathy.
    Liam C Kalas, Delia D Wang, Timothy J Sullivan.
      Chimeric antigen receptor T-cell (CAR T) therapy is an innovative form of cancer treatment, wherein a patient's own T cells are genetically modified to incorporate chimeric antigen receptors (CARs), enabling them to selectively identify and destroy cancer cells. This personalised T cell-based immunotherapy has shown promising results in treating hematological malignancies, such as certain types of relapsed or refractory leukaemia and lymphoma. However, it can also cause severe side effects, including cytokine release syndrome and neurologic toxicity, which need to be carefully managed. We present a case of a 42 year old man who developed severe periorbital inflammation as an adverse reaction to CAR T therapy for his systemic relapsed follicular lymphoma, which has not been reported in the literature before. This periorbital inflammation was presumed to be secondary to cytokine release syndrome, which is seen with CAR T treatment. He was treated with IV and oral corticosteroid, the periorbital swelling settled, and has not recurred to date.
    Keywords:  CAR T therapy; Orbital inflammation; cytokine release syndrome; immunotherapy related orbitopathy
    DOI:  https://doi.org/10.1080/01676830.2025.2601123
  13. Blood Rev. 2025 Dec 16. pii: S0268-960X(25)00103-1. [Epub ahead of print] 101358
    CAR-T for all? Barriers, facilitators, and interventions to commercial CAR T-cell therapy access.
    Sofia Kaparis, Khashayar Eshaghi, Luca Paruzzo, Jalpa Doshi, Marco Ruella, Carmen E Guerra.
      Chimeric antigen receptor T-cell (CAR-T) immunotherapy has revolutionized the treatment of hematologic malignancies, especially in B-cell acute lymphoblastic leukemia, B-cell non-Hodgkin lymphoma, and multiple myeloma. However, inequitable access to CAR T-cell immunotherapy has been demonstrated among racial and ethnic minority populations. This scoping review examined 37 works of published literature on barriers and facilitators to accessing commercial CAR-T therapy, as well as interventions to mitigate access inequities. The results are organized using the socio-ecological model across patient, provider, institutional, and policy levels, and highlight how these barriers and facilitators can disproportionately affect racial and ethnic minority populations. Barriers are complex and present at all socio-ecological levels, and only two published interventions that target minority access disparities to CAR-T therapy were identified. Key research gaps, including the limited number of barriers supported by objective, primary data and the absence of patient-identified barriers, are discussed. Collectively, the barriers, facilitators, and interventions identified in this scoping review can inform comprehensive, multilevel strategies to eliminate access inequities to commercial CAR T-cell immunotherapy.
    Keywords:  Access; Access disparity; CAR T-cell immunotherapy; Intervention strategies; Minority health
    DOI:  https://doi.org/10.1016/j.blre.2025.101358
  14. Curr Res Transl Med. 2025 Dec 17. pii: S2452-3186(25)00072-8. [Epub ahead of print]74(1): 103563
    Lipid nanoparticle mediated delivery of Anti-CD19 CAR mRNA to umbilical blood cord NK cells for targeting CD19⁺ primary B-ALL cells.
    Hossein Salehi-Shadkami, Mosslim Sedghi, Shima Tavoosi, Masoumeh Alimohammadi, Reza Alimohammadi, Maryam Barkhordar, Ahmadreza Mofayezi, Mohammad Sadra Modaresi, Mohammad Vaezi, Somaye Dehghanizadeh, Mohammad Ahmadvand, Vahid Khoddami.
      Chimeric antigen receptor natural killer (CAR-NK) cell therapy is recognized as a promising modality for the treatment of hematologic malignancies, particularly B-cell malignancies. In this study, we developed "off-the-shelf" anti-CD19 CAR-NK cells using anti-CD19 CAR mRNAs formulated in proprietary ionizable lipid nanoparticles (LNPs). The efficiency of mRNA-LNP delivery into umbilical cord blood (UCB)-derived NK cells and primary T cells was evaluated in an in vitro setting, demonstrating superior delivery efficiency in NK cells. Further investigation showed a probable role for an endocytic mechanism, macropinocytosis, in efficient transfection of NK cells with LNPs. Nevertheless, CAR-NK cells generated through this mRNA-LNP platform exhibited significantly enhanced cytotoxicity against CD19+ target cells, such as EGFP+Raji stable cell line and primary malignant B cells derived from refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL) patients. These findings highlight the promise of the mRNA-LNP platform in advancing CAR-NK therapies against B-cell malignancies.
    Keywords:  B-ALL; CAR-NK cell therapy; Lipid nanoparticles (LNP); NK cell therapy; mRNA technology
    DOI:  https://doi.org/10.1016/j.retram.2025.103563
  15. bioRxiv. 2025 Dec 17. pii: 2025.12.15.692195. [Epub ahead of print]
    Synthesis of mRNA lipid nanoparticles for engineering GD2 CAR T and CAR NK cells against neuroblastoma.
    Chih-Chun Chang, Lei Shi, Soon H Choi, Andrea Pennati, Vasiliki Valkanioti, Christian M Capitini, Sandro Mecozzi, Jacques Galipeau.
      Engineering T and natural killer (NK) cells with chimeric antigen receptors (CAR) creates effective adoptive cell transfer therapies for cancer treatment. However, using viral transduction as a primary genetic modification method adds regulatory burdens and is expensive to produce at scale. Delivering mRNA encoding CAR via lipid nanoparticles (LNPs) has been explored as a potent non-viral method to generate CAR immune cells. Still, it has not been optimized for CAR treatment of neuroblastoma to date. An LNP formulation to deliver mRNA encoding a GD2 CAR into human T and NK cells was designed and characterized by dynamic light scattering for size distribution, z-average diameter, polydispersity index, and ζ potential. Fluorescent reporter detection persisted for more than 1 week after mRNA LNP transfection, without affecting T or NK cell viability. The potency of GD2 CAR T cells with 79.9% reporter positivity and GD2 CAR NK cells with 26.6% reporter positivity was assessed in vitro against the GD2 + neuroblastoma cell line CHLA20. GD2 CAR T or CAR NK cells could effectively target and kill neuroblastoma cells in a dose-dependent fashion, and GD2 CAR T cells showed increased IFNγ production. This study shows mRNA LNPs are a promising non-viral approach for generating GD2 CAR T and CAR NK cells, potentially offering a safer and more cost-effective alternative to current viral vector-based methods.
    DOI:  https://doi.org/10.64898/2025.12.15.692195
  16. Patient Prefer Adherence. 2025 ;19 4131-4140
    Personalised Rational Drug Monitoring Combined with KABP Model Health Education to Improve Adherence and Prognosis of CAR-T Cell Therapy.
    Guimei Yang, Lihong Li, Yanchun Li, Huihua Yuan, Tingting Chen, Ting Wei, Zhiqiang Peng.
       Purpose: Complications such as tumor lysis syndrome occur during the Chimeric antigen receptor (CAR)-T cell treatment process, which adversely affects the treatment effect. The aim of this study is to study the combination of personalised rational medication monitoring and the Knowledge, Attitude, and Behavior (KABP) model health education to improve the adherence and prognosis of CAR-T cell therapy.
    Patients and Methods: 91 patients with lymphoma and multiple myeloma who received CAR-T cell therapy in our hospital from January 2021 to December 2024 were included in this single-retrospective study and divided into the control group (n=46, routine care) and the observation group (n=45, routine care + personalised rational medication monitoring combined with KABP model health education) based on the treatment methods. Compliance, clinical treatment efficacy, self-care ability, Functional Assessment of Cancer Therapy-General (FACT-G) scale, State-Trait Anxiety Inventory (STAI), and Knowledge, Attitude, and Behavior (KAB) scale were compared between the two groups.
    Results: The observation group demonstrated significantly higher total compliance and clinical efficacy compared to the control group (P < 0.05). Following personalized rational drug monitoring and KABP model health education post-management, the observation group also exhibited higher scores in self-care ability, FACT-G, and KAB, along with lower STAI scores than the control group (P < 0.05).
    Conclusion: This approach proves beneficial in enhancing patient adherence, treatment effectiveness, and quality of life in CAR-T cell therapy.
    Keywords:  KABP model health education; adherence; chimeric antigen receptor T cells; personalised rational medication monitoring
    DOI:  https://doi.org/10.2147/PPA.S547864
  17. Carcinogenesis. 2025 Dec 26. pii: bgaf083. [Epub ahead of print]
    Adverse events and recent advances in CAR-T-cell therapy.
    Zhimin Bai, Xiaoyu Huang, Hui Jia, Zenghua Lin, Hong Liu.
      Chimeric antigen receptor (CAR-T) cell therapy has been widely used in haematological malignancies and has achieved remarkable results. However, two major toxicities of CAR-T-cell therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), have been reported in many studies and often require hospitalization. There is evidence that CAR-T-cell therapy is being increasingly used clinically, so it is important to pay attention to its serious adverse events that may be life-threatening. In this review, we provide a detailed discussion of the clinical manifestations, classification, risk factors, and management and treatment of serious adverse events to provide theoretical support for clinicians to manage such cases. Although the clinical application of CAR-T cells continues to expand, adverse events associated with CAR-T-cell therapy are inevitable. With the identification of risk factors and the application of various new therapeutic approaches, the incidence and severity of these adverse events can be effectively controlled.
    Keywords:  Adverse event; CAR-T therapy; CRS; Hematological malignancies; ICANS
    DOI:  https://doi.org/10.1093/carcin/bgaf083
  18. Angew Chem Int Ed Engl. 2025 Dec 26. e24097
    Nanoparticle-Based Tolerogenic Vaccines: Next-Generation Strategies for Autoimmune and Allergic Disease Therapies.
    Benjamin E Nachod, Ajay S Thatte, Rohan Palanki, Michael J Mitchell.
      The concurrent rise of autoimmune diseases, which affect nearly 10% of the global population, along with allergic conditions such as asthma, food allergy, and atopic disease, together pose substantial health and economic burdens. Traditional therapies rely on systemic immunosuppression that temporarily mitigates symptoms but often compromises protective immunity, increases infection and malignancy risk, and fails to restore central or peripheral tolerance. These limitations underscore the need for antigen-specific strategies capable of re-establishing durable immune balance. Tolerogenic vaccines have emerged as a promising solution by retraining the immune system to restore antigen-specific tolerance while preserving normal host defense, though challenges remain in efficiently targeting antigen-presenting cells (APCs), avoiding their overactivation, and minimizing off-target effects. Nanoparticles provide a versatile platform to address these hurdles, as their size, composition, and surface modifications can be tailored to direct biodistribution, enhance antigen delivery, and modulate immune signaling. By co-delivering antigens and immunomodulators in programmable ways, nanoparticles offer a pathway to overcome key translational barriers and achieve precise immune reprogramming. This review explores how advances in nanomedicine are being applied to tolerogenic vaccines, focusing on three areas: (1) current nanoparticle platforms, (2) the role of biomaterial selection, and (3) multifunctional engineering strategies, while also considering the clinical outlook and translational challenges of bringing these therapies from bench to bedside.
    Keywords:  Allergy; Autoimmunity; Immune tolerance; Immunomodulatory materials; Nanoparticle design strategies; Vaccine
    DOI:  https://doi.org/10.1002/anie.202524097
  19. Signal Transduct Target Ther. 2025 Dec 23. 10(1): 411
    Scarless circular mRNA-based CAR-T cell therapy elicits superior antitumor efficacy.
    Qinchao Hu, Hui Zhao, Kaicheng Zhou, Xuefei Tian, Qian Wang, Xianxin Hua, Xuyao Zhang.
      Messenger RNA (mRNA)-based transient expression of chimeric antigen receptors (CARs) results in optimal safety profiles and provides promising opportunities to address existing challenges associated with viral vector-based CAR-T-cell therapies and to meet emerging medical needs for noncancerous indications. Conventional linear mRNAs, however, are intrinsically unstable and typically support short-lived protein expression, which can constrain therapeutic activity. Here, we engineered a high-efficiency permuted intron exon (PIE) platform to synthesize scarless circular mRNAs (cmRNAs) that drive robust CAR expression with extended durability. The scarless design avoids extraneous junction sequences, streamlining manufacturability and potentially reducing innate immune sensing. Compared with linear mRNAs, cmRNAs significantly increased both the magnitude and duration of anti-CD19 CAR and anti-GPRC5D CAR expression in primary human T cells. Functionally, cmRNA-based CAR-T cells elicited superior antitumor efficacy over their linear mRNA counterparts, as demonstrated by parallel lines of evidence, including in vitro antigen-specific cytotoxicity, cytokine release, and transcriptomics patterns consistent with sustained activation and absence of exhaustion signatures, as well as in vivo models demonstrating tumor elimination and prolonged survival benefits. Collectively, these findings position cmRNA as a next-generation mRNA modality for potent and controllable CAR expression, thereby providing a robust platform to unleash the full potential of mRNA technologies in cellular immunotherapy and precision medicine.
    DOI:  https://doi.org/10.1038/s41392-025-02512-4
  20. Biochim Biophys Acta Rev Cancer. 2025 Dec 20. pii: S0304-419X(25)00261-6. [Epub ahead of print]1881(1): 189519
    The race between 4-1BB- and CD28-based CD19 CAR-T products in the therapy of B-cell malignancies.
    Marta Krawczyk, Magdalena Drużyńska, Emilia Bednarska, Magdalena Winiarska.
      Chimeric antigen receptor T-cell (CAR-T) therapy targeting CD19 has revolutionized the treatment of B-cell malignancies. One of the critical factors influencing CAR-T efficacy and durability is the costimulatory domain, with 4-1BB and CD28 emerging as the two dominant signaling platforms. While CD28-based CAR-T cells exhibit strong initial potency and rapid expansion, 4-1BB-based CAR-T cells demonstrate greater persistence and long-term efficacy. However, resistance to CAR-T therapy remains a significant challenge. Tumor cells develop a variety of mechanisms to evade immune surveillance, including CD19 antigen escape due to epigenetic factors or genetic aberrations of the CD19 gene. This review article summarizes the mechanistic differences between both costimulatory domains, their impact on clinical outcomes, and how they might influence resistance occurrence. By dissecting the battle of potency and the race of persistence, we provide insights into the evolving landscape of CAR-T therapy for B-cell malignancies.
    Keywords:  CAR-T; CD19; Costimulatory domain; Immunotherapy; Resistance
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189519
  21. Rheumatol Ther. 2025 Dec 23.
    Is a Functional Cure Possible in Autoimmune Diseases? Evidence from Trigger Eradication, Transplantation, and Cellular Therapies.
    Jozélio Freire de Carvalho, Carlos Ewerton Maia Rodrigues.
       INTRODUCTION: Traditionally considered incurable, autoimmune diseases (AIDs) may-in specific circumstances-achieve sustained remission or even a "functional cure," defined as durable clinical and laboratory remission without immunosuppression. This review evaluates evidence across five therapeutic axes: infectious trigger eradication, immune reset via autologous hematopoietic stem cell transplantation (HSCT), cellular therapies (CAR-T, extracorporeal photopheresis), environmental/nutritional strategies, and paraneoplastic syndromes.
    METHODS: Systematic review according to PRISMA guidelines in PubMed/MEDLINE, Embase, Scopus, Web of Science, and Cochrane (up to September 2025). Eligible studies included trials, meta-analyses, cohorts, case series, and reports describing sustained or drug-free remission. Definitions applied were clinical remission, complete remission, sustained remission ≥ 12 months, drug-free remission, and functional cure (complete, off-therapy remission with stable biomarkers and no new organ damage).
    RESULTS: Strong evidence supports Helicobacter pylori eradication in immune thrombocytopenic purpura, with signals in dermatoses and urticaria. In systemic sclerosis, HSCT outperformed cyclophosphamide in randomized trials, improving survival and reducing prolonged immunosuppression; lupus series reported extended drug-free remissions. Anti-CD19 CAR-T therapies induced deep remission in B-cell-mediated AIDs, normalizing autoantibodies over 12-24 months. Photopheresis showed safety but heterogeneous efficacy. Environmental interventions (vitamin D, plant-based diet, microbiota modulation) suggested benefit, though with limited evidence for cure. In paraneoplastic syndromes, tumor control often coincided with autoimmune remission.
    CONCLUSIONS: Functional cure in AIDs appears achievable in selected cases through trigger removal, immune reset, or profound immune depletion. Advancing this paradigm requires standardized definitions, predictive biomarkers, and long-term controlled trials to integrate these strategies into routine care.
    Keywords:   Helicobacter pylori ; Autoimmune diseases; Autologous hematopoietic stem cell transplantation; CAR-T; Extracorporeal photopheresis; Functional cure; Paraneoplastic syndromes; Plant-based diet; Sustained remission; Vitamin D
    DOI:  https://doi.org/10.1007/s40744-025-00816-z
  22. Brain Behav Immun. 2025 Dec 22. pii: S0889-1591(25)00481-7. [Epub ahead of print] 106239
    Neural control of Immunotherapy: how Tumor-innervation shapes Anti-Tumor immune responses.
    Hatice Satilmis, Adrien Denis, Karin Vanderkerken, Elke De Bruyne, Eline Menu, Erica Sloan, Kim De Veirman.
      The role of the sympathetic nervous system (SNS) in cancer biology has gained increasing attention, and its ability to affect immunotherapy is starting to become clearer. Extensive evidence shows that neuro-onco-immune interactions significantly influence tumor progression and the effectiveness of cancer treatments. Blocking SNS signaling, primarily through β-adrenergic receptors, enhances immune cell functions, by increasing CD8+ T-cell activation and cytokine production, while reducing immunosuppressive cell populations. This review explores the relationship between SNS signaling and cancer immunotherapy, emphasizing how SNS activation affects the efficacy of various immunotherapies, including immune modulators, immune checkpoint inhibitors, oncolytic virus therapy, therapeutic vaccines, and CAR-T cell therapies. We summarize retrospective studies investigating the use of β-blockers during immunotherapy, suggesting potential benefits for treatment outcomes of blocking SNS signaling in the tumor microenvironment. We examine ongoing clinical trials that evaluate the use of beta-blockers with immune checkpoint inhibitors, which aim to improve patient outcomes. While translational and preclinical studies provide ample evidence for targeting SNS signaling in cancer immunotherapy, clinical studies are only beginning to emerge. Ultimately, this review underscores the need for further research to better understand how SNS signaling can be targeted to optimize immunotherapy, paving the way for more effective treatment strategies.
    Keywords:  Adrenergic signaling; Cancer Immunotherapy; Immune microenvironment; Neuro-immune interaction; Sympathetic nervous system; β-blocker
    DOI:  https://doi.org/10.1016/j.bbi.2025.106239
  23. Front Immunol. 2025 ;16 1652211
    Multi-omics-driven biomarker discovery in autoimmune diseases: a comprehensive review.
    Yi Zhang, Haofeng Xu, Lijuan Xu, Shasha Jiang, Yan Yu, Heping Zhao.
      Autoimmune diseases (ADs) exhibit complex heterogeneity and dynamic pathological mechanisms. Traditional biomarkers face numerous challenges in the diagnosis and treatment of ADs. However, the rapid development of multi-omics technologies and bioinformatics has not only deepened the understanding of the pathogenesis of ADs but also identified many novel diagnostic and therapeutic biomarkers with good diagnostic performance. These biomarkers are now beginning to overcome these limitations. This review systematically explores the discovery of novel biomarkers driven by multi-omics technologies such as genomics, epigenomics, transcriptomics, proteomics, metabolomics, and microbiomics, in response to the limitations of traditional biomarkers. It emphasises the significant importance of discovering novel biomarkers through multi-omics in the diagnosis and treatment of ADs, and proposes a concept from omics analysis to solving clinical problems, providing new directions for the diagnosis and treatment of ADs.
    Keywords:  autoimmune diseases; biomarker; machine learning; multi -omics; network analysis
    DOI:  https://doi.org/10.3389/fimmu.2025.1652211
  24. Front Immunol. 2025 ;16 1687478
    Sequential pseudoallogeneic CAR20/22/19 T-cell therapy in patient with diffuse large B-cell lymphoma relapse after allo-HSCT: a case report.
    Yu Xiong, Shaomei Feng, Weicheng Liu, Qinlong Zheng, Biping Deng, Zhihui Li, Defeng Zhao.
       Purpose: The prognosis for patients with refractory/relapsed diffuse large B-cell lymphoma (R/R DLBCL) is dismal. Recurrence in R/R DLBCL is mostly determined by antigen loss or mutation and the limited in vivo survival of chimeric antigen receptor (CAR) T cells.
    Methods: A 38-year-old female patient was diagnosed with left breast DLBCL in March 2018. After undergoing immunochemotherapy, autologous stem cell transplantation, and radiotherapy, she relapsed in May 2019. The peripheral blood (PB) morphology showed that 36% of cells were classified as unknown. The bone marrow (BM) smear showed 71% of abnormal lymphocytes. BM flow cytometric (FCM) analysis revealed 70.24% abnormal phenotype of mature B lymphocytes. The patient's abnormal karyotype was complex, and the 17th chromosome was missing. The p53 gene deletion (which accounted for approximately 82%) was revealed by fluorescence in situ hybridization (FISH) investigation.
    Results: Autologous CD19 CAR T cells were infused after lymphodepletion chemotherapy with cyclophosphamide and fludarabine. The patient experienced Grade I cytokine release syndrome (CRS) and achieved complete remission (CR). The genetic susceptibility gene test results suggested that the patient had potential susceptibility gene mutations for hematological tumors; therefore, allogeneic hematopoietic stem cell transplantation (allo-HSCT) was conducted as consolidation therapy. Unfortunately, the patient relapsed 5 months after allo-HSCT. Then, the patient received sequential pseudoallogeneic CAR20/22/19 T-cell therapy. The patient is currently at 4 years after allo-CAR-T treatment with BM morphology CR, negative minimal residual disease, complete donor chimerism, and no graft versus host disease (GVHD).
    Conclusion: Our findings suggest that pseudoallogeneic CAR-T therapy was safe and effective in patients with DLBCL who experienced relapse after allo-HSCT. Sequential administration of CAR20/22/19 T cells may have reduced the antigen escape relapse in DLBCL. For patients with DLBCL relapse after allo-HSCT, larger trials are required to validate the safety and effectiveness of pseudoallogeneic CAR-T therapy as well as its ability to lower the rate of antigen escape relapse.
    Keywords:  allogeneic hematopoietic stem cell transplantation; autologous stem cell transplantation; cytokine release syndrome; pseudoallogeneic CAR-T; refractory/relapsed diffuse large B-cell lymphoma
    DOI:  https://doi.org/10.3389/fimmu.2025.1687478
  25. Int J Nanomedicine. 2025 ;20 15185-15211
    Self-Assembled Nanoparticles: Overcoming Limitations of Conventional Nanomedicines for Enhanced Tumor Therapy.
    Xinlei Tang, Rujia Xie, Bozhi Zeng, Chengcheng Yi, Hui Su, Congcong Chen, Lili Zhou, Xinhua Xia, Jianguo Zeng, Jing Yang.
      The high mortality rate associated with cancer presents a significant clinical challenge, necessitating breakthroughs to overcome the limitations of traditional therapies, which often entail substantial side effects, as well as the complexities associated with existing nanodelivery systems (NDDS) that lack adequate targeting capabilities. Self-assembled nanoparticles (SANs) form spontaneously through weak interactions between drugs and functional molecules, such as hydrogen bonds and hydrophobic interactions. They exhibit revolutionary advantages, including ultra-high drug loading capacity, stimulus responsiveness, precise drug release, self-driven targeting capabilities, and a straightforward preparation process that does not require complex carrier synthesis. This review systematically summarizes the latest advancements in SANs for tumor therapy, emphasizing their molecular design principles and mainstream preparation strategies, while detailing their efficacy in multi-modal synergistic therapies, including chemotherapy, photodynamic/photothermal therapy, immunotherapy, and gene therapy. The technology of SANs establishes a robust foundation for the development of highly efficient and low-toxicity anti-cancer strategies, demonstrating significant potential to offer a transformative new paradigm for clinical precision therapy. We believe that the continued evolution of SANs holds great promise for clinical translation, potentially offering transformative solutions for personalized oncology in the near future.
    Keywords:  molecular design; nanodrug delivery system; non-covalent interactions; self-assembled nanoparticles; tumor therapy
    DOI:  https://doi.org/10.2147/IJN.S568952
  26. Cancer Treat Res Commun. 2025 Dec 19. pii: S2468-2942(25)00210-2. [Epub ahead of print]46 101074
    Hematologic malignancies and an overview of emerging therapies for hematologic malignancies: a systematic review.
    Kazem Ghaffari, Amin Moradi Hasan-Abad, Masoud Etedali, Shaban Alizadeh, Ali Ghasemi.
      Hematologic malignancies remain a major therapeutic challenge due to disease heterogeneity, treatment resistance, and significant toxicity associated with conventional therapies. In recent years, rapid advances in molecular oncology and immunotherapy have led to the development of multiple emerging therapeutic strategies. This review synthesizes evidence on novel approaches, including targeted therapies such as BTK inhibitors (e.g., ibrutinib), BCL-2 inhibitors (e.g., venetoclax), FLT3 and JAK inhibitors, and next-generation monoclonal and bispecific antibodies that enhance immune-mediated cytotoxicity. In addition, gene- and cell-based modalities-including CAR T-cell therapy and CRISPR-mediated gene correction-have demonstrated promising efficacy, particularly in relapsed or refractory leukemia and lymphoma. Despite these advances, significant limitations remain, including treatment-related toxicities, mechanisms of resistance, high relapse rates after CAR-T therapy, and substantial financial and accessibility barriers. Gaps in predictive biomarkers, optimal sequencing of therapies, and long-term safety also limit widespread implementation. Precision medicine approaches, driven by molecular diagnostics and genomic profiling, continue to refine individualized treatment strategies and hold potential to overcome current challenges. Overall, this review provides an updated and comprehensive evaluation of emerging therapeutic modalities in hematologic malignancies and outlines key areas where further research is critically needed.
    Keywords:  Clinical trial; Emerging therapies; Hematologic malignancies; Immunotherapies; Precision medicine
    DOI:  https://doi.org/10.1016/j.ctarc.2025.101074
  27. bioRxiv. 2025 Dec 10. pii: 2025.12.07.692875. [Epub ahead of print]
    Precise Control of Switchable Chimeric Antigen Receptor T Cells Allows Enhanced Safety and Less T Cell Exhaustion.
    Zihan Anna Zhang, Logan Herring, Thuzar Hla Shwe, Yue Hu, Xiaotong Song, Wenyue Cao, Wenshe Ray Liu.
      Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in treating hematologic malignancies, yet their clinical utility remains limited by safety concerns, poor persistence, and T-cell exhaustion driven by continuous receptor signaling. Although switchable CAR systems offer external control, most existing designs are irreversible, binary, or compromising CAR-T potency. Here, we introduce a chemically switchable CAR platform that enables graded, reversible regulation of CAR-T activity while retaining full therapeutic capacity. Using engineered CAR-T cells, we evaluate drug-controlled activation, cytotoxicity, and cytokine release against CD19⁺ tumor cells and screened clinically approved NS3/4A inhibitors to identify optimal small-molecule controllers. Compared with conventional CAR-T cells, switchable CAR-T cells exhibited minimal background activity in the OFF state, preventing antigen-driven activation and cytokine release in the absence of drug. Upon drug addition, CAR expression was rapidly restored, with full-length CAR detectable within 1 hour and ∼80% of maximal expression achieved by 4 hours. Reversible suppression of CAR expression protected normal CD19⁺ B cells once malignant cells were eliminated, addressing the clinical challenge of persistent CD19 CAR-T activity that can lead to B-cell aplasia, hypogammaglobulinemia, and recurrent infections. Furthermore, switchable CAR-T cells displayed reduced exhaustion, enhanced persistence, stable CAR expression, and preferential central memory differentiation following tumor clearance. Together, these findings establish the switchable CAR-T system as a next-generation, reversible, and clinically compatible CAR-T platform.
    Key Points: Optimized switchable CAR enables precise control of functional CAR expression, T-cell activation, cytokine release, and cytotoxicity.External regulation of CAR-T cells enhances safety and promotes sustained persistence in chronic stimulation models.
    DOI:  https://doi.org/10.64898/2025.12.07.692875
  28. Front Immunol. 2025 ;16 1705002
    Editorial: Enhancing CAR T-cell therapy with imaging.
    Egesta Lopci, Dorine de Jong, Laurent Dercle.
      
    Keywords:  CAR-T; MRI; PET; cell tracking; multimodal imaging; optical imaging
    DOI:  https://doi.org/10.3389/fimmu.2025.1705002
  29. Crit Rev Oncol Hematol. 2025 Dec 23. pii: S1040-8428(25)00491-3. [Epub ahead of print] 105103
    Immunotherapy-Mediated Cancer Reversion: Possibilities and Prospects.
    Emmanuel O Oisakede, Odunola Atitebi, Raphael Igbarumah Ayo Daniel, Eghosasere Egbon, John Oluwatosin Alabi, David B Olawade.
      Immunotherapy has revolutionized cancer treatment by enabling durable tumor control through immune activation. Emerging evidence suggests that beyond cytotoxic elimination, immune responses can reprogram malignant cells toward normalized, differentiated states, a phenomenon termed immunotherapy-mediated cancer reversion. This paradigm shift positions the immune system as a restorative rather than solely destructive force. This review synthesizes contemporary evidence on immunotherapy-mediated cancer reversion, evaluating mechanistic pathways and clinical implications across diverse malignancies to establish a conceptual framework for immune-driven phenotypic normalization. A comprehensive narrative review was conducted across PubMed, Web of Science, and Scopus databases, encompassing literature from 2015-2025. Evidence was synthesized thematically across immune checkpoint blockade, adoptive cell therapies, cytokine modulation, and microenvironmental remodeling. Immune-mediated reversion arises through coordinated epigenetic, metabolic, and microenvironmental reprogramming. Checkpoint inhibitors restore differentiation programs via IFNγ-driven chromatin remodeling, while CAR-T and NK-cell therapies induce metabolic normalization and epithelial restoration. Cytokine signaling and macrophage reprogramming reinforce reversion by modulating angiogenesis and stromal architecture. Clinical observations across melanoma, lung cancer, breast cancer, hematologic malignancies, and hepatocellular carcinoma support this restorative immune process. Single-cell and spatial omics identify transitional states bridging malignancy and normalcy. Immunotherapy-mediated cancer reversion represents a conceptual frontier shifting oncology from eradication to restoration. Future progress requires defining biomarkers, confirming mechanistic permanence, and redesigning clinical endpoints. As integrative immuno-epigenetic frameworks mature, immune-driven reversion may evolve from biological curiosity to clinically reproducible pathway toward durable remission and functional cure.
    Keywords:  Cancer Reversion; Epigenetic Reprogramming; Immune Normalization; Immune Plasticity; Immunotherapy
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105103
  30. Front Immunol. 2025 ;16 1669688
    JAK/STAT in human diseases: a common axis in immunodeficiencies and hematological disorders.
    Reda Djidjik, Lydia Lamara Mahammed, Lilya Meriem Berkani, Ines Allam, Alaa Hamidou Benmoussa, Merzak Gharnaout, Brahim Belaid.
      The JAK-STAT signaling pathway (Janus Kinase-Signal Transducer and Activator of Transcription) is a crucial molecular cascade that regulates immune responses, cell proliferation, and hematopoiesis. Germline or somatic mutations affecting this pathway leads to a wide range of pathologies, from severe immunodeficiencies to inflammatory and autoimmune diseases, as well as hematologic malignancies. Loss-of-function mutations impair cytokine signaling and primarily result in immunodeficiency, while gain-of-function mutations cause excessive pathway activation, promoting autoimmune diseases and myeloproliferative syndromes. Advances in our understanding of the JAK-STAT pathway and its involvement in various diseases have opened new perspectives in precision medicine and targeted therapies including JAK inhibitors (JAKi), gene therapy, and hematopoietic stem cell transplantation (HSCT). A detailed understanding of specific mutations and their effects on intracellular signaling allows for the refinement of therapeutic strategies and optimization of patient management. In this review, we examined the biology of the JAK-STAT pathway, highlighted the key pathogenic mutations and their clinical consequences, and described the laboratory and diagnostic approaches used to investigate this pathway.
    Keywords:  JAK; STAT; cancers; inborn errors of immunity; mutations; signaling pathway
    DOI:  https://doi.org/10.3389/fimmu.2025.1669688
  31. Front Bioeng Biotechnol. 2025 ;13 1706927
    "Live" cell shipment-a forward-looking transport option for cryo-sensitive cell-based therapies.
    Lutz Roßbach, Thea Eichenberg, Nicole Pietzsch, Paul Franz, Stephan Fricke, Robin Sieg, Anna Dünkel, Kathrin Sabine Adlkofer.
      Cell therapies, which use the transplantation or manipulation of cells to treat diseases, are highly promising for conditions such as cancer, autoimmune diseases, and genetic disorders. Their success depends on the quality and viability of the administered cell products, which is especially critical for patients already weakened by chemotherapy or radiation. In such cases, ensuring high-quality cells that can engraft, proliferate, and function properly is essential for improving outcomes and survival. Natural killer (NK) cells are strong candidates for cancer treatment due to their innate cytotoxic activity without the side effects of graft-versus-host disease (GvHD). However, cryopreservation has significantly hindered their clinical application, as it reduces both survival and function. Current "off-the-shelf" allogeneic NK therapies, therefore, face limitations because freezing and thawing lead to cell loss and impaired activity. To address this challenge, we evaluated live shipment of NK cells using the Cellbox™ Shipper Flight, a transportable incubator maintaining 37°C and 5% CO2, versus cryopreservation and static laboratory incubation. Three independent NK cell batches, expanded under clinically compliant conditions, were tested. Optimized cryopreservation yielded 78% ± 9% of initial cell counts with >96% viability immediately after thawing. However, phenotypic analyses revealed a loss of NK markers, reduced cytotoxic activity, and an additional 50% ± 1% loss during 3 days of recovery, indicating that nearly half of the thawed cells were non-functional. In contrast, NK cells shipped live in the Cellbox™ retained an unaffected phenotype and cytotoxic function. After transport, cell counts recovered, and proliferation was observed during 3 days of static recultivation. Overall, live shipment delivered 2.5 times more functional NK cells after recovery than cryopreservation. These findings demonstrate that shipping NK cells in culture using Cellbox™ is both feasible and advantageous, preserving cell function and ensuring a full therapeutic dose. By contrast, cryopreservation not only reduces immediate viability but also compromises long-term recovery and functionality, potentially limiting clinical efficacy. Mobile incubators like Cellbox™, therefore, represent a critical advance, enabling the reliable transport of living therapeutic cells and unlocking the full potential of cell therapies for patient benefit.
    Keywords:  NK cells; cancer; cell-based therapies; live cell shipment; regenerative medicine
    DOI:  https://doi.org/10.3389/fbioe.2025.1706927
  32. Expert Opin Pharmacother. 2025 Dec 25. 1-12
    Reshaping multiple myeloma treatment: recent breakthroughs.
    Enrica Antonia Martino, Santino Caserta, Ernesto Vigna, Antonella Bruzzese, Francesco Mendicino, Maria Eugenia Alvaro, Caterina Labanca, Eugenio Lucia, Virginia Olivito, Nicola Amodio, Fortunato Morabito, Massimo Gentile.
       INTRODUCTION: The therapeutic landscape of multiple myeloma (MM) is rapidly evolving through advances in immune-based strategies. Bispecific antibodies (BsAbs), chimeric antigen receptor T-cell (CAR-T) therapies, and emerging trispecific antibodies (TsAbs) are reshaping expectations by delivering deep and durable responses even in heavily pretreated disease.
    AREAS COVERED: Off-the-shelf BsAbs such as teclistamab, elranatamab, and talquetamab show robust activity in triple-class - exposed patients, with earlier use and combination regimens further enhancing response depth. However, challenges remain, including T-cell exhaustion, infection risk, hypogammaglobulinemia, and logistical issues related to step-up dosing and cytokine release syndrome. CAR-T therapies, particularly idecabtagene vicleucel and ciltacabtagene autoleucel, achieve high response rates and rapid MRD negativity, but wider use is limited by manufacturing time, toxicity management, and relapse mechanisms such as antigen loss. Innovations including dual-target CAR-T, armored constructs, and allogeneic platforms aim to improve durability and expand access. MRD assessment has become a biomarker guiding treatment intensity, and duration. In parallel, refined risk stratification -especially for high-risk cytogenetic, functional, and extramedullary disease- helps identify patients who may benefit from early integration of immunotherapies.
    EXPERT OPINION: Overall, these advances support a shift toward personalized strategy designed to achieve deep remission, reduce toxicity, and approach functional cure in selected patients.
    Keywords:  CAR-T cell therapy; Multiple myeloma; bispecific antibodies; immunotherapy; minimal residual disease
    DOI:  https://doi.org/10.1080/14656566.2025.2610373
  33. Acta Biochim Biophys Sin (Shanghai). 2025 Dec 24.
    Immune checkpoint TIM-3 in tumor immunotherapy.
    Shuaiya Ma, Mengyao Zhu, Chunhong Ma, Chunyang Li.
      Over the past decade, immunotherapy has emerged as a pivotal therapeutic strategy in cancer treatment. Immune checkpoint inhibitors (ICIs), such as CTLA-4 and PD-1 monoclonal antibodies, have demonstrated remarkable clinical efficacy in different types of cancer. However, the overall success rate of immune checkpoint therapies remains low. Investigating alternative immune checkpoint molecules is imperative. T-cell immunoglobulin and mucin-containing molecule-3 (TIM-3), which is expressed in T cells, natural killer (NK) cells, macrophages, and dendritic cells, has gained recognition as a promising candidate for tumor immunotherapy. Targeting TIM-3 represents a promising approach for cancer immunotherapy, particularly through the rational design of novel combination therapies with other ICIs. In this review, we present a comprehensive summary of the research advancements concerning the role of TIM-3 in regulating immune responses in different cell types and explore theoretical frameworks for targeting TIM-3 to achieve more effective immunotherapeutic breakthroughs.
    Keywords:  TIM-3; immune checkpoint; immunotherapy
    DOI:  https://doi.org/10.3724/abbs.2025235
  34. Clin Transl Sci. 2026 Jan;19(1): e70461
    Clinical Pharmacology Perspective on Direct-To-Subcutaneous Dosing of T Cell Engagers in Oncology First-In-Human Studies.
    Wenlian Qiao, Azar Shahraz, Karthick Vishwanathan, Aarti Sawant-Basak.
      While the subcutaneous (SC) route of administration (RoA) is more patient-centric and cost-effective than the intravenous (IV) RoA, the Switch-to-SC paradigm has been employed in oncology antibody drug development. T cell engagers (TCEs) are typically highly potent and efficacious at low doses, supporting their suitability for the Direct-to-SC in FIH paradigm. This perspective discusses anticipated clinical pharmacology challenges associated with the Direct-to-SC in FIH paradigm and provides potential solutions to address the challenges.
    Keywords:  antibodies; oncology; pharmacokinetics; pharmacology; translational pharmacokinetics‐pharmacodynamics
    DOI:  https://doi.org/10.1111/cts.70461
  35. J Drug Target. 2025 Dec 24. 1-20
    Recent Advances in Theranostic-based Extracellular Vesicles in Cancer Stem Cell Diagnosis and Therapy.
    Yunlan Huang, Linlin Chang, He Wang, Huiyang Sun, Yibin Feng, Dongqing Li.
      Cancer remains a leading cause of mortality worldwide, with treatment failure and disease recurrence often driven by cancer stem cells (CSCs), which constitute a resilient subpopulation within tumors characterized by self-renewal, differentiation capacity, and resistance to conventional therapies. Extracellular vesicles (EVs), including exosomes and microvesicles, are secreted by CSCs and play pivotal roles in tumor progression, immune evasion, and therapeutic resistance by transporting bioactive molecules such as heat shock proteins and regulatory RNAs. These vesicles reflect the molecular signature of their parent cells and offer unique opportunities for noninvasive diagnostics and targeted therapy. The theranostic paradigm, which integrates diagnostic and therapeutic functions, leverages EVs for CSC-specific biomarker detection, drug delivery, and real-time monitoring of treatment response. Advances in nanotechnology and molecular engineering have enabled the functionalization of EVs with imaging agents and therapeutic payloads, increasing their specificity and efficacy in preclinical and early clinical settings. This narrative review synthesizes current knowledge on CSC biology, EV biogenesis, and the evolving landscape of EV-based theranostics, highlighting translational progress, technical challenges, and future directions. Theranostic EVs represent a promising frontier in precision oncology, offering transformative potential for the management of CSC-driven tumorigenesis and relapse.
    Keywords:  Cancer Stem Cells; Extracellular Vesicles; Precision Oncology; Theranostics; Tumor Microenvironment
    DOI:  https://doi.org/10.1080/1061186X.2025.2609201
  36. Cytokine. 2025 Dec 23. pii: S1043-4666(25)00245-5. [Epub ahead of print]198 157098
    Advances in lipid nanoparticle delivery systems for targeted cytokine immunotherapy in autoimmune disorders.
    Dilpreet Singh.
      Autoimmune diseases result from dysregulated immune responses, primarily driven by CD4+ T cell imbalances, leading to chronic inflammation and tissue destruction. Conventional cytokine-based therapies, including IL-2 for regulatory T cell (Treg) expansion and IL-6 or IL-17 inhibition for inflammation suppression, have shown promise in modulating immune responses. However, challenges such as systemic toxicity, short half-life, and off-target effects limit their therapeutic efficacy. Lipid nanoparticles (LNPs) have emerged as a next-generation drug delivery platform, offering enhanced cytokine stability, targeted cellular uptake, and controlled release, thereby overcoming limitations associated with free cytokine administration. Preclinical studies have demonstrated that LNP-IL-2 selectively expands Tregs in type 1 diabetes models, while IL-10-loaded LNPs suppress synovial inflammation in rheumatoid arthritis more effectively than conventional cytokine therapies. Optimization of ligand density and affinity on LNP surfaces is emerging as a key determinant of CD4+ T cell targeting efficiency. Additionally, LNP-encapsulated siRNA targeting IL-6 and IL-23 has shown superior suppression of inflammatory pathways in lupus and psoriasis. These findings underscore the potential of LNP-mediated cytokine delivery to precisely modulate CD4+ T cell function, restoring immune homeostasis in autoimmune diseases. Despite promising preclinical and early clinical data, challenges remain, including optimizing biodistribution, ensuring selective T cell targeting, and mitigating immune activation risks. This review provides an in-depth analysis of CD4+ T cell subsets in autoimmunity, the advantages of LNP-based cytokine therapies, and their translational potential. The integration of LNP technology into cytokine immunotherapy offers a novel, minimally toxic, and durable approach to reprogramming immune responses, paving the way for precision medicine in autoimmune disease management. SIGNIFICANCE: Autoimmune disorders are characterized by chronic inflammation driven by dysregulated cytokine activity. Traditional cytokine therapies often suffer from systemic toxicity and limited targeting precision. This manuscript highlights recent advancements in lipid nanoparticle (LNP) technology for the targeted delivery of cytokines, offering enhanced therapeutic efficacy and safety. By enabling precise modulation of immune responses at disease sites, LNP-based delivery systems represent a transformative approach in immunotherapy. This review underscores the potential of LNPs to overcome current limitations in autoimmune treatment, paving the way for next-generation precision medicine strategies.
    Keywords:  Autoimmune diseases; CD4+ T cells; Cytokine therapy; Immunomodulation; Lipid nanoparticles; Targeted drug delivery
    DOI:  https://doi.org/10.1016/j.cyto.2025.157098
  37. Int J Nanomedicine. 2025 ;20 14977-15016
    Recent Advances in Plant-Derived Extracellular Vesicles as Nanoparticles for Cancer Drug Delivery.
    Qiongdan Zhang, Huihong Duan, Yupei Yang, Huanghe Yu, Wei Wang, Bin Li.
      Plant-derived extracellular vesicles (PDEVs) have emerged as a highly promising and disruptive class of natural nanoparticles for anticancer drug delivery. This review provides a comprehensive analysis of PDEVs, positioning them within the broader landscape of nanomedicine through a direct comparison with conventional synthetic nanoparticles (eg, liposomes) and mammalian cell-derived extracellular vesicles (EVs). We highlight how the unique origin of PDEVs confers significant advantages, including superior natural biocompatibility, low immunogenicity, and the remarkable "dual-functionality" of acting as both inherent therapeutic agents and efficient drug carriers. The capacity of PDEVs to efficiently encapsulate a diverse range of therapeutic agents-from chemotherapeutic drugs and RNA interference molecules to gene-editing tools-is discussed in contrast to the more limited loading versatility and complex manufacturing of some alternative systems. The review systematically covers recent advances in PDEV isolation, characterization, and drug-loading techniques, emphasizing their demonstrated ability to cross biological barriers for targeted therapy and controlled release. Finally, we critically address the translational pathway, outlining key challenges in standardization and clinical translation, while forecasting their pivotal role in advancing personalized cancer nanomedicine. Through this comparative and functional perspective, PDEVs are poised to transition from a promising biological curiosity to a cornerstone of next-generation anticancer strategies.
    Keywords:  PDEVs; drug delivery; isolation; plant-derived extracellular vesicles; tumor therapy
    DOI:  https://doi.org/10.2147/IJN.S559440
  38. Pediatr Blood Cancer. 2025 Dec 22. e70081
    What to Do When Medical Evidence Can Only Be Generated Through Routine Data: An Example From Pediatric Oncology.
    Birgit Burkhardt, Antje Walz, Dietrich Knoerzer.
      Children undergoing allogeneic stem cell transplantation often receive off-label rituximab treatment for Epstein-Barr virus reactivation, using adult dosing without pediatric evidence. This project aims to develop a clinical decision support tool (CDSS) that provides evidence-based dosing scenarios by analyzing real-world patient data. The CDSS integrates clinical and laboratory data across institutions and includes dynamic models that guide therapy decisions while incorporating feedback to improve over time. It addresses a critical evidence gap for vulnerable populations and represents a scalable approach for individualized care. The project also highlights the need for regulatory and infrastructural adaptations to support data-driven, post-approval evidence generation.
    Keywords:  Clinical decision support tool; evidence generation; routine data; small populations; vulnerable populations
    DOI:  https://doi.org/10.1002/1545-5017.70081
  39. Semin Hematol. 2025 Nov 25. pii: S0037-1963(25)00053-8. [Epub ahead of print]
    Chemical evolution of antibody-drug conjugates focused on linker design and conjugation strategies in hematology.
    Seungbin Park, Geetanjali B Gone, Dohee Ahn, Sang J Chung.
      Antibody-drug conjugates (ADCs) have transformed the treatment of hematologic malignancies by coupling antibody selectivity with potent cytotoxic payloads. Their clinical performance depends largely on chemical design, particularly linker stability and conjugation strategy. Advances in site-specific and site-selective platforms, such as ThioMab, GlycoConnect, AJICAP, and AbClick, enable homogeneous ADCs with controlled drug-to-antibody ratio (DAR) and improved safety. Cleavable linkers-protease-sensitive, acid-labile, and redox-responsive-facilitate intracellular drug release, while non-cleavable and solubility-enhancing designs improve stability and pharmacokinetics (PK). Case studies of FDA-approved ADCs, including brentuximab vedotin, polatuzumab vedotin, inotuzumab ozogamicin, and loncastuximab tesirine, demonstrate how these innovations translate into therapeutic benefit. Nonetheless, challenges such as antigen heterogeneity, resistance mechanisms, and off-target toxicities persist. By integrating advances in conjugation chemistry, linker engineering, and payload selection, next-generation ADCs are poised to expand efficacy and safety in hematologic oncology and further refine targeted therapy in blood cancers.
    Keywords:  ADCs; Bioconjugation Chemistry; DAR; Hematological malignancies; Linker chemistry
    DOI:  https://doi.org/10.1053/j.seminhematol.2025.11.004
  40. J Mark Access Health Policy. 2025 Dec;13(4): 61
    How Patients Can Contribute to the Assessments of Health Technologies.
    François Houÿez, Julien Delaye.
      In the process of determining whether a health technology should be covered by healthcare systems, patients and their representatives were initially excluded from both evaluations and decision-making. In Europe, direct dialogue between patient organisations and regulatory authorities-particularly in the pharmaceutical sector-began in the early 1990s. It was only decades later, as the high cost of medicines created new challenges, that authorities recognised the necessity of engaging with patients. Patients' contributions to the assessment of a health technology begin with discussions about the need for the technology in question. Initially, these discussions involve the developer, and later-after research and development-regulators, HTA assessors, and payers. Given that multiple technologies may be under development, patients and their organisations often prioritise those that generate the most interest within the patient community. They can then share their perspectives with evaluators during the horizon-scanning phase. Another key contribution is the role patients play in guiding clinical research by participating in scientific advice. Finally, during the assessment and appraisal stages, various methods are used to gather their views.
    Keywords:  appraisal; capacity building; community advisory boards; health technology assessment; horizon scanning; mentoring programme; patent engagement/involvement; scientific advice
    DOI:  https://doi.org/10.3390/jmahp13040061
  41. Bull Cancer. 2025 Dec 23. pii: S0007-4551(25)00533-8. [Epub ahead of print]
    [Estimating the real price of CAR-T cells in France: From list price to net price].
    Carole-Anne Brugère, Pascal Deschaseaux, Emmanuel Gomez, Charlotte Roffiaen, Théau Brigand, Guillaume Esposito, André Baruchel, Roch Houot, Christian Chabannon.
       INTRODUCTION: CAR-T cells represent a breakthrough in relapsed or refractory hematologic malignancies. In France, they are commonly associated with prices ranging from €300,000 to more than €400,000, based on early access indemnities and initial list prices. Yet these figures do not reflect the actual cost for the healthcare system, which is reduced by confidential rebates and pricing adjustments negotiated between companies and public authorities. This study aims to estimate the real (net) price of commercial CAR-T cells therapies in France and analyze the evolution of their public list prices over time.
    METHODS: The WP5 "Value & Access" working group of the UNITC consortium conducted a document-based analysis using list prices published in the Journal Officiel (JO), therapeutic value assessments (SMR/ASMR) from the French Health Technology Assessment agency (HAS), early access prices, and average rebate rates reported by the public agency in charge of pricing negotiations (CEPS). A sensitivity analysis was conducted using various rebate scenarios.
    RESULTS: Applying the 2023 average rebate rate for antineoplastics (36.2 %) yields an estimated median net price of €220,110. The sensitivity analysis, using rebate assumptions from 25 to 45 %, gives a median of €212,550 (IQR: €51,750). Public list prices have decreased by an average of 14 % at each new negotiation round.
    CONCLUSION: While the list price published in the JO serves as a public and international benchmark, it does not reflect the actual financial burden. Net price represents only one part of the broader societal cost, which also includes organizational and infrastructure-related expenses.
    Keywords:  CAR-T cells therapies; Cellules CAR-T; Drug pricing; Estimation du prix net; France; Net price estimation; Prix des médicaments; Rebate analysis; Remises
    DOI:  https://doi.org/10.1016/j.bulcan.2025.11.010
  42. MedComm (2020). 2026 Jan;7(1): e70547
    The Role of Macrophages in Cancer: From Basic Research to Clinical Applications.
    Zhimei Liu, Yan Li, Jingchao Cao, Yefeng Qiu, Kun Yu, Shoulong Deng.
      Macrophages are innate immune cells that extensively infiltrate and play a key role in the tumor microenvironment (TME). Tumor cell-secreted factors recruit monocytes into the TME, where they differentiate into tumor-associated macrophages (TAMs), which can polarize into distinct phenotypes: M1 and M2. M1 TAMs promote antitumor immunity through cytokine secretion and antigen presentation, whereas M2 TAMs support tumor progression by facilitating angiogenesis, invasion, and immune escape. Despite these dual roles, the specific mechanisms governing macrophage plasticity and polarization remain insufficiently understood. This review comprehensively summarizes the origin, polarization, and functional diversity of macrophages in the TME, with emphasis on pathways that regulate TAM-mediated immune responses. Furthermore, this article examines current TAM-targeted therapeutic strategies, including recruitment inhibition, phenotypic reprogramming, and the development of chimeric antigen receptor macrophages (CAR-Ms), as well as macrophage-based drug delivery and exosome therapy. By integrating recent advances in cell engineering and immunometabolism, this review highlights the translational potential of TAM-targeted therapies and their value in reshaping the immunosuppressive TME to enhance cancer immunotherapy.
    Keywords:  CAR‐M; cell therapy; macrophages; tumor microenvironment; tumor‐associated macrophages
    DOI:  https://doi.org/10.1002/mco2.70547
  43. Cancer Lett. 2025 Dec 24. pii: S0304-3835(25)00807-9. [Epub ahead of print] 218235
    Anti-BCMA-CAR-IL15 natural killer cells prevent multiple myeloma growth in the bone marrow but allow subsequent emergence of extramedullary disease.
    Shelby Kaczmarek, Donghyeon Jo, Safa Ghaziasgar, Bryan Marr, Stefania Berton, Lisheng Wang, Mehdi Arbabi Ghahroudi, Mihue Jang, Alissa Visram, Scott McComb, Seung-Hwan Lee.
      Multiple myeloma (MM) is an aggressive blood cancer arising from plasma cells. B cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell (α-BCMA-CAR-T) immunotherapies currently provide life-saving treatment for MM patients. Unfortunately, the high cost and manufacturing complexity of autologous CAR-T therapy remain important limitations. Novel research is underway to use CAR-expressing natural killer (NK) cells as an allogeneic CAR-T alternative, but studies have yet to evaluate long-term CAR-NK efficacy against MM. In this study, NK cells were isolated, expanded via feeder-cell stimulation, and engineered to express α-BCMA-CAR with or without human IL-15 co-expression using lentiviral vectors. In a xenograft model, both α-BCMA-CAR and IL-15 expression were required for persistent restriction of MM growth in the blood and bone marrow. Despite near complete and sustained elimination of MM in the bone marrow, long-term assessment of mice treated with α-BCMA-CAR-IL15 NK cells revealed the emergence of extramedullary disease (EMD) in the form of BCMA-positive MM plasmacytomas. This study showcases α-BCMA-CAR-IL15 NK cell therapy as a potent anti-MM therapeutic, achieving sustained MM elimination from the bone marrow and greatly extending survival. However, α-BCMA-CAR-IL15 NK cells appeared ineffective at eliminating extramedullary disease. By demonstrating the strengths and weaknesses of α-BCMA-CAR-IL15 cells, we hope this study could help direct the use of such therapies in clinical trials and provide a valuable pre-clinical MM model for studying and developing interventions for aggressive MM-EMD.
    Keywords:  BCMA-CAR; chimeric antigen receptor; extramedullary disease; multiple myeloma; natural killer cells; plasmacytomas
    DOI:  https://doi.org/10.1016/j.canlet.2025.218235
  44. Cancer Causes Control. 2025 Dec 24. 37(1): 1
    Bridging the rural cancer gap: why clinical trials must include rural patients.
    Ingrid Jacobson, Emily McGovern, Wade Swenson.
      Oncology clinical trials are not readily available to rural residents in the United States despite rural disparities in preventable cancer incidence, prevalence, and mortality. We comment on the underrepresentation of rural populations in oncology clinical trials, identify key barriers to rural participation, and highlight ways to overcome these barriers, including successful national and international models of inclusive oncology trial design.
    DOI:  https://doi.org/10.1007/s10552-025-02106-z
  45. Am Psychol. 2025 Dec;80(9): 1410-1424
    Translating neurophysiological biomarkers into clinical tools: A psychometric blueprint illustrated with the error-related negativity.
    Peter E Clayson.
      Clinical neuroscience seeks reliable biomarkers for psychiatric diagnosis, prognosis, and treatment, but translation has stalled because replication is inconsistent, theory is incomplete, and links to psychological processes are unclear. These shortcomings largely stem from inadequate attention to psychometric principles. This review focuses on event-related potentials and shows how assessment of reliability and validity, as well as optimization and standardization, can support the development of actionable biomarkers. Biomarker development can falter when measures are adapted from basic research protocols that emphasize within-person contrasts and minimize between-person variance, a strategy poorly suited to examining individual differences. Many biomarkers show poor internal and test-retest reliability when used to distinguish individuals or predict clinical outcomes, especially in patient populations in which data are more variable. Furthermore, the validity of any biological measure depends on well-articulated causal models linking brain activity to psychological phenomena. A roadmap, guided by the U.S. Food and Drug Administration and the National Institutes of Health Biomarkers, EndpointS, and other Tools resource, aligns psychometric work with analytic validation, clinical validation, and context-of-use qualification. This framework is illustrated with the error-related negativity (ERN), an event-related potential that has progressed from basic cognitive research to a prognostic biomarker for anxiety. Priorities for ERN development include meeting high reliability thresholds, optimizing tasks and pipelines for clinical samples, and harmonizing acquisition and analysis to support cross-site generalization. Although the focus of the review is on ERN, the principles apply broadly to all biological measures. The proposed process for guiding biomarker evaluation through psychometrics will pave the way for better selection of biomarkers, ultimately improving their clinical utility in precision medicine. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
    DOI:  https://doi.org/10.1037/amp0001620
  46. Transfusion. 2025 Dec 23.
    Training in cell and gene therapy manufacturing: Unmet needs and arguments for graduate medical education.
    Yongping Wang, David McKenna, Thomas Spitzer, Patricia Brunker, Elena Nedelcu, Andrew Fesnak, Christina Celluzzi, Margaret DiGuardo, Eapen K Jacob.
      
    DOI:  https://doi.org/10.1111/trf.70021
  47. Mol Ther. 2025 Dec 24. pii: S1525-0016(25)01070-6. [Epub ahead of print]
    Cre-dependent gene expression enables thymic development of autoreactive tumor associated antigen targeting chimeric antigen receptor T cells.
    Manpreet Bariana, Michael McGuire, Andrea Tuckett, Elena Cassella, Sidharth Anand, Shaina A Anuncio, Sara Mina, Sharoni Avtalion, Megan A Lloren, Nicolai Bogert, Mathias Konstandin, Justin Boucher, Nolan Beatty, Shannon McSain, Wei Hu, Hai-Hui Xue, Marco L Davila, Johannes L Zakrzewski.
      Chimeric antigen receptor (CAR) T cells have revolutionized cancer therapy by enabling highly specific adoptive cellular treatments. However, limited in vivo persistence and tumor relapse remain major challenges. To address this, we developed a platform for continuous in vivo generation of CAR-T cells by genetically engineering hematopoietic stem and progenitor cells (HSPC) to express a tumor-specific CAR followed by administration directly into the thymus. We demonstrated in single-cell RNA sequencing and serial transplantation studies that the thymic microenvironment supports short-term hematopoietic stem cells and initiates a transcriptional program that drives T cell lineage differentiation. A key challenge of thymic CAR-T cell development is thymic negative selection, which eliminates developing thymocytes expressing autoreactive antigen receptors such as CD19 CARs. We show that reducing CAR co-stimulation and modifying the endogenous TCR repertoire can enhance the survival of these cells during thymic development. Additionally, inducible CAR gene expression enables sustained thymic production of CD19 CAR-T cells, which can target both normal B cells and CD19-positive tumor cells. Our findings highlight mechanisms governing the fate of CAR-T cell precursors in the thymus and support inducible expression systems as a strategy to bypass central tolerance, offering a path toward durable, self-renewing CAR-T cell therapies.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.047
  48. Saudi Pharm J. 2025 Dec 24. 34(1): 1
    AI-powered in silico twins: redefining precision medicine through simulation, personalization, and predictive healthcare.
    Sitah Alharthi.
      In silico twins (ISTs) are emerging as a transformative paradigm in precision medicine, offering dynamic, high-fidelity representations of individual patients through real-time integration of multimodal data. In this work, we define an in silico twin (IST) as a high-fidelity, artificial intelligence(AI)-augmented computational replica of an individual's biological systems that integrates mechanistic modeling (e.g., PBPK, QSP) with patient-specific data streams to simulate, predict, and optimize therapeutic outcomes in real time. By combining AI, physiological and biomechanical modeling, and advanced simulation engines, these systems enable continuous monitoring, predictive diagnostics, and personalized treatment planning. Unlike conventional digital tools, ISTs provide iterative, adaptive simulations that evolve with patient states, fostering a shift from reactive to proactive healthcare. This review explores the technological foundations underpinning ISTs -including machine learning architectures, multi-scale physiological modeling, data integration, and cloud-edge infrastructure- and maps their clinical applications across the patient care continuum. We also distinguish ISTs from digital twins, virtual patients, and traditional computational models, emphasizing their unique contribution to decision support, drug development, and therapeutic optimization. As digital healthcare ecosystems mature, ISTs represent a crucial step toward simulation-driven, individualized medicine. Their continued development offers substantial potential for improving outcomes, accelerating discovery, and reshaping the clinical landscape. Uniquely, this review introduces a practical taxonomy of IST architectures, a verification and validation checklist for model credibility, and a deployment blueprint to guide their clinical translation and real-world adoption.
    Keywords:   In silico twins; Digital health; Personalized therapy; Precision medicine; Predictive modeling
    DOI:  https://doi.org/10.1007/s44446-025-00055-x
  49. Front Immunol. 2025 ;16 1711887
    Significance and challenges of immunopharmacogenomics.
    Lara Hanci Handzha, Yusuke Nakamura.
      Pharmacogenomics traditionally examines how inherited genetic variations influence drug metabolism, pharmacodynamics, and toxicity. Recent advances have highlighted the immune system as a critical determinant of therapeutic efficacy and safety. Immunopharmacogenomics integrates genetic information, particularly HLA polymorphisms and immune repertoire dynamics of T-cell and B-cell receptors (TCRs and BCRs), to explain interindividual differences in drug responses, immune-related toxicities/diseases. This review summarizes how HLA diversity, immune repertoire heterogeneity, and tolerance mechanisms shape therapeutic outcomes across diverse clinical contexts, including immune-mediated adverse drug reactions, cancer immunotherapy, graft-versus-host disease, autoimmune disorders, food allergy, transplantation, and vaccination. Emerging evidence indicates that immune repertoire sequencing captures dynamic clonal shifts and diversity alterations associated with disease states and treatment responses, providing both mechanistic insight and predictive biomarkers. By integrating genetic and immune repertoire analyses, immunopharmacogenomics establishes a framework for individualized prediction, safer drug design, and more precise immunotherapies, thereby advancing the next phase of precision medicine.
    Keywords:  BCR; HLA; TCR; immunopharmacogenomics; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2025.1711887
  50. Vaccines (Basel). 2025 Dec 03. pii: 1222. [Epub ahead of print]13(12):
    Engineering Anti-Tumor Immunity: An Immunological Framework for mRNA Cancer Vaccines.
    Olivia Roy, Karen S Anderson.
      The landscape of cancer immunotherapy has been redefined by mRNA vaccines as rapid clinically viable strategies that help induce potent, tumor-specific immune responses. This review highlights the current advances in mRNA engineering and antigen design to establish an integrated immunological framework for cancer vaccine development. Achieving durable clinical benefit requires more than antigen expression. Effective vaccines need precise epitope selection, optimized delivery systems, and rigorous immune monitoring. The field is shifting from merely inducing immune responses to focusing more on the biochemistry and molecular design principles that combine magnitude, polyfunctionality, and longevity to overcome tumor-induced immune suppression. We examine an integrated immunological framework for mRNA cancer vaccine development, examining how rational molecular engineering of vaccine components, from nucleoside modifications and codon optimization to untranslated regions and linker sequences, shapes immunogenicity and therapeutic efficacy. Future directions will depend on balancing combinatorial strategies combining vaccination with immune checkpoint inhibitors and adoptive cell therapies.
    Keywords:  antigen presentation; cancer immunotherapy; epitope engineering; lipid nanoparticles; mRNA vaccines; multi-epitope vaccine design; precision oncology; tumor microenvironment
    DOI:  https://doi.org/10.3390/vaccines13121222
  51. Cureus. 2025 Nov;17(11): e97517
    Current Status of Colorectal Cancer Screenings: Tailoring Them to Mississippi's Rural Geography, Demographics, Infrastructure and Community Needs.
    Srinivasan Vijayakumar, Sudheer Koutha, Catherine Young, Vani Vijayakumar, Cecelia Brewington, Felisa Wilson-Simpson, Lilanta J Bradley.
      Colorectal cancer (CRC) is a major cancer problem not only in western nations, but also now even in the developing world such as the Global South (GS). Within the US, the outcomes are worse in resource-scarce Deep South (DS) states including Mississippi (MS). The irony is that CRC can be diagnosed in precancerous and early stages with CRC screening (CRCS) - thus can stop progression to CRC (improving the survival outcomes). This irony is due to the low CRCS uptakes in MS and DS. Why CRCS uptake remains low in MS and DS was recently reviewed by us ("How to Change the Tide of Bad News to a Success Story") and that the solution is in 'using the right health care intervention at the right time for the right population', using an interdisciplinary, continuum of care approach with an emphasis on the involvement of community health care workers (CHCW). Use of cutting-edge new innovations such as precision population medicine concepts that include telemedicine, wearable devices, socioeconomic deprivation indexes with an emphasis on community education including for the CHCW. However, the sheer number of CRCS options and possible combinations make it even more complex for an average practitioner (let alone for a CHCW) to comprehend and offer the right choice for the population at risk. To remedy, this second report in this series aims to serve as a comprehensive source describing various state-of-the-art options in CRCS as well as outlining the advantages and disadvantages of each. This 'guide' emphasizing an interdisciplinary approach as well as not using one-size-fits-all models in CRCS policies is likely to improve CRC uptake and outcomes in MS and DS. This team of interdisciplinary experts synthesized a conceptual framework from a peer-reviewed literature review of the past decade leading to new hypotheses, innovations and ideas for practice and future research. CRCS options recommended by professional societies, including invasive direct visualization (colonoscopy and sigmoidoscopy), non-invasive direct visualization (CT colonography and colon capsule endoscopy), and stool- and blood-based screening, are detailed, highlighting relative advantages, limitations, and optimal use scenarios. Using insights from simulation models and population-level studies, the cost-effectiveness and clinical outcomes of 13 different CRCS strategies are considered. Evidence from international randomized trials and national healthcare systems provided key perspectives on tailoring screening practices based on patient risk, access, provider readiness, and local infrastructure is presented. Cluster-randomized trials from rural U.S. regions supported the integration of CHCW and patient navigation in improving CRCS uptake are described. Finally, a conceptual framework to guide implementation of precision, community-tailored CRCS interventions in high-risk and underserved populations, aligning with current U.S. Multi-Society Task Force recommendations are proposed, focusing on equity, early initiation of screening, and informed choice of testing strategies. The paper concludes with listing short-, mid- and long-term potential practical implementation and research ideas. These steps, especially with the rapidly evolving technological and biological innovations, can lead to more successful, efficient and cost-effective CRCS strategies for the state of MS, other states in DS as well as similar communities in the Global South.
    Keywords:  ai based modeling; colon capsule endoscopy; colonoscopy; colorectal cancer; colorectal cancer screening; ct colonography; deep south; fecal immunochemical test; global south; mississippi
    DOI:  https://doi.org/10.7759/cureus.97517
  52. Public Health Chall. 2025 Dec;4(4): e70179
    Charters in Patient-Engaged Research: A Scoping Review of Current Evidence.
    Jenny Martínez, Catherine Verrier Piersol, Richard W Hass, Felicia Chew, Amy Cunningham, Sharon Larson.
       Aims: Research study charters facilitate shared governance and power sharing with research partners when developed collaboratively and early on in a study. Study charters are negotiated and developed on a study-by-study basis, offering insight into study-specific dynamics between research partners and investigators, as well as the factors that each identify as important for their collaboration. This review aimed to map and synthesize existing evidence on the development, structure, and implementation of research study charters used in patient-engaged research.
    Methods: We searched peer-reviewed literature published worldwide in English between January 2019 and January 2025.
    Results: Our final sample consisted of 17 citations, including 5 journal articles and 12 charters available on Patient-Centered Outcomes Research Institute's (PCORI's) Engagement Tool and Resource Repository. Research study charters varied in their development, structure, and content.
    Conclusions: We identified research study charters that varied in quality, detail, and methods. Valid, systematic, and inclusive study charters that are developed with research partners and reflect a diversity of perspectives can improve governance and engagement in research partnerships. Their adoption may enhance the quality and inclusivity of patient-centered research and represent an important area for future investigation.
    Keywords:  comparative effectiveness research; methodology; patient engagement; systematic review; translational research
    DOI:  https://doi.org/10.1002/puh2.70179
  53. Zhonghua Yi Xue Za Zhi. 2025 Dec 25. 106 1-5
    [Innovation-driven pharmaceutical development and clinical advancement].
    X T Cao.
      With a focus on strengthening innovative drug development and promoting the clinical application of emerging medical technologies, we have summarized innovation-driven pharmaceutical development and clinical advancement, highlighting the key challenges, current hotspots, and potential breakthroughs, while outlining priority directions for fostering deeper integration between pharmaceutical development and medical practice. This paper provides a systematic analysis of the progress, challenges, and future directions of China's innovative drug development. Currently, through biomedical technology innovation, comprehensive policy support, accelerated regulatory reviews and approval processes, and reforms in the payment system, China has risen to a leading global position in terms of the number of innovative drugs developed and license-out deals. However, challenges remain, including weak capacity for original innovation, insufficient alignment with clinical needs, and limited international engagement. To address these, the country has recently launched the national major science and technology special project on drug development in the new phase. This initiative aims to shift the focus toward capacity building, drug discovery and original innovation, while optimizing the project organization and management to foster a collaborative innovation ecosystem. The goal is to establish an independent, controllable, and world-leading drug innovation system by 2035, thereby providing strong support for the "Healthy China" initiative.
    DOI:  https://doi.org/10.3760/cma.j.cn112137-20251221-03372
  54. Ann Pharm Fr. 2025 Dec 18. pii: S0003-4509(25)00220-2. [Epub ahead of print]
    Comparative Study of Regulatory Frameworks for Medicinal Products in Eurasian Economic Union and European Union.
    C P Keerthana, Sanjay Sharma.
       OBJECTIVE: The Eurasian Economic Union aims in harmonizing the pharmaceutical regulations among the member states while aligning with the international standards. The transition to harmonized regulation in the Eurasian Economic Union faces unique challenges, including ambiguity in regulatory pathways and alignment with international benchmarks. The objective of this study is to compare and analyze the gaps between the regulatory frameworks for medicinal products within the Eurasian Economic Union and European Union. Thus, this study explores similarities and differences in both the regulatory frameworks and provides suggestions to address these gaps.
    METHODS: The study follows a descriptive and comparative analysis of the regulatory frameworks for medicinal products of Eurasian Economic Union and European Union. The data regarding the regulations were collected from the official documents, regulations and guidelines published on their official websites (EudraLex and legal portal of Eurasian Economic Union) by the Eurasian Economic Commission and European Commission.
    RESULTS: The findings suggest that while the Eurasian Economic Union's regulatory framework for medicinal products shares similarities with the European Union's system, particularly in adopting mutual recognition and decentralized procedure, significant gaps remain in timelines, labelling requirements, clinical trial process, pharmacovigilance, dossier requirements and other aspects.
    CONCLUSION: While the European Union has a well-established system, the Eurasian Economic Union is still navigating the operational complexities and adapting to the challenges. By aligning with the European Union's framework, the Eurasian Economic Union can increase its credibility at the global level. This study underscores the importance of the Eurasian Economic Union's ongoing harmonization effort as a major step towards strengthening its position in the global market.
    Keywords:  EAEU; EU regulations; UEE; common market of EAEU; marché commun de l’UEE; medicinal product regulations; règlements de l’UE; règlements sur les médicaments
    DOI:  https://doi.org/10.1016/j.pharma.2025.12.011
  55. Zhonghua Zhong Liu Za Zhi. 2025 Dec 23. 47(12): 1195-1210
    [Expert consensus on clinical application of whole nutritional oncology foods for special medical purposes (2025 edition)].
    Specialised Committee on Tumour Nutrition Therapy of Chinese Society of Clinical Oncology
      Malnutrition and metabolic disorders occur in a high proportion of oncology patients, and malnutrition has a significant impact on both treatment and prognosis, resulting in a heavy disease and economic burden. In recent years, as awareness of the nutritional status of oncology patients has improved, especially the multiple negative effects of malnutrition, it has highlighted the lack of clinical treatment and insufficient knowledge of adverse effects, leading to the lack of special medical use foods for oncology patients as well as irregularities in their use. In order to further promote the clinical and family standardised application of special medical purpose foods for oncology patients, the expert group collects and collates high-quality evidence in recent years, and discusses and summarises the opinions on clinical application, and consolidates the consensus "Expert consensus on clinical application of whole nutritional oncology foods for special medical purposes (2025 edition)", aiming to promote the standardisation of oncology nutritional treatment, meet the special nutritional needs of oncology patients, improve the clinical knowledge on the application of special medical purpose foods for oncology, and provide detailed and practical guidance on clinical operation.
    DOI:  https://doi.org/10.3760/cma.j.cn112152-20250529-00246
  56. Front Immunol. 2025 ;16 1723383
    From immune suppression to immunotherapy sensitization: the dual roles of circRNAs in cancer progression.
    Quan Dai, Xiaoli Yuan, Hang Dong, Haiyi Xue.
      Circular RNAs (circRNAs) have recently emerged as critical regulators of tumor-immune interactions. Owing to their covalently closed structure, remarkable stability, and tissue-specific expression, circRNAs not only serve as molecular sponges and protein regulators but also play multifaceted roles in shaping the tumor immune microenvironment. Accumulating evidence indicates that circRNAs drive immune suppression by stabilizing PD-L1 through post-translational modifications and RNA-binding protein interactions, transmitting suppressive signals via exosomes to T cells and myeloid-derived suppressor cells, reprogramming glucose and lipid metabolism to deprive effector lymphocytes, and reinforcing cancer stemness and therapy resistance. In striking contrast, a subset of circRNAs has been shown to sensitize tumors to immunotherapy by activating innate immune pathways such as RIG-I/MAVS and STING, inducing immunogenic cell death, and overcoming resistance to endocrine therapy or ferroptosis inducers, thereby enhancing the efficacy of immune checkpoint blockade. Beyond their mechanistic functions, circRNAs also hold promise as stable and accessible biomarkers for prognosis, patient stratification, and therapeutic monitoring, particularly when enriched in circulating exosomes. Advances in antisense oligonucleotides, RNA interference, and nanomedicine provide new opportunities to therapeutically target oncogenic circRNAs or deliver engineered pro-immunogenic circRNAs. While significant challenges remain in detection accuracy, functional annotation, delivery specificity, and clinical validation, circRNAs represent a new frontier in immuno-oncology. Harnessing their dual roles may unlock innovative biomarker platforms and next-generation RNA-based therapeutics, ultimately improving the efficacy of cancer immunotherapy.
    Keywords:  PD-L1 regulation and immune escape; biomarkers and RNA therapeutics; circular RNAs (circRNAs); immunotherapy sensitization; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1723383
  57. Biogerontology. 2025 Dec 22. 27(1): 27
    CD47 signaling in aging and age-related diseases: mechanisms, challenges, and therapeutic opportunities.
    Arsene Mutombo Menga, Xin Hong, Lei Zhu.
      Aging is marked by progressive dysfunction in cellular maintenance pathways, including mitochondrial impairment, reduced autophagic capacity, and accumulation of senescent cells, which contribute to chronic low-grade inflammation. The transmembrane protein CD47 best known for delivering a "don't eat me" signal through SIRPα is increasingly recognized as an important modulator of several aging-related processes. Its upregulation in aged or inflamed tissues can inhibit the clearance of damaged or senescent cells, reinforce inflammatory signaling through pathways such as NF-κB, and influence metabolic and autophagy-related regulation in a context-dependent manner. This review synthesizes current evidence identifying CD47 as an integrative node that intersects with multiple hallmarks of aging. We examine its roles across cardiovascular, neurodegenerative, and metabolic pathologies, and evaluate the emerging therapeutic landscape targeting the CD47-SIRPα axis. Although CD47 blockade has shown promise in enhancing immune clearance and improving tissue homeostasis, clinical translation remains challenged by on-target toxicities such as anemia and by age-dependent variability in immune responsiveness. Targeting CD47 therefore represents a mechanistically grounded but inherently complex strategy for mitigating age-related functional decline.
    Keywords:  Age-related diseases; Aging; CD47; Phagocytosis; Senescence
    DOI:  https://doi.org/10.1007/s10522-025-10370-4
  58. Genes Cells. 2026 Jan;31(1): e70077
    TCR Repertoire Analysis Quantifies Effect of Irradiation on Homeostasis of iNKT Cell Development in the Thymus of Mice.
    Kazumasa B Kaneko, Mio Hayama, Nanako Uchida, Takahisa Miyao, Nobuko Akiyama, Taishin Akiyama, Tetsuya J Kobayashi.
      Thymic T cell development shows homeostasis against various stressors. Invariant natural killer T (iNKT) cells in the thymus contribute to recovery of thymic development after irradiation owing to their initial tolerance to irradiation compared to conventional thymocytes. However, whether and how iNKT cell development recovers from irradiation remains unknown. Here we show that iNKT cells in the thymus exhibit much slower postirradiation recovery than conventional thymocytes. We observed that fluctuation of V and J genes usage does not correlate with the decrease of iNKT cell population and that irradiation markedly elevated the frequency of cell death relative to proliferation in iNKT cells. Mathematical modeling of recovery dynamics of iNKT cell progenitors implied that lack of rapid proliferation immediately after irradiation, unlike conventional thymocytes, contributes to the prolonged reduction of iNKT cell population. These findings indicate that the development of iNKT cells is subject to long-term effects of irradiation which leads to an increased rate of cell death and raise the possibility of an association between the prolonged reduction of iNKT cells after irradiation and autoimmune diseases caused by irradiation in bone marrow transplantation.
    Keywords:  TCR repertoire; iNKT cells; mathematical modeling; thymocytes; thymus regeneration; total body irradiation
    DOI:  https://doi.org/10.1111/gtc.70077
  59. Med Oncol. 2025 Dec 26. 43(2): 90
    Nanovaccines in hepatocellular carcinoma: a new frontier in cancer immunotherapy.
    Afreen Usmani, Mohd Aftab Siddiqui, Anuradha Mishra, Rania I M Almoselhy, Ambreen Shoaib, Mirunalini Gobinath, Mohd Nazam Ansari.
      Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, underscoring the urgent need for novel therapeutic approaches beyond standard treatments. Nanovaccines are a revolutionary platform in cancer immunotherapy, providing improved antigen delivery, enhanced immune activation, and targeted tumor targeting. This review critically discusses the promise of nanovaccines in HCC therapy, specifically focusing on their ability to induce strong antitumor immune responses while avoiding systemic toxicity. Key nanoplatforms such as lipid-based nanoparticles, polymeric carriers, and dendrimers are explained in detail to describe their mechanisms for encapsulating adjuvants and tumor-associated antigens to enhance immunogenicity. Further, we explain underlying mechanisms of action such as antigen cross-presentation, T-cell activation, and regulating the tumor microenvironment for immune evasion in HCC. Possible future directions in preclinical and clinical research and issues involving large-scale manufacturing and deployment are discussed, including combinatorial approaches using immune checkpoint inhibitors. This paper emphasizes the potentially transformative role of nanovaccines in the therapeutic regimen of HCC. It offers critical feedback on how their efficacy, safety, and translatability can be maximized for designing the next generation of cancer immunotherapies.
    Keywords:  Antigen delivery; Cancer immunotherapy; Hepatocellular carcinoma; Nanovaccines; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12032-025-03204-3
  60. Front Immunol. 2025 ;16 1718256
    Nanocarrier-based delivery of siRNA therapeutics in rheumatoid arthritis: immune mechanisms and translational perspectives.
    Longbin Bai, Peng Su.
      Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation, pannus formation, and progressive joint destruction. Conventional therapies, including methotrexate, NSAIDs, and biologics, have improved outcomes but remain limited by incomplete efficacy, adverse effects, and resistance. Small interfering RNA (siRNA) has emerged as a promising strategy due to its ability to selectively silence pathogenic genes such as TNF-α, IL-1β, IL-6, IL-17, VEGFA, and key signaling pathways including NF-κB, JAK/STAT, and MAPK. Preclinical studies have shown that siRNA can suppress inflammation, reduce pannus formation, and protect cartilage; however, clinical translation is hindered by instability, nuclease degradation, poor biodistribution, and off-target effects. Nanocarrier-based systems offer solutions by improving siRNA stability, cellular uptake, and targeted delivery to inflamed joints. Lipid nanoparticles, PLGA, chitosan, and polyethyleneimine have been widely studied, while emerging carriers such as dendrimers, self-assembling peptides, mesoporous silica, and metal-organic frameworks (MOFs) further enhance controlled release and specificity. Functional modifications with ligands such as folic acid, hyaluronic acid, or RGD peptides enable active targeting, and stimuli-responsive designs allow pH-, ROS-, or enzyme-triggered release. Theranostic platforms also provide opportunities for real-time monitoring of biodistribution and therapeutic efficacy. Overall, siRNA-based nanomedicine represents a promising therapeutic paradigm for rheumatoid arthritis; however, its clinical translation remains constrained by several important challenges. Although current nanocarrier platforms demonstrate strong gene-silencing efficiency and encouraging anti-inflammatory outcomes in preclinical models, their behavior in humans is far less predictable. Key obstacles-including systemic stability, protein corona formation, endosomal escape efficiency, batch-to-batch manufacturing consistency, and long-term biosafety-must be rigorously addressed before clinical application can be realized. In addition, the heterogeneous nature of RA and its fluctuating inflammatory microenvironment imply that a single siRNA target or delivery strategy may not be universally effective across patient populations. Regulatory considerations also pose significant barriers, as siRNA nanomedicines must meet strict requirements for GMP production, quality control, sterility, pharmacokinetics, immunogenicity, and degradation profiling.
    Keywords:  RNA interference; nanocarriers; rheumatoid arthritis; siRNA; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1718256
  61. Expert Rev Hematol. 2025 Dec 24.
    Improving transfusion access through improved policy: a call for a less fragmented blood supply.
    Jeremy W Jacobs, Sheharyar Raza, Suzanne Maynard, Beth H Shaz, Aaron Ar Tobian, Evan M Bloch.
       INTRODUCTION: Fragmentation across operations, data systems, governance, and regulation leaves many blood supply networks ill-equipped to provide timely, equitable, and crisis-resilient transfusion support. Public health emergencies, such as COVID-19 and natural disasters, have exposed the human and economic costs of these structural flaws, and how variability in practice about who can see and share data still impedes coordination even when the overall blood inventory is adequate.
    AREAS COVERED: This Critical Perspective examines blood supply coordination challenges in high-income countries, focusing on governance structures, operational isolation, regulatory inconsistencies, and data system incompatibilities. We analyze evidence from crisis events including pandemics, natural disasters, and mass casualty incidents to illustrate coordination failures and successful response models. The review synthesizes peer-reviewed literature identified through PubMed searches (January 2010 - September 2025), supplemented by regulatory documents, industry reports, and government policy analyses from blood regulatory agencies in the United States, United Kingdom, Canada, and other high-income countries.
    EXPERT OPINION: Effective solutions require coordinated interventions across multiple domains rather than isolated or localized improvements. Priority areas include governance structures that enable cross-institutional collaboration, interoperable data systems with standardized sharing protocols, regulatory frameworks that incentivize coordination, and value-based reimbursement models that reward system-wide performance.
    Keywords:  Blood supply; blood transfusion; emergency preparedness; health policy; high-income country; inventory management; supply chain
    DOI:  https://doi.org/10.1080/17474086.2025.2610282
  62. J Cancer Policy. 2025 Dec 20. pii: S2213-5383(25)00143-2. [Epub ahead of print]47 100699
    Progression-free survival is strongly associated with overall survival in relapsed/refractory diffuse large B-cell lymphoma in the CAR T-cell era.
    Alexander M Gorzewski, Rebecca Z Steuer, Charmi Trivedi, Kaavya Mandi, Christina A Raker, Charles J Milrod, Ari R Pelcovits.
       INTRODUCTION: In clinical trials for diffuse large B-cell lymphoma (DLBCL), progression-free survival (PFS) has been used as a validated surrogate endpoint to help expedite drug development and regulatory approval. The advent of chimeric antigen receptor (CAR) T-cell therapies has radically changed the treatment landscape, potentially prolonging post-progression survival and weakening the correlation between PFS and overall survival (OS). This study evaluates the utility of PFS as a surrogate endpoint for OS in relapsed/refractory (R/R) DLBCL in the CAR T-cell era.
    MATERIALS AND METHODS: A systematic review of Phase 3 randomized clinical trials for R/R DLBCL initiated after 2015 was conducted. A weighted linear regression analysis was performed to assess the correlation between PFS and OS.
    RESULTS: Six trials, comprising 1577 patients, met the inclusion criteria. Weighted linear regression demonstrated a coefficient of determination (R²) of 0.88 (p = 0.0054), indicating a strong association between PFS and OS in R/R DLBCL trials conducted since the introduction of CAR T-cell therapy.
    DISCUSSION: These findings provide evidence that PFS remains a valid and strong surrogate endpoint for OS in the contemporary R/R DLBCL treatment landscape. This supports the continued use of PFS as a primary endpoint in regulatory studies for new therapies for R/R DLBCL and provides important information for health policy discussions on drug approval, insurance coverage, and reimbursement decisions for aggressive lymphomas.
    Keywords:  CAR T-cell therapy; Diffuse large B-cell lymphoma; Surrogate endpoints
    DOI:  https://doi.org/10.1016/j.jcpo.2025.100699
  63. Alzheimers Dement. 2025 Dec;21 Suppl 3 e107832
    Clinical Manifestations.
    Steffen Thirstrup.
       BACKGROUND: Regulatory agencies approval of medicines is always associated with a guidance to the prescriber and patient on the correct use. This include among other a detailed description of the target indication, ie the population for which the product has been shown to have an acceptable benefit:risk ratio. The population of the approved target indication is reflected in the patient population in which the supporting clinical evidence has been generated, which then again is linked to the design and conduct of therapeutic confirmatory clinical trials.
    METHOD: Review of current EMA policy RESULTS: Having globally agreed diagnostic criteria for a certain condition/disease is favouring global drug development and global regulatory alignment. Without such alignment clinical trials many have to be replicated or designed to meet different diagnostic criteria to meet regulatory expectations.
    CONCLUSION: This intervention will briefly outline the position of the European Medicines Agency on the above challenges with special attention to the current debate on diagnostic criteria for Alzheimer's Disease.
    DOI:  https://doi.org/10.1002/alz70857_107832
  64. Stem Cell Res Ther. 2025 Dec 24.
    The roles and clinical applications of mesenchymal stem cells and their exosomes in hematologic diseases.
    Mengxue Deng, Xiaoying Zhang, Yicheng Zhang.
      Mesenchymal stem cells (MSCs) are multipotent stem cells with critical functions, including immunomodulation, multidirectional differentiation, anti-inflammatory activity, tissue repair, and regeneration. Recent studies demonstrate that MSCs can enhance hematopoietic stem cell engraftment, mitigate graft-versus-host disease (GVHD), address transplant-related complications, and treat conditions such as immune thrombocytopenia (ITP) and severe aplastic anemia (SAA). These therapeutic effects are largely attributable to the immunomodulatory and anti-inflammatory properties of MSCs. However, in hematologic malignancies, MSCs can exert both pro-tumor and anti-tumor influences. Exosomes, which are extracellular vesicles derived from MSCs (MSC-EVs), not only replicate many MSC functions but also exhibit greater chemical stability and lower immunogenicity. These characteristics make MSC-EVs particularly significant in the context of hematopoietic stem cell transplantation (HSCT). This review provides a detailed overview of the roles and clinical applications of MSCs in hematologic diseases, the properties of MSC-EVs, and their emerging significance in HSCT.
    Keywords:  Exosomes; Graft-versus-host disease; Hematologic diseases; Hematopoietic stem cell transplantation; Immunomodulation; Mesenchymal stem cells
    DOI:  https://doi.org/10.1186/s13287-025-04880-8
  65. Adv Med Educ Pract. 2025 ;16 2369-2383
    Mapping the Landscape: A Systematic Review of Technology Trends in Medical Education and Competency Development.
    Ehsan Toofaninejad, Siamak Mirzaei, Ali Mahdavi Shakib, Dariush Gholipour Morad Dashtaki, Hosnieh Raoufian, Zohrehsadat Mirmoghtadaie, Somaye Sohrabi.
      Medical education has undergone significant transformations, driven by rapid technological advancements. This systematic review aims to map and analyze educational technology trends from the late 1970s to 2024, tracing their evolution and their Impacts on competency development. Following PRISMA guidelines, a comprehensive search was conducted across seven databases in August 2024, yielding 18 studies published between 1978 and 2024 for qualitative, thematic synthesis. The findings indicate that technology integration has evolved through distinct trends. While simulation-based approaches were most frequently reported to enhance clinical reasoning and psychomotor skills, blended learning was highlighted for enabling flexible delivery, and other technologies, such as e-learning platforms and Web 2.0 tools, also played significant roles in supporting knowledge acquisition and collaborative learning. Despite these benefits, high costs, infrastructure limitations, and the need for specialized faculty training were identified as persistent barriers to adoption. In conclusion, the literature review indicates that technological trends have enriched medical education by fostering interactive, accessible, and flexible learning environments. Future strategies must therefore focus on developing scalable, cost-effective solutions. A dedicated systematic review of AI's trajectory and impact is strongly recommended as a critical next step, building upon the historical foundation laid by this study.
    Keywords:  blended learning; computer-assisted instruction; educational technology; medical education; simulation training; systematic review
    DOI:  https://doi.org/10.2147/AMEP.S561949
  66. Prog Rehabil Med. 2025 ;10 20250041
    Physical Inactivity Syndrome: A Risk Factor and Target for Intervention-A Narrative Review.
    Masahiro Kohzuki.
      The aging of the world's population has caused a dramatic change in the overall health of patients, with many suffering from disuse syndrome-a condition caused by immobility and bed rest. Even among people who are able to live independently, newly defined issues such as frailty, sarcopenia, locomotive syndrome, and hospitalization-associated disability have rapidly emerged, and it has been found that physical inactivity is a key cause of these issues. Disuse syndrome is a term that is mainly used in Japan but not widely accepted elsewhere because of its negative connotations. Moreover, although the term physical inactivity is widely used, it has a strong connotation of simply referring to reduced physical activity and does not emphasize that it also poses systemic and multi-organ risks. To solve these problems, in this narrative review, I propose a new academic term-physical inactivity syndrome (PIS)- to describe the diverse physical, mental, and social symptoms and disorders caused by bed rest and decreased physical activity. PIS serves as an umbrella term for disuse syndrome, physical inactivity, frailty, sarcopenia, and related diseases. Furthermore, the effects of rehabilitation and exercise therapy required to prevent and treat PIS are introduced. It is necessary for medical professionals to be fully aware of the risks of PIS, properly acquire the skills needed to improve patient activity, and carry out prevention and treatment with sufficient confidence.
    Keywords:  multimorbidity; multiple disabilities; rehabilitation; rest; super-aged society
    DOI:  https://doi.org/10.2490/prm.20250041
  67. Patient Prefer Adherence. 2025 ;19 4091-4105
    Preferences for Non-Pharmacological Traditional Chinese Medicine in Cancer Care: A Mixed-Methods Systematic Review.
    Ying-Xiang Chen, You Zhou, Xiao-Lan Zhang, Wen-Yan He, Qin Ye, Min Xu.
       Background: Non-pharmacological therapies in traditional Chinese medicine (TCM) are gradually gaining popularity. However, there has been no systematic understanding about cancer patients' preferences regarding these treatments.
    Objective: This review aims to clarify cancer patients' preferences for these therapies and the factors influencing them through systematic integration of evidence.
    Methods: A systematic search was conducted among eight databases. The time period spanned from the inception of each database to April 7, 2025. The Mixed Methods Assessment Tool was employed to assess the quality of the studies that met inclusion criteria. The JBI Convergent Synthesis Method was used to transform the extracted quantitative data into qualitative data that was then synthesized with qualitative data. A socio-ecological model was applied to group factors that influence TCM choices.
    Results: A total of 27 studies were included in this review, consisting of 13 quantitative and 14 qualitative studies. The factors that might affect cancer patients' preferences in favor of TCM non-pharmacological therapies are multifaceted, covering every level that exists within the socio-ecological model, including the individual (belief and past experiences), interpersonal (professional recommendations and family), healthcare system (service accessibility and cost), society (cultural origins and resources), and governmental (insurance and standards). The PROSPERO registration was dated April 6, 2025 (Registration Number: CRD420251026914).
    Conclusion: Patients' preference for TCM non-pharmacological therapies is driven by cultural affinity and interpersonal care needs rather than objective clinical evidence. This reminds us that while respecting patient preferences is essential for achieving patient-centered care, we must also adhere to evidence-based science to ensure safety and effectiveness. Future research should prioritize non-pharmacological therapies other than acupuncture (eg, massage, qigong) to bridge the evidence gap regarding their safety and efficacy. One limitation of this review lies in the overemphasis on acupuncture among cited studies and the cultural homogeneity.
    Keywords:  cancer; influencing factors; mixed-methods study; non-pharmacological therapies; preferences; systematic review; traditional chinese medicine
    DOI:  https://doi.org/10.2147/PPA.S567999
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