bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–08–03
seven papers selected by
Luca Bolliger, lxBio
  1. Research progress on chimeric antigen receptor-based immunotherapy against autoimmune diseases.
  2. Future perspectives on novel CAR-T therapeutics beyond CD19 and BCMA in onco-hematology.
  3. Applications of nanoparticles in CAR-T cell therapy: non-viral manufacturing, enhancing in vivo function, and in vivo generation of CAR-T cells.
  4. Discordant CAR-T cell signaling: implications of divergence from physiological T cell activation.
  5. Advancing CAR-T Cell Therapy: Insights into Patient Biology, Leukapheresis, and Cryopreservation.
  6. Advances and obstacles of T cell-based immunotherapy in gynecological malignancies.
  7. Navigating the manufacturing, testing and regulatory complexities of regulatory T cells for adoptive cell therapy.
  1. Hum Vaccin Immunother. 2025 Dec;21(1): 2538350
    Research progress on chimeric antigen receptor-based immunotherapy against autoimmune diseases.
    Mingwei Jiang, Jin Zhao, Jinguo Yuan, Zixian Yu, Jie Liu, Zhanxin Zhu, Xiaoxuan Ning, Shiren Sun.
      Emerging as a paradigm-shifting therapeutic strategy initially developed for hematological malignancies, chimeric antigen receptor (CAR)-based cell therapy has recently proved transformative potential in autoimmune disease management. CAR T cell therapy has achieved long-term remission without drugs in a variety of autoimmune diseases. Chimeric autoantigen receptor T cell therapy targeting specific B cell receptors has transitioned from preclinical research to clinical trials. CAR natural killer cell therapy has shown promising efficacy and safety in early-stage clinical trials. The evolution of CAR regulatory T cell and mesenchymal stem cell therapy has also achieved initial results. These achievements have greatly inspired researchers, and more research is being actively carried out in the field of autoimmune diseases, aiming to develop more efficient, safe and convenient cell products. This article will detail the effectiveness and applicability of CAR-based immunotherapy in the management of autoimmune diseases, and explore its limitations and future trends.
    Keywords:  Autoimmune diseases; CAR NK; CAR T; CAR treg; chimeric antigen receptors; immunotherapy
    DOI:  https://doi.org/10.1080/21645515.2025.2538350
  2. Front Immunol. 2025 ;16 1592377
    Future perspectives on novel CAR-T therapeutics beyond CD19 and BCMA in onco-hematology.
    Alina Ershova, Alexandra Goldaeva, Alena Staliarova, Emil Bulatov, Alexey Petukhov, Nikolai Barlev.
      CAR-T cell therapy is a type of adoptive immune therapy that relies on the specific targeting of cytotoxic T-cells to eliminate the malfunctioning cells in the body. Genetic engineering allows the generation of an almost infinite variety of chimeric antigen receptors (CAR) to ensure specificity for antigens on the surface of target cells. Therefore, CAR-T appears to be a powerful and versatile therapy for the treatment of various diseases, including cancer. Recently, CAR-T has emerged as a significant advancement in the management of hematological tumors, particularly B-cell malignancies, mainly due to the presence of specific antigens such as CD19 and BCMA. As a result, the market for CAR-T therapy is experiencing significant growth. However, the problem of relapses remains and warrants the search for new therapeutic approaches, including CAR-T technology. In this case, one of the major challenges is finding and evaluating new targets for CAR-T in terms of their likelihood of success. Here we propose a set of established criteria for the evaluation of potential targets for CAR-T cell therapy to treat hematological malignancies. These criteria include assessing the target in terms of its biological characteristics, such as expression level, cellular localization, tissue specificity, and clinical aspects, including unmet clinical needs and the success of clinical trials. Using these criteria, we validate our prediction of the next CAR-T cell therapy targets that will likely emerge soon.
    Keywords:  CAR-T target; CAR-T therapy; chimeric antigen receptor; hematological malignancies; oncology
    DOI:  https://doi.org/10.3389/fimmu.2025.1592377
  3. Med Oncol. 2025 Jul 26. 42(9): 378
    Applications of nanoparticles in CAR-T cell therapy: non-viral manufacturing, enhancing in vivo function, and in vivo generation of CAR-T cells.
    Yasmeen A Albalawi.
      As evidenced by the seven U.S. Food and Drug Administration (FDA)-approved products, chimeric antigen receptor (CAR)-T cell therapy has gained unprecedented success in cancer treatment, particularly in blood cancers. Nonetheless, despite these impressive results, CAR-T cell therapy is a complex and challenging procedure with several hurdles that reduce its affordability and accessibility. These issues include time-consuming and labor-intensive ex vivo manufacturing, safety concerns regarding the viral-based gene delivery, and limited in vivo persistence and function. In recent years, nanoparticles (NPs) have been introduced as versatile tools with the potential to overcome these limitations and improve the efficacy and safety profile of CAR-T cells. Given the lack of a comprehensive analysis of the transformative potential of the use of NPs in CAR-T cell therapy and the roadblocks to their clinical translation in current literature, this review aims to provide a comprehensive and critical overview of NP-based strategies in CAR-T cell therapy, focusing on three key applications: production of CAR-T cells using a fully non-viral approach, enhancing the in vivo persistence and function of CAR-T cells, and in vivo generation and genome editing of CAR-T cells to circumvent the laborious ex vivo cell engineering and expansion stages. We explore the comparative advantages of different types of NPs (e.g., lipid-based and polymeric NPs) and discuss various approaches for optimizing NP design to address manufacturing and regulatory barriers. Finally, to provide a holistic view of the current state and future opportunities in these emerging fields, various roadblocks to their clinical translation (such as safety, scalability, and regulatory hurdles) and potential solutions are discussed. By exploring preclinical innovations and their clinical applicability, this review can guide future research toward scalable, efficient, and safe NP-assisted CAR-T cell therapy.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor (CAR); Clinical translation; Nanoparticle; Nanotechnology
    DOI:  https://doi.org/10.1007/s12032-025-02928-6
  4. J Transl Med. 2025 Jul 25. 23(1): 834
    Discordant CAR-T cell signaling: implications of divergence from physiological T cell activation.
    Pablo Gonzalez-Garcia, Noelia Moares, Isabel Serrano-García, Ricardo Fernandez-Cisnal, Rosa Luna-Espejo, Javier Ocaña-Cuesta, Wenjie Yi-He, Juan P Muñoz-Miranda, Antonio Gabucio, Cecilia M Fernandez-Ponce, Francisco Garcia-Cozar.
      Chimeric antigen receptor (CAR) T cell therapy constituted a recent breakthrough in the treatment of poor prognosis cancers by harnessing therapeutic T cells with an engineered non-MHC restricted antigen recognition transgene. CAR constructs are expressed in addition to endogenous T cell receptor (TCR) and utilize their activation machinery by a process still not yet fully understood. Despite the great success and widespread presence of CAR-T cells in clinical trials, they still have some shortcomings that may stem in part from their failure to fully mimic physiological TCR-mediated T cell activation, causing dysfunctional states and impaired responses that limit their persistence and causes incomplete remission of tumors or severe side effects. Recent studies have shown that much of the differences among CAR-T cell activation and natural TCRs occur early in the antigen recognition process, upon formation of the immune synapse when the first signaling events occur. In this review, by comparing the mechanisms of lymphocyte activation by CARs vs. TCRs, we will discuss how these chimeric constructs induce a stimulation characterized by un-orchestrated, incomplete, or impaired signaling events that in turn could explain some of their shortcomings.
    Keywords:  Chimeric antigen receptors (CAR); Costimulation; Hematological tumor; Immune Synapsis; Phosphorylation; Signaling; Solid tumor; TCR
    DOI:  https://doi.org/10.1186/s12967-025-06857-w
  5. Mol Ther. 2025 Jul 30. pii: S1525-0016(25)00581-7. [Epub ahead of print]
    Advancing CAR-T Cell Therapy: Insights into Patient Biology, Leukapheresis, and Cryopreservation.
    Beatriz Vega Blanco, Bechara Mfarrej, Hoang Jack Lu, Leah Irwin, James Salmon, Donald Morris, Robert Bowden.
      Commercial chimeric antigen receptor T (CAR-T) cells are manufactured from autologous patient-derived leukapheresis starting material. The quality and characteristics of the leukapheresis starting material has been identified as a potential root cause of manufacturing failure in autologous CAR-T cell products. An unsuccessful CAR-T production constitutes not only an obstacle for treatment, but also presents several hurdles for patients, healthcare providers, and CAR-T manufacturers. In this literature review, we describe published factors that might affect the quality of autologous leukapheresis starting materials. We characterize patient-related factors such as cancer treatments and wash-out periods prior to collection, disease status, and clinical/laboratory findings and their impact on the leukapheresis cell composition. Factors relating to the leukapheresis procedure including cell collection procedures, current best practices and guidelines, nurse experience, and challenges are also addressed. Next, cryopreservation prior to manufacturing is discussed in relation to timing, cryoprotectants, concentration, cooling rates, and cellular stability. Last, gaps in knowledge and future directions are presented for each of these arguments. Our thorough literature assessment can support discussions for process optimization, reducing manufacturing failures, and long-term harmonization practices.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.07.045
  6. Mol Cancer. 2025 Jul 26. 24(1): 207
    Advances and obstacles of T cell-based immunotherapy in gynecological malignancies.
    Xi Zhao, Jialing Ran, Shenglong Li, Jinxin Chen.
      T cell-mediated immunotherapy has revolutionized oncology by enabling precision immune responses against malignant cells. Chimeric Antigen Receptor (CAR) T-cell therapy, which involves genetically reprogramming T lymphocytes to recognize tumor-specific antigens, has shown clinical success in hematologic malignancies and is expanding its potential in solid tumors. Gynecological cancers, including ovarian, cervical, and endometrial carcinomas, present persistent therapeutic challenges due to their aggressive recurrence patterns and limited responses to conventional therapies in advanced disease stages. This review offers a comprehensive analysis of CAR-T cell therapy advancements in gynecologic oncology, examining fundamental biological mechanisms of tumor-immune interactions, clinical progress in target antigen validation, and innovative approaches to counter immunosuppressive tumor microenvironments. Key challenges specific to these malignancies are discussed, such as molecular heterogeneity in endometrial tumors, ascites-mediated T-cell dysfunction in ovarian cancer (OC), and viral antigen dynamics in HPV- driven cervical carcinomas. Recent clinical evidence shows improved therapeutic outcomes through optimized CAR architectures and preconditioning regimens, with objective response rates demonstrating progressive enhancement across successive clinical trial generations. The discussion addresses ongoing limitations regarding treatment durability and manufacturing consistency while exploring emerging solutions such as synthetic biology approaches and multi-omics guided antigen selection. By integrating preclinical insights with translational clinical data, this work establishes a strategic framework for advancing adoptive T-cell therapies in gynecologic oncology, emphasizing the synergistic potential of combining CAR-T technology with personalized neoantigen vaccines and microenvironment-reprogramming agents. These collective advances underscore the transformative prospects of engineered T-cell immunotherapies while providing actionable strategies to overcome the unique biological barriers inherent to female reproductive tract malignancies.
    Keywords:  CAR-T cell therapy; Gynecological malignancies; Immunotherapy; T cell; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-025-02411-w
  7. Front Immunol. 2025 ;16 1626085
    Navigating the manufacturing, testing and regulatory complexities of regulatory T cells for adoptive cell therapy.
    Larissa A Pikor, Sindhu Arivazhagan, Michael Mendicino, Sarmitha Sathiamoorthy.
      Regulatory T cells (Tregs) are a small, unique subset of suppressive T cells that play a pivotal role in regulating the immune system by maintaining tolerance to self-antigens and preventing autoimmune disease. Adoptive transfer of Tregs for the treatment of autoimmune disorders such as arthritis and allergic airway inflammation, graft-versus-host disease (GvHD) and rejection following transplant have shown promise in early phase clinical trials. Despite over a decade of clinical manufacturing, there remains significant manufacturing and testing complexities for this class of therapies, including the need for specialized facilities and highly trained personnel that make clinical and commercial supply challenging. In this review, we discuss the current Chemistry, Manufacturing and Controls (CMC) and regulatory complexities and challenges to the development and commercialization of Treg therapies. Some of these are specific to Tregs while others are broadly applicable to the field of cell-based therapy. Discussion topics include the importance of starting material selection, the availability of GMP quality reagents and material, isolation and characterization of regulatory T cells, cGMP manufacturing considerations and limitations, the complexity of testing, release and distribution of cell-based therapies, as well as the regulatory challenges associated with Treg therapy. Treg cell therapies can be fraught with technical challenges which are mirrored by a sponsor's ability to meet regulatory requirements. Despite these hurdles, the promise of Tregs as a therapeutic for the treatment of autoimmune and other diseases warrants continued development.
    Keywords:  ACT; CMC; Treg; analytics; manufacturing; regulatory
    DOI:  https://doi.org/10.3389/fimmu.2025.1626085
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