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Molecular Diagnosis & Therapy Jul 2024Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by... (Review)
Review
Zevorcabtagene autoleucel () is a fully humanised B cell maturation antigen (BCMA)-targeting specific chimeric antigen receptor (CAR) T-cell therapy being developed by CARsgen for the treatment of multiple myeloma. Zevorcabtagene autoleucel is an autologous CAR T cell comprising a fully human BCMA-specific scFv (25C2), a CD8α hinge region and transmembrane domain, a 4-1BB costimulatory domain and a CD3-ζ T cell activation domain. Zevorcabtagene autoleucel recognizes and induces selective toxicity against BCMA-expressing tumour cells leading to their elimination. In February 2024, zevorcabtagene autoleucel received its first approval in China for the treatment of adults with relapsed or refractory multiple myeloma who have progressed after ≥ 3 prior lines of therapy (including ≥ 1 proteasome inhibitor and an immunomodulatory agent). Clinical studies of zevorcabtagene autoleucel are underway in Canada and the US. This article summarizes the milestones in the development of zevorcabtagene autoleucel leading to this first approval for relapsed or refractory multiple myeloma.
Topics: Humans; Multiple Myeloma; B-Cell Maturation Antigen; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Clinical Trials as Topic; Drug Approval; Treatment Outcome
PubMed: 38888762
DOI: 10.1007/s40291-024-00723-z -
Frontiers in Immunology 2024Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological... (Review)
Review
Although adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has achieved unprecedented response rates in patients with certain hematological malignancies, this therapeutic modality is still far from fulfilling its remarkable potential, especially in the context of solid cancers. Antigen escape variants, off-tumor destruction of healthy tissues expressing tumor-associated antigens (TAAs), poor CAR-T cell persistence, and the occurrence of functional exhaustion represent some of the most prominent hurdles that limit CAR-T cell ability to induce long-lasting remissions with a tolerable adverse effect profile. In this review, we summarize the main approaches that have been developed to face such bottlenecks, including the adapter CAR (AdCAR) system, Boolean-logic gating, epitope editing, the modulation of cell-intrinsic signaling pathways, and the incorporation of safety switches to precisely control CAR-T cell activation. We also discuss the most pressing issues pertaining to the selection of co-stimulatory domains, with a focus on strategies aimed at promoting CAR-T cell persistence and optimal antitumor functionality.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Neoplasms; Antigens, Neoplasm; Animals; T-Lymphocytes; Receptors, Antigen, T-Cell
PubMed: 38887285
DOI: 10.3389/fimmu.2024.1407992 -
Stem Cell Research & Therapy Jun 2024Chimeric antigen receptor (CAR)-T cell adoptive immunotherapy is a promising cancer treatment that uses genetically engineered T cells to attack tumors. However, this... (Review)
Review
Chimeric antigen receptor (CAR)-T cell adoptive immunotherapy is a promising cancer treatment that uses genetically engineered T cells to attack tumors. However, this therapy can have some adverse effects. CAR-T cell-derived exosomes are a potential alternative to CAR-T cells that may overcome some limitations. Exosomes are small vesicles released by cells and can carry a variety of molecules, including proteins, RNA, and DNA. They play an important role in intercellular communication and can be used to deliver therapeutic agents to cancer cells. The application of CAR-T cell-derived exosomes could make CAR-T cell therapy more clinically controllable and effective. Exosomes are cell-free, which means that they are less likely to cause adverse reactions than CAR-T cells. The combination of CAR-T cells and exosomes may be a more effective way to treat cancer than either therapy alone. Exosomes can deliver therapeutic agents to cancer cells where CAR-T cells cannot reach. The appropriate application of both cellular and exosomal platforms could make CAR-T cell therapy a more practicable treatment for cancer. This combination therapy could offer a safe and effective way to treat a variety of cancers.
Topics: Humans; Exosomes; Neoplasms; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; T-Lymphocytes; Animals
PubMed: 38886844
DOI: 10.1186/s13287-024-03783-4 -
Journal For Immunotherapy of Cancer Jun 2024Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and...
BACKGROUND
Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.
METHODS
Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.
RESULTS
EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.
CONCLUSIONS
MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Topics: Animals; Mice; Humans; Matrix Metalloproteinase 9; Macrophages; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Receptors, Cell Surface; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Receptors, Antigen, T-Cell; Tumor Microenvironment; Cell Line, Tumor; Xenograft Model Antitumor Assays; Female; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 38886114
DOI: 10.1136/jitc-2023-008375 -
Proceedings of the National Academy of... Jun 2024Treatment with autologous chimeric antigen receptor (CAR) T cells has emerged as a highly effective approach in neuroimmunological disorders such as myasthenia gravis....
Treatment with autologous chimeric antigen receptor (CAR) T cells has emerged as a highly effective approach in neuroimmunological disorders such as myasthenia gravis. We report a case of successful anti-CD19 CAR T cell use in treatment-refractory stiff-person syndrome (SPS). To investigate clinical and immunological effects of anti-CD19 CAR T cell use in treatment-refractory SPS, a 69-y-old female with a 9-y history of treatment-refractory SPS with deteriorating episodes of stiffness received an infusion of autologous anti-CD19 CAR T cells (KYV-101) and was monitored clinically and immunologically for more than 6 mo. CAR T cell infusion resulted in reduced leg stiffness, drastic improvement in gait, walking speed increase over 100%, and daily walking distance improvement from less than 50 m to over 6 km within 3 mo. GABAergic medication (benzodiazepines) was reduced by 40%. KYV-101 CAR T cells were well tolerated with only low-grade cytokine release syndrome. This report of successful use of anti-CD19 CAR T cells in treatment-refractory SPS supports continued exploration of this approach in SPS and other B cell-related autoimmune disorders.
Topics: Humans; Stiff-Person Syndrome; Female; Aged; Immunotherapy, Adoptive; Antigens, CD19; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome
PubMed: 38885382
DOI: 10.1073/pnas.2403227121 -
Gan To Kagaku Ryoho. Cancer &... May 2024
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 38881061
DOI: No ID Found -
Biochemistry. Biokhimiia May 2024Chimeric antigen receptors (CARs) are genetically engineered receptors that recognize antigens and activate signaling cascades in a cell. Signal recognition and... (Review)
Review
Chimeric antigen receptors (CARs) are genetically engineered receptors that recognize antigens and activate signaling cascades in a cell. Signal recognition and transmission are mediated by the CAR domains derived from different proteins. T cells carrying CARs against tumor-associated antigens have been used in the development of the CAR T cell therapy, a new approach to fighting malignant neoplasms. Despite its high efficacy in the treatment of oncohematological diseases, CAR T cell therapy has a number of disadvantages that could be avoided by using other types of leukocytes as effector cells. CARs can be expressed in a wide range of cells of adaptive and innate immunity with the emergence or improvement of cytotoxic properties. This review discusses the features of CAR function in different types of immune cells, with a particular focus on the results of preclinical and clinical efficacy studies and the safety of potential CAR cell products.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Animals; Receptors, Antigen, T-Cell; Antigens, Neoplasm
PubMed: 38880641
DOI: 10.1134/S0006297924050018 -
Methods in Cell Biology 2024Despite being the most common adult leukemia in the western world, Chronic Lymphocytic Leukemia (CLL) remains a life-threatening and incurable disease. Efforts to...
Despite being the most common adult leukemia in the western world, Chronic Lymphocytic Leukemia (CLL) remains a life-threatening and incurable disease. Efforts to develop new treatments are highly dependent on the availability of appropriate mouse models for pre-clinical testing. The Eμ-TCL1 mouse model is the most established pre-clinical approach to study CLL pathobiology and response to treatment, backed by numerous studies highlighting its resemblance to the most aggressive form of this malignancy. In contrast to the transgenic Eμ-TCL1 model, employing the adoptive transfer of Eμ-TCL1-derived splenocytes in immunocompetent C57BL/6 mice results in a comparably rapid (e.g., leukemic development within weeks compared to months in the transgenic model) and reliable model mimicking CLL. In this chapter, we would like to provide readers with a thoroughly optimized, detailed, and comprehensive protocol to use the adoptive transfer Eμ-TCL1 model in their research.
Topics: Animals; Leukemia, Lymphocytic, Chronic, B-Cell; Mice; Adoptive Transfer; Disease Models, Animal; Mice, Inbred C57BL; Mice, Transgenic; Spleen; Humans; Proto-Oncogene Proteins
PubMed: 38880520
DOI: 10.1016/bs.mcb.2024.03.012 -
Med (New York, N.Y.) Jun 2024The efficacy of CD19 chimeric antigen receptor (CAR) T cells in B cell malignancies has generated recent interest in their application to other B cell-related...
The efficacy of CD19 chimeric antigen receptor (CAR) T cells in B cell malignancies has generated recent interest in their application to other B cell-related pathologies, such as autoimmune diseases. Fischbach et al. report on the use of CD19 CAR T cells in two patients with progressive multiple sclerosis, demonstrating feasibility and safety for the first time in this disease process.
Topics: Humans; Antigens, CD19; Multiple Sclerosis; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Receptors, Antigen, T-Cell
PubMed: 38878763
DOI: 10.1016/j.medj.2024.04.005 -
Med (New York, N.Y.) Jun 2024Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department...
Med discusses the future of CAR T cell therapy for autoimmune diseases with Dr. Fabian Müller, Senior Attending Physician and Head of the CAR T Cell Unit, Department of Medicine 5 (Hematology and Oncology), University Hospital Erlangen, Germany.
Topics: Humans; Autoimmune Diseases; Immunotherapy, Adoptive; Germany; Receptors, Chimeric Antigen
PubMed: 38878762
DOI: 10.1016/j.medj.2024.04.004