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Cells Feb 2023Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment option for patients suffering from B-cell- and plasma cell-derived hematologic malignancies and... (Review)
Review
Chimeric Antigen Receptor (CAR) T-cell therapy is a promising treatment option for patients suffering from B-cell- and plasma cell-derived hematologic malignancies and is being adapted for the treatment of solid cancers. However, CAR T is associated with frequently severe toxicities such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), macrophage activation syndrome (MAS), and prolonged cytopenias-a reduction in the number of mature blood cells of one or more lineage. Although we understand some drivers of these toxicities, their mechanisms remain under investigation. Since the CAR T regimen is a complex, multi-step process with frequent adverse events, ways to improve the benefit-to-risk ratio are needed. In this review, we discuss a variety of potential solutions being investigated to address the limitations of CAR T. First, we discuss the incidence and characteristics of CAR T-related cytopenias and their association with reduced CAR T-cell efficacy. We review approaches to managing or mitigating cytopenias during the CAR T regimen-including the use of growth factors, allogeneic rescue, autologous hematopoietic stem cell infusion, and alternative conditioning regimens. Finally, we introduce novel methods to improve CAR T-cell-infusion products and the implications of CAR T and clonal hematopoiesis.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Hematopoiesis; Cell- and Tissue-Based Therapy
PubMed: 36831198
DOI: 10.3390/cells12040531 -
JCO Oncology Practice Sep 2023Chimeric antigen receptor T-cell (CAR-T) therapy has become an established therapeutic approach for the treatment of hematologic malignancies. The field continues to... (Review)
Review
Chimeric antigen receptor T-cell (CAR-T) therapy has become an established therapeutic approach for the treatment of hematologic malignancies. The field continues to evolve rapidly and newer-generation constructs are being designed to enhance proliferative capacity, and achieve long-term persistence and greater efficacy with an overall lower incidence of toxicity. Initial clinical application of CAR-T therapies has focused on relapsed and/or refractory hematologic malignancies, and Food and Drug Administration-approved CAR-T products targeting CD19 are available for B-cell acute lymphoblastic leukemia and low- and high-grade B-cell non-Hodgkin lymphoma, and targeting B-cell maturation antigen are available for multiple myeloma. Cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome have been recognized as class specific toxicities associated with these novel therapies. In this review, we focus on the clinical application of CAR-T therapies in adult patients with hematologic malignancies, including access issues, outpatient administration, and appropriate timing for referring a patient to a CAR-T treatment center.
Topics: United States; Adult; Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Hematologic Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 37406255
DOI: 10.1200/OP.22.00819 -
Open Biology Feb 2021In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus.... (Review)
Review
In vertebrates, the development of lymphocytes from undifferentiated haematopoietic precursors takes place in so-called primary lymphoid organs, such as the thymus. Therein, lymphocytes undergo a complex differentiation and selection process that culminates in the generation of a pool of mature T cells that collectively express a self-tolerant repertoire of somatically diversified antigen receptors. Throughout this entire process, the microenvironment of the thymus in large parts dictates the sequence and outcome of the lymphopoietic activity. In vertebrates, direct genetic evidence in some species and circumstantial evidence in others suggest that the formation of a functional thymic microenvironment is controlled by members of the Foxn1/4 family of transcription factors. In teleost fishes, both and contribute to thymopoietic activity, whereas is both necessary and sufficient in the mammalian thymus. The evolutionary history of genes suggests that an ancient gene lineage gave rise to the genes in early vertebrates, raising the question of the thymopoietic capacity of the ancestor common to all vertebrates. Recent attempts to reconstruct the early events in the evolution of thymopoietic tissues by replacement of the mouse gene by -like genes isolated from various chordate species suggest a plausible scenario. It appears that the primordial thymus was a bi-potent lymphoid organ, supporting both B cell and T cell development; however, during the course of vertebrate, evolution B cell development was gradually diminished converting the thymus into a site specialized in T cell development.
Topics: Animals; Forkhead Transcription Factors; Humans; Lymphopoiesis; Receptors, Antigen; Stem Cell Niche; Thymus Gland
PubMed: 33622100
DOI: 10.1098/rsob.200383 -
Journal of Materials Chemistry. B Sep 2022With the outstanding achievement of chimeric antigen receptor (CAR)-T cell therapy in the clinic, cell-based medicines have attracted considerable attention for... (Review)
Review
With the outstanding achievement of chimeric antigen receptor (CAR)-T cell therapy in the clinic, cell-based medicines have attracted considerable attention for biomedical applications and thus generated encouraging progress. As the basic construction unit of organisms, cells harbor low immunogenicity, desirable compatibility, and a strong capability of crossing various biological barriers. However, there is still a long way to go to fix significant bottlenecks for their clinical translation, such as facile preparation, strict stability requirements, scale-up manufacturing, off-target toxicity, and affordability. The rapid development of biotechnology and engineering approaches in materials sciences has provided an ideal platform to assist cell-based therapeutics for wide application in disease treatments by overcoming these issues. Herein, we survey the most recent advances of various cells as bioactive ingredients and outline the roles of biomaterials in developing cell-based therapeutics. Besides, a perspective of cell therapies is offered with a particular focus on biomaterial-involved development of cell-based biopharmaceuticals.
Topics: Biocompatible Materials; Biological Products; Cell- and Tissue-Based Therapy; Humans; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35612089
DOI: 10.1039/d2tb00583b -
Advances in Experimental Medicine and... 2019Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T... (Review)
Review
Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T cells are emerging as a novel therapeutic that is giving other direction to T-cell specificity and precision medicine. T cells are engineered modification to recognize specific target antigen and are co-stimulated with intracellular signal to increase the T cell response. CAR-T cells have impressive involvement in outcome on hematological malignancies; however severe toxicities as cytokine release syndrome or neurotoxicity are a challenge to face. Solid tumors have heterogeneous antigens and tumor microenvironment that hinder CAR-T cell efficacy and increase the risk of on-target/off-tumor. Novel strategies to increase CAR-Ts specificity, safety and efficacy are ongoing in clinical trials to improve clinical outcomes in hematological and solid malignances.
Topics: Antigens, Neoplasm; Humans; Immunotherapy, Adoptive; Neoplasms; Precision Medicine; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 31713169
DOI: 10.1007/978-3-030-24100-1_9 -
Klinicka Onkologie : Casopis Ceske a... 2022Chimeric antigen receptor (CAR) T cell therapy has been gradually building its position in the treatment of hematological malignancies. Currently, there are three types... (Review)
Review
BACKGROUND
Chimeric antigen receptor (CAR) T cell therapy has been gradually building its position in the treatment of hematological malignancies. Currently, there are three types of autologous anti-CD19 CAR-T cells approved for the treatment of selected relapsed B cell non-Hodgkins lymphomas and acute B-lymphoblastic leukemia in the Czech Republic. Additional clinical trials are ongoing to evaluate CAR-T cell therapy that targets other tumor-specific antigens. It is expected that some of these CAR-T cells will be approved for the treatment of other hemato-oncological dia-gnoses in the near future. Manufacturing and management of CAR-T cell therapy have been optimized. European Society for Blood and Marrow Transplantation and American Society for Transplantation and Cellular Therapy have updated their recommendations for the management and treatment of early CAR-T cell toxicity based on valuable experience gained during several years. Nevertheless, late toxicity remains an issue. It is crucial for patients undergoing this highly specific therapy to stay in follow-up for several decades. Intensive research and development have been devoted to manufacturing new CAR constructs with higher efficacy and lesser toxicity. A significant improvement in the availability of this, otherwise very expensive treatment, is expected from universal allogeneic T cells that will express CAR binding to tumor-specific antigen.
PURPOSE
This review is focused on the preparation and administration of autologous CAR-T lymphocytes.
Topics: Antigens, CD19; Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 35236081
DOI: 10.48095/ccko202244 -
Current Opinion in Pediatrics Apr 2019Chimeric antigen receptor -(CAR) T-cell therapy has become a commonly used immunotherapy originally used in the treatment of B-cell leukemias but which are now applied... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor -(CAR) T-cell therapy has become a commonly used immunotherapy originally used in the treatment of B-cell leukemias but which are now applied broadly across tumor classes. Although high rates of remission are associated with CAR T-cell therapy, toxicities associated with these novel treatment regimens can be lethal if not recognized in a timely manner.
RECENT FINDINGS
Cytokine release syndrome and neurotoxicity are the two most common toxicities associated with CAR T-cell therapy. Cytokine release syndrome is characterized by a flu-like illness accompanied by significant hemodynamic instability; treatments include administration of tocilizumab and corticosteroids. Neurotoxicity is associated with nonpattern-specific neurological changes and can rapidly progress to a comatose state from cerebral edema and death. Other potential toxicities from CAR T-cell therapy include tumor lysis syndrome, B-cell aplasia, graft versus host disease, and dermatological eruptions.
SUMMARY
Clinical awareness of CAR T-cell toxicities is important because prompt treatment leads to improved survival and remission rates.
Topics: Graft vs Host Disease; Humans; Immunotherapy; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Lysis Syndrome
PubMed: 30762706
DOI: 10.1097/MOP.0000000000000747 -
Frontiers in Immunology 2020Chimeric antigen receptor-T (CAR-T) cell therapy is a promising frontier of immunoengineering and cancer immunotherapy. Methods that detect, quantify, track, and... (Review)
Review
Chimeric antigen receptor-T (CAR-T) cell therapy is a promising frontier of immunoengineering and cancer immunotherapy. Methods that detect, quantify, track, and visualize the CAR, have catalyzed the rapid advancement of CAR-T cell therapy from preclinical models to clinical adoption. For instance, CAR-staining/labeling agents have enabled flow cytometry analysis, imaging applications, cell sorting, and high-dimensional clinical profiling. Molecular assays, such as quantitative polymerase chain reaction, integration site analysis, and RNA-sequencing, have characterized CAR transduction, expression, and CAR-T cell expansion kinetics. visualization methods, including confocal and total internal reflection fluorescence microscopy, have captured the molecular details underlying CAR immunological synapse formation, signaling, and cytotoxicity. tracking methods, including two-photon microscopy, bioluminescence imaging, and positron emission tomography scanning, have monitored CAR-T cell biodistribution across blood, tissue, and tumor. Here, we review the plethora of CAR detection methods, which can operate at the genomic, transcriptomic, proteomic, and organismal levels. For each method, we discuss: (1) what it measures; (2) how it works; (3) its scientific and clinical importance; (4) relevant examples of its use; (5) specific protocols for CAR detection; and (6) its strengths and weaknesses. Finally, we consider current scientific and clinical needs in order to provide future perspectives for improved CAR detection.
Topics: Humans; Immunologic Techniques; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 32849635
DOI: 10.3389/fimmu.2020.01770 -
Frontiers in Immunology 2024Major Histocompatibility Complex (MHC) I and II and the αβ T-cell antigen receptor (TCRαβ) govern fundamental traits of adaptive immunity. They form a membrane-borne... (Review)
Review
Major Histocompatibility Complex (MHC) I and II and the αβ T-cell antigen receptor (TCRαβ) govern fundamental traits of adaptive immunity. They form a membrane-borne ligand-receptor system weighing host proteome integrity to detect contamination by nonself proteins. MHC-I and -II exhibit the "MHC-fold", which is able to bind a large assortment of short peptides as proxies for self and nonself proteins. The ensuing varying surfaces are mandatory ligands for Ig-like TCRαβ highly mutable binding sites. Conserved molecular signatures guide TCRαβ ligand binding sites to focus on the MHC-fold (MHC-restriction) while leaving many opportunities for its most hypervariable determinants to contact the peptide. This riveting molecular strategy affords many options for binding energy compatible with specific recognition and signalling aimed to eradicated microbial pathogens and cancer cells. While the molecular foundations of αβ T-cell adaptive immunity are largely understood, uncertainty persists on how peptide-MHC binding induces the TCRαβ signals that instruct cell-fate decisions. Solving this mystery is another milestone for understanding αβ T-cells' self/nonself discrimination. Recent developments revealing the innermost links between TCRαβ structural dynamics and signalling modality should help dissipate this long-sought-after enigma.
Topics: T-Lymphocytes; Ligands; Receptors, Antigen, T-Cell; Receptors, Antigen, T-Cell, alpha-beta; Peptides
PubMed: 38415261
DOI: 10.3389/fimmu.2024.1343575 -
International Journal of Molecular... Oct 2023TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen...
TCR-like chimeric antigen receptor (CAR-T) cell therapy has emerged as a game-changing strategy in cancer immunotherapy, offering a broad spectrum of potential antigen targets, particularly in solid tumors containing intracellular antigens. In this study, we investigated the cytotoxicity and functional attributes of in vitro-generated T-lymphocytes, engineered with a TCR-like CAR receptor precisely targeting the cancer testis antigen MAGE-A4. Through viral transduction, T-cells were genetically modified to express the TCR-like CAR receptor and co-cultured with MAGE-A4-expressing tumor cells. Flow cytometry analysis revealed a significant surge in cells expressing activation markers CD69, CD107a, and FasL upon encountering tumor cells, indicating robust T-cell activation and cytotoxicity. Moreover, immune transcriptome profiling unveiled heightened expression of pivotal T-effector genes involved in immune response and cell proliferation regulation. Additionally, multiplex assays also revealed increased cytokine production and cytotoxicity driven by granzymes and soluble Fas ligand (sFasL), suggesting enhanced anti-tumor immune responses. Preliminary in vivo investigations revealed a significant deceleration in tumor growth, highlighting the therapeutic potential of these TCR-like CAR-T cells. Further investigations are warranted to validate these revelations fully and harness the complete potential of TCR-like CAR-T cells in overcoming cancer's resilient defenses.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Neoplasms; Immunotherapy, Adoptive; Cytotoxicity, Immunologic; Receptors, Antigen, T-Cell
PubMed: 37894816
DOI: 10.3390/ijms242015134