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Advances in Immunology 2023The key to mounting an immune response is that the host cells must be coordinated to generate an appropriate immune response against the pathogenic invaders. Antigen... (Review)
Review
The key to mounting an immune response is that the host cells must be coordinated to generate an appropriate immune response against the pathogenic invaders. Antigen receptors recognize specific molecular structures and recruit adaptors through their effector domains, triggering trans-membrane transduction signaling pathway to exert immune response. The T cell antigen receptor (TCR) and B cell antigen receptor (BCR) are the primary determinant of immune responses to antigens. Their structure determines the mode of signaling and signal transduction determines cell fate, leading to changes at the molecular and cellular level. Studies of antigen receptor structure and signaling revealed the basis of immune response triggering, providing clues to antigen receptor priming and a foundation for the rational design of immunotherapies. In recent years, the increased research on the structure of antigen receptors has greatly contributed to the understanding of immune response, different immune-related diseases and even tumors. In this review, we describe in detail the current view and advances of the antigen structure and signaling.
Topics: Humans; T-Lymphocytes; Lymphocyte Activation; Receptors, Antigen, T-Cell; Signal Transduction; Receptors, Antigen, B-Cell; Antigens
PubMed: 37061286
DOI: 10.1016/bs.ai.2023.01.001 -
The New England Journal of Medicine Feb 2024
Topics: Humans; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Neoplasms, Second Primary; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 38265704
DOI: 10.1056/NEJMp2400209 -
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 -
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 -
Cancer Journal (Sudbury, Mass.)The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This... (Review)
Review
The US Food and Drug Administration has approved 3 chimeric antigen receptor (CAR) T-cell therapies. For continued breakthroughs, novel CAR designs are needed. This includes different antigen-binding domains such as antigen-ligand binding partners and variable lymphocyte receptors. Another recent advancement in CAR design is Boolean logic gates that can minimize on-target, off-tumor toxicities. Recent studies on the optimization of costimulatory signaling have also shown how CAR design can impact function. By using specific signaling pathways and transcription factors, CARs can impact T-cell gene expression to enhance function. By using these techniques, the promise of CAR T-cell therapies for solid tumors can be fulfilled.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 33750067
DOI: 10.1097/PPO.0000000000000514 -
Cell Jul 2023Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that...
Chimeric antigen receptor (CAR) T cell therapy effectively treats human cancer, but the loss of the antigen recognized by the CAR poses a major obstacle. We found that in vivo vaccine boosting of CAR T cells triggers the engagement of the endogenous immune system to circumvent antigen-negative tumor escape. Vaccine-boosted CAR T promoted dendritic cell (DC) recruitment to tumors, increased tumor antigen uptake by DCs, and elicited the priming of endogenous anti-tumor T cells. This process was accompanied by shifts in CAR T metabolism toward oxidative phosphorylation (OXPHOS) and was critically dependent on CAR-T-derived IFN-γ. Antigen spreading (AS) induced by vaccine-boosted CAR T enabled a proportion of complete responses even when the initial tumor was 50% CAR antigen negative, and heterogeneous tumor control was further enhanced by the genetic amplification of CAR T IFN-γ expression. Thus, CAR-T-cell-derived IFN-γ plays a critical role in promoting AS, and vaccine boosting provides a clinically translatable strategy to drive such responses against solid tumors.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasms; T-Lymphocytes; Immunotherapy, Adoptive; Cancer Vaccines; Receptors, Antigen, T-Cell
PubMed: 37413990
DOI: 10.1016/j.cell.2023.06.002 -
Hematology/oncology and Stem Cell... Dec 2022Chimeric antigen receptor T (CAR T) cell therapy has revolutionized the management of lymphoid malignancies. However, it is still in its early phase and is facing many... (Review)
Review
Chimeric antigen receptor T (CAR T) cell therapy has revolutionized the management of lymphoid malignancies. However, it is still in its early phase and is facing many obstacles in solid tumors. Therapeutic challenges in solid tumor lead to tumor target diversification and drive new innovations for the improvement of clinical efficacy. This review showcases early clinical works and sheds light on the most notable successes, drawbacks, and strategies employed to allow CAR T therapy to go full speed ahead.
Topics: Humans; Receptors, Chimeric Antigen; T-Lymphocytes; Neoplasms; Immunotherapy, Adoptive; Cell- and Tissue-Based Therapy; Receptors, Antigen, T-Cell
PubMed: 36537910
DOI: 10.56875/2589-0646.1028 -
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 -
Current Opinion in Hematology Mar 2022Treatment outcome of relapsed or refractory AML patients remains dismal and new treatment options are needed. Adoptive cell therapy using CAR-T cells is a potentially... (Review)
Review
PURPOSE OF REVIEW
Treatment outcome of relapsed or refractory AML patients remains dismal and new treatment options are needed. Adoptive cell therapy using CAR-T cells is a potentially interesting approach in this.
RECENT FINDINGS
Several potentially interesting AML targets are being investigated with CAR-T therapy with over 60 clinical trials listed on clinicaltrials.gov. The first clinical data are only just emerging with mixed results, once more proving that further research is needed.
SUMMARY
Adoptive cell therapy using chimeric antigen receptor T cells is being investigated in AML through many clinical trials. So far, no AML-specific antigen has been identified, requiring additional strategies to mitigate on-target off-tumor toxicity and to increase efficacy. Focus point is to acquire control over the CAR T cells once administered. Strategies to do so include biodegradable CARs, inducible CARs, suicide-switch containing CARs and two-component modular CARs. Limited and mixed results are available, confirming the risk of lasting toxicity for nonswitchable CARs. Initial results of modular CARs suggest toxicity can be mitigated whilst maintaining CAR activity by the use of modular CAR concepts that allows for 'ON' and 'OFF' switching.
Topics: Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Leukemia, Myeloid, Acute; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 35013048
DOI: 10.1097/MOH.0000000000000703 -
Frontiers in Immunology 2022Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the... (Review)
Review
Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Antigens, Neoplasm; Tumor Microenvironment
PubMed: 36389701
DOI: 10.3389/fimmu.2022.984864