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Annals of Oncology : Official Journal... Jan 2021Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or... (Review)
Review
Chimeric antigen receptor (CAR) T cells directed against the B-cell marker CD19 are currently changing the landscape for treatment of patients with refractory and/or relapsed B-cell malignancies. Due to the nature of CAR T cells as living drugs, they display a unique toxicity profile. As CAR T-cell therapy is extending towards other diseases and being more broadly employed in hematology and oncology, optimal management strategies of side-effects associated with CAR T-cell therapy are of high relevance. Cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias constitute challenges in the treatment of patients with CAR T cells. This review summarizes the current understanding of CAR T-cell toxicity and its management.
Topics: Cell- and Tissue-Based Therapy; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Neurotoxicity Syndromes; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 33098993
DOI: 10.1016/j.annonc.2020.10.478 -
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 -
Molecular Cancer Feb 2023In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However,... (Review)
Review
In recent decades, immune checkpoint blockade and chimeric antigen receptor T cell (CAR-T) therapy are two milestone achievements in clinical immunotherapy. However, both show limited efficacies in most solid neoplasms, which necessitates the exploration of new immunotherapeutic modalities. The failure of CAR-T and immune checkpoint blockade in several solid neoplasms is attributed to multiple factors, including low antigenicity of tumor cells, low infiltration of effector T cells, and diverse mechanisms of immunosuppression in the tumor microenvironment. New adoptive cell therapies have been attempted for solid neoplasms, including TCR-T, CAR-natural killer cells (CAR-NK), and CAR-macrophages (CAR-M). Compared to CAR-T, these new adoptive cell therapies have certain advantages in treating solid neoplasms. In this review, we summarized the 40-year evolution of adoptive cell therapies, then focused on the advances of TCR-T, CAR-NK, and CAR-M in solid neoplasms and discussed their potential clinical applications.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Immune Checkpoint Inhibitors; Neoplasms; Immunotherapy; Tumor Microenvironment
PubMed: 36750830
DOI: 10.1186/s12943-023-01735-9 -
Frontiers in Immunology 2022To redirect T cells against tumor cells, T cells can be engineered to express cancer-antigen specific T cell receptors (TCRs), generating products known as... (Review)
Review
To redirect T cells against tumor cells, T cells can be engineered to express cancer-antigen specific T cell receptors (TCRs), generating products known as TCR-engineered T cells (TCR T). Unlike chimeric antigen receptors (CARs), TCRs recognize HLA-presented peptides derived from proteins of all cellular compartments. The use of TCR T cells for adoptive cellular therapies (ACT) has gained increased attention, especially as efforts to treat solid cancers with ACTs have intensified. In this review, we describe the differing mechanisms of T cell antigen recognition and signal transduction mediated through CARs and TCRs. We describe the classes of cancer antigens recognized by current TCR T therapies and discuss both classical and emerging pre-clinical strategies for antigen-specific TCR discovery, enhancement, and validation. Finally, we review the current landscape of clinical trials for TCR T therapy and discuss what these current results indicate for the development of future engineered TCR approaches.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 35309357
DOI: 10.3389/fimmu.2022.835762 -
Nature Reviews. Drug Discovery Dec 2023Chimeric antigen receptor (CAR)-T cells have recently emerged as a powerful therapeutic approach for the treatment of patients with chemotherapy-refractory or relapsed... (Review)
Review
Chimeric antigen receptor (CAR)-T cells have recently emerged as a powerful therapeutic approach for the treatment of patients with chemotherapy-refractory or relapsed blood cancers, including acute lymphoblastic leukaemia, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma and multiple myeloma. Nevertheless, resistance to CAR-T cell therapies occurs in most patients. In this Review, we summarize the resistance mechanisms to CAR-T cell immunotherapy by analysing CAR-T cell dysfunction, intrinsic tumour resistance and the immunosuppressive tumour microenvironment. We discuss current research strategies to overcome multiple resistance mechanisms, including optimization of the CAR design, improvement of in vivo T cell function and persistence, modulation of the immunosuppressive tumour microenvironment and synergistic combination strategies.
Topics: Humans; Receptors, Chimeric Antigen; Neoplasm Recurrence, Local; T-Lymphocytes; Hematologic Neoplasms; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; Tumor Microenvironment
PubMed: 37907724
DOI: 10.1038/s41573-023-00807-1 -
Blood May 2023Increasing use of chimeric antigen receptor T-cell therapy (CAR-T) has unveiled diverse toxicities warranting specific recognition and management. Cytopenias occurring...
Increasing use of chimeric antigen receptor T-cell therapy (CAR-T) has unveiled diverse toxicities warranting specific recognition and management. Cytopenias occurring after CAR-T infusion invariably manifest early (<30 days), commonly are prolonged (30-90 days), and sometimes persist or occur late (>90 days). Variable etiologies of these cytopenias, some of which remain incompletely understood, create clinical conundrums and uncertainties about optimal management strategies. These cytopenias may cause additional sequelae, decreased quality of life, and increased resource use. Early cytopenias are typically attributed to lymphodepletion chemotherapy, however, infections and hyperinflammatory response such as immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome may occur. Early and prolonged cytopenias often correlate with severity of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. Bone marrow biopsy in patients with prolonged or late cytopenias is important to evaluate for primary disease and secondary marrow neoplasm in both pediatric and adult patients. Commonly, cytopenias resolve over time and evidence for effective interventions is often anecdotal. Treatment strategies, which are limited and require tailoring based upon likely underlying etiology, include growth factors, thrombopoietin-receptor agonist, stem cell boost, transfusion support, and abrogation of infection risk. Here we provide our approach, including workup and management strategies, for cytopenias after CAR-T.
Topics: Adult; Humans; Child; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Quality of Life; Neoplasms
PubMed: 36800563
DOI: 10.1182/blood.2022017415 -
Biomolecules Sep 2022T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor T (CAR-T) cell therapy... (Review)
Review
T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor T (CAR-T) cell therapy represents a prominent synthetic biology approach to re-direct the specificity of a patient's autologous T cells toward a desired tumor antigen. CAR-T therapy is currently FDA approved for the treatment of hematological malignancies, including subsets of B cell lymphoma, acute lymphoblastic leukemia (ALL) and multiple myeloma. Mechanistically, CAR-mediated recognition of a tumor antigen results in propagation of T cell activation signals, including a co-stimulatory signal, resulting in CAR-T cell activation, proliferation, evasion of apoptosis, and acquisition of effector functions. The importance of including a co-stimulatory domain in CARs was recognized following limited success of early iteration CAR-T cell designs lacking co-stimulation. Today, all CAR-T cells in clinical use contain either a CD28 or 4-1BB co-stimulatory domain. Preclinical investigations are exploring utility of including additional co-stimulatory molecules such as ICOS, OX40 and CD27 or various combinations of multiple co-stimulatory domains. Clinical and preclinical evidence implicates the co-stimulatory signal in several aspects of CAR-T cell therapy including response kinetics, persistence and durability, and toxicity profiles each of which impact the safety and anti-tumor efficacy of this immunotherapy. Herein we provide an overview of CAR-T cell co-stimulation by the prototypical receptors and discuss current and emerging strategies to modulate co-stimulatory signals to enhance CAR-T cell function.
Topics: Antigens, Neoplasm; CD28 Antigens; Cell Line, Tumor; Humans; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Xenograft Model Antitumor Assays
PubMed: 36139142
DOI: 10.3390/biom12091303 -
Nature Reviews. Clinical Oncology Jan 2024Chimeric antigen receptor (CAR) T cells have been approved for use in patients with B cell malignancies or relapsed and/or refractory multiple myeloma, yet efficacy... (Review)
Review
Chimeric antigen receptor (CAR) T cells have been approved for use in patients with B cell malignancies or relapsed and/or refractory multiple myeloma, yet efficacy against most solid tumours remains elusive. The limited imaging and biopsy data from clinical trials in this setting continues to hinder understanding, necessitating a reliance on imperfect preclinical models. In this Perspective, I re-evaluate current data and suggest potential pathways towards greater success, drawing lessons from the few successful trials testing CAR T cells in patients with solid tumours and the clinical experience with tumour-infiltrating lymphocytes. The most promising approaches include the use of pluripotent stem cells, co-targeting multiple mechanisms of immune evasion, employing multiple co-stimulatory domains, and CAR ligand-targeting vaccines. An alternative strategy focused on administering multiple doses of short-lived CAR T cells in an attempt to pre-empt exhaustion and maintain a functional effector pool should also be considered.
Topics: Humans; Immunotherapy, Adoptive; Receptors, Antigen, T-Cell; T-Lymphocytes; Multiple Myeloma; Lymphocytes, Tumor-Infiltrating
PubMed: 37904019
DOI: 10.1038/s41571-023-00832-4 -
Cancer Treatment Reviews Dec 2022Chimeric antigen receptor T-cell (CAR-T) therapy has improved outcomes in patients with relapsed/refractory hematological malignancies. Research is also extending to... (Review)
Review
Chimeric antigen receptor T-cell (CAR-T) therapy has improved outcomes in patients with relapsed/refractory hematological malignancies. Research is also extending to other diseases, including solid tumors, infections and autoimmune disorders. As living drugs, CAR-T cells are associated with potentially life-threatening immunological toxicities, which frequently require a multidisciplinary team approach. Cytokine-release syndrome, immune effector cell-associated neurotoxicity syndrome, infections and hematotoxicity (including cytopenias, immune reconstitution dysfunction and hypogammaglobulinemia) are associated with significant morbidity and mortality. This review takes a practical approach to summarize current knowledge on CAR-T toxicity, addressing pathogeny, risk factors, and prophylactic and therapeutic strategies.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Neoplasm Recurrence, Local; Immunotherapy, Adoptive; Hematologic Neoplasms; Neurotoxicity Syndromes
PubMed: 36308910
DOI: 10.1016/j.ctrv.2022.102479 -
Science Translational Medicine Mar 2021Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in...
Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR-T cells have shown limited efficacy, which is partially attributed to intrinsic defects in CAR signaling. Here, we construct a double-chain chimeric receptor, termed as synthetic T cell receptor (TCR) and antigen receptor (STAR), which incorporates antigen-recognition domain of antibody and constant regions of TCR that engage endogenous CD3 signaling machinery. Under antigen-free conditions, STAR does not trigger tonic signaling, which has been reported to cause exhaustion of traditional CAR-T cells. Upon antigen stimulation, STAR mediates strong and sensitive TCR-like signaling, and STAR-T cells exhibit less susceptibility to dysfunction and better proliferation than traditional 28zCAR-T cells. In addition, STAR-T cells show higher antigen sensitivity than CAR-T cells, which holds potential to reduce the risk of antigen loss-induced tumor relapse in clinical use. In multiple solid tumor models, STAR-T cells prominently outperformed BBzCAR-T cells and generated better or equipotent antitumor effects to 28zCAR-T cells without causing notable toxicity. With these favorable features endowed by native TCR-like signaling, STAR-T cells may provide clinical benefit in treating refractory solid tumors.
Topics: Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes
PubMed: 33762437
DOI: 10.1126/scitranslmed.abb5191