-
Cancer Cell Oct 2020T cells engineered to express chimeric antigen receptors (CARs) with tumor specificity have shown remarkable success in treating patients with hematologic malignancies... (Review)
Review
T cells engineered to express chimeric antigen receptors (CARs) with tumor specificity have shown remarkable success in treating patients with hematologic malignancies and revitalized the field of adoptive cell therapy. However, realizing broader therapeutic applications of CAR-T cells necessitates engineering approaches on multiple levels to enhance efficacy and safety. Particularly, solid tumors present unique challenges due to the biological complexity of the solid-tumor microenvironment (TME). In this review, we highlight recent strategies to improve CAR-T cell therapy by engineering (1) the CAR protein, (2) T cells, and (3) the interaction between T cells and other components in the TME.
Topics: Animals; Antigens, Neoplasm; Humans; Immunotherapy, Adoptive; Neoplasms; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Treatment Outcome; Tumor Microenvironment
PubMed: 32735779
DOI: 10.1016/j.ccell.2020.07.005 -
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 -
EBioMedicine Mar 2022Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of... (Review)
Review
Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of hematological malignancies. However, CAR T cell exhaustion is a major limitation to their efficacy, particularly in the application of CAR T cells to solid tumors. CAR T cell exhaustion is thought to be due to persistent antigen stimulation, as well as an immunosuppressive tumor microenvironment, and mitigating exhaustion to maintain CAR T cell effector function and persistence and achieve clinical potency remains a central challenge. Here, we review the underlying mechanisms of exhaustion and discuss emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. Additionally, we discuss the potential of these strategies for improving clinical outcomes of CAR T cell therapy.
Topics: Humans; Immunotherapy; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35301179
DOI: 10.1016/j.ebiom.2022.103941 -
Molecular Cancer Oct 2022Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients... (Review)
Review
Chimeric antigen receptor T (CAR-T) cells therapy has revolutionized the treatment paradigms for hematological malignancies, with multi-line therapy-refractory patients achieving durable complete remissions (CR) and relatively high objective response rate (ORR). So far, many CAR-T products, such as Kymriah, Yescarta and Tecartus, have been developed and got the unprecedented results. However, some patients may relapse afterwards, driving intense investigations into promoting the development of novel strategies to overcome resistance and mechanisms of relapse. Notable technical progress, such as nanobodies and CRISPR-Case9, has also taken place to ensure CAR-T cell therapy fully satisfies its medical potential. In this review, we outline the basic principles for the development and manufacturing processes of CAR-T cell therapy, summarize the similarities and differences in efficacy of different products as well as their corresponding clinical results, and discuss CAR-T immunotherapy combined with other clinical effects of drug therapy.
Topics: Hematologic Neoplasms; Humans; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; Single-Domain Antibodies
PubMed: 36209106
DOI: 10.1186/s12943-022-01663-0 -
Current Hematologic Malignancy Reports Apr 2023Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies.... (Review)
Review
PURPOSE OF REVIEW
Chimeric antigen receptor (CAR) T cell therapy is an immunotherapy that has resulted in tremendous progress in the treatment of patients with B cell malignancies. However, the remarkable efficacy of therapy is not without significant safety concerns. Herein, we will review the unique and potentially life-threatening toxicities associated with CAR-T cell therapy and their association with treatment efficacy.
RECENT FINDINGS
Currently, CAR-T cell therapy is approved for the treatment of B cell relapsed or refractory leukemia and lymphoma, and most recently, multiple myeloma (MM). In these different diseases, it has led to excellent complete and overall response rates depending on the patient population and therapy. Despite promising efficacy, CAR-T cell therapy is associated with significant side effects; the two most notable toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The treatment of CAR-T-induced toxicity is supportive; however, as higher-grade adverse events occur, toxicity-directed therapy with tocilizumab, an IL-6 receptor antibody, and steroids is standard practice. Overall, a careful risk-benefit balance exists between the efficacy and toxicities of therapies. The challenge lies in the underlying pathophysiology of CAR-T-related toxicity which relies upon the activation of CAR-T cells. Some degree of toxicity is expected to achieve an effective response to therapy, and certain aspects of treatment are also associated with toxicity. As progress is made in the investigation and approval of new CARs, novel toxicity-directed therapies and toxicity-limited constructs will be the focus of attention.
Topics: Humans; Receptors, Chimeric Antigen; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Multiple Myeloma; Cell- and Tissue-Based Therapy
PubMed: 36763238
DOI: 10.1007/s11899-023-00687-7 -
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 -
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 -
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. 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