Adoptive T-Cell Therapy for Solid Tumors

Abstract

OVERVIEW Chimeric antigen receptor (CAR) T-cell therapy is an innovative form of immunotherapy wherein autologous T cells are genetically modified to express chimeric receptors encoding an antigen-specific single-chain variable fragment and various costimulatory molecules. Upon administration, these modified T cells traffic to, and recognize, cancer cells in an HLA-independent manner. CAR T-cell therapy has shown remarkable success in the treatment of CD-19–expressing B-cell acute lymphocytic leukemia. However, clinical gains to the same magnitude have not been reported in solid tumors. Several known obstacles to CAR T-cell therapy for solid tumors include target antigen identification, effective trafficking to the tumor, robust activation, proliferation, and in vivo cytotoxicity. Beyond these T-cell intrinsic properties, a complex and dynamic immunosuppressive tumor microenvironment in solid tumors hinders T-cell efficacy. Notable advancements in CAR design to include multiple costimulatory molecules, ligands, and soluble cytokines have shown promise in preclinical models, and some of these are currently in early-phase clinical trials. In this review, we discuss selected solid tumor malignancies and relevant preclinical data and highlight clinical trial results that are available. Furthermore, we outline some obstacles to CAR T-cell therapy for each tumor and propose strategies to overcome some of these limitations.

TGF-β inhibition via CRISPR promotes the long-term efficacy of CAR T cells against solid tumors

“…One of the main reasons for the poor clinical efficacy of CAR T cells in treating solid tumor is the lack of robust in vivo proliferation (34)(35)(36)(37). In this study, we demonstrated that knocking out TGFBR2 enables CAR T cells to survive and proliferate better in tumor xenograft mouse models, leading to significantly improved antitumor efficacy.…”

Reinforce the antitumor activity of CD8+ T cells via glutamine restriction

“…2 In particular, the number of clinical trials of chimeric antigen receptor T cells has dramatically increased in the recent decade. 3 The main goal of such immunotherapies is to enhance the activity of tumor-specific CD8 + T cells in order to achieve tumor eradication. However, in vitro activated CD8 + T cells often exhibit dysfunction, also known as "exhaustion," before achieving sufficient elimination of tumor cells, which restricts the therapeutic efficacy of cancer immunotherapies.…”

Chimeric Antigen Receptor T-Cell Therapy for Colorectal Cancer

“…These two seem to be the culprits for the resistance mechanisms of CAR T-cell therapy in solid tumors. By changing the design of CAR T-cells incorporating co-stimulatory molecules, ligands, targeted therapies, or immunomodulatory agents can improve the clinical outcome [54]. Wang et al [55] suggest that targeting more than one antigen and building a dual-targeted CAR can overcome the risk of antigen escape relapse and diminish the effect of antigen heterogeneity.…”