The recent advancement of TCR-T cell therapies for cancer treatment

Abstract

Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells. Adoptive cell therapy, as a form of living drug, has undergone explosive growth over the past decade. The recognition of tumor antigens by the T-cell receptor (TCR) is one of the natural mechanisms that the immune system used to eliminate tumor cells. TCR-T cell therapy, which involves introducing exogenous TCRs into patients’ T cells, is a novel cell therapy strategy. TCR-T cell therapy can target the entire proteome of cancer cells. Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials, particularly in treating solid tumors. In this review, we examine the progress of TCR-T cell therapy over the past five years. This includes the discovery of new tumor antigens, protein engineering techniques for TCR, reprogramming strategies for TCR-T cell therapy, clinical studies on TCR-T cell therapy, and the advancement of TCR-T cell therapy in China. We also propose several potential directions for the future development of TCR-T cell therapy.

1. Introduction

The immune system is the body’s natural defense system that recognizes and kills tumor cells [1]. Although the immune system may fail to eliminate tumor cells due to the exhaustion of immune cells [2], a suppressive tumor microenvironment [3,4], and multiple tumor escape strategies [5,6], we can enhance the immune system through protein engineering or cell engineering to combat cancer. In the last two decades, we have witnessed a boom in basic immunology, particularly in the understanding of the checkpoint mechanism of T-cell activation and the design of chimeric antigen receptors (CARs). Meanwhile, mechanisms related to tumor immunology, therapeutic targets, and molecular design have been successfully translated into approved immunotherapy, saving many cancer patients. The discovery of the immune checkpoint mechanism and the development of T-cell engineering have made immunotherapy one of the key pillars in the contemporary treatment of cancer [7–10].

Immunotherapy can take many forms, but the majority of clinical success comes from antibody blockade treatment and adoptive cell transfer therapy (ACT). Antibody blockade treatment includes immune checkpoint blockade (ICB), such as anti-PD-1 and anti-CTLA-4 treatments [9,11–14]. Over six anti-PD-1 and anti-CTLA-4 drugs have been approved by the FDA [15]. For adoptive cell therapy, chimeric antigen receptor T-cell (CAR-T) therapy has achieved significant success, including the complete cure of leukemia patients [16]. CAR-T therapy involves transducing T cells with artificial receptors that can recognize surface antigens on tumor cells and deliver activation signals to the T cells. More than six CAR-T therapies have been approved for B-cell lymphoma, but no CAR-T therapy has been approved for solid tumors [17]. Both checkpoint blockade and CAR-T cell therapy have cured many, but not all, cancer patients [18,19]. As of now, there are no approved adoptive cell therapies (including CAR-T, CAR-NK, etc.) for solid tumors [20–22].

T cells play important roles in killing tumors. The immune system naturally uses T cell receptors (TCRs) to recognize tumor antigens and eradicate tumor cells. The TCR molecule has evolved over 450 million years as an elegant system to balance antigen recognition, cross-reactivity, and sensitive signaling [23–26]. It is not surprising that people have been considering using TCR to enhance the immune system for over 30 years [27,28]. One idea is to isolate a potent TCR that can effectively eliminate tumor cells and then administer the TCR to patients by modifying their autologous T cells. TCR-T cell therapy is the name of the treatment. Rosenberg and his colleagues were pioneers in the first clinical trial of TCR-T cell therapy for the treatment of melanoma. They observed a positive response in two patients [29]. Based on TCR research, in the 2010s, significant success has been achieved in the development of TCR-T cell therapy for solid tumors [21].