TCR Redirected T Cells for Cancer Treatment: Achievements, Hurdles, and Goals

Abstract

Adoptive T cell therapy (ACT) is a rapidly evolving therapeutic approach designed to harness T cell specificity and function to fight diseases. Based on the evidence that T lymphocytes can mediate a potent anti-tumor response, initially ACT solely relied on the isolation, in vitro expansion, and infusion of tumor-infiltrating or circulating tumor-specific T cells. Although effective in a subset of cases, in the first ACT clinical trials several patients experienced disease progression, in some cases after temporary disease control. This evidence prompted researchers to improve ACT products by taking advantage of the continuously evolving gene engineering field and by improving manufacturing protocols, to enable the generation of effective and long-term persisting tumor-specific T cell products. Despite recent advances, several challenges, including prioritization of antigen targets, identification, and optimization of tumor-specific T cell receptors, in the development of tools enabling T cells to counteract the immunosuppressive tumor microenvironment, still need to be faced. This review aims at summarizing the major achievements, hurdles and possible solutions designed to improve the ACT efficacy and safety profile in the context of liquid and solid tumors.

Keywords: TCR - T cell receptor; adoptive T cell immunotherapy; cancer immunoediting; cancer immunotherapy; genetic engineering.

Figure 1

Overview of the TCR adoptive T cell therapy. Tumor-reactive lymphocytes can be isolated from either the tumor mass (tumor-infiltrating lymphocytes, TILs) or from the T cell pool circulating in patients' peripheral blood. T cells can be expanded in vitro and then re-infused back into the patient such as in TILs therapy. Else, the tumor-reactive T cell Receptor (TCR) genes can be isolated, sequenced, and transferred into acceptor T cells via vectors to redirect T cell specificities against tumor epitopes.

Figure 2

The landscape of gene delivery methods. The genetic transfer of an exogeneous T cell receptor (TCR) into a donor T cell can be obtained with different vectors, the most widely used being viral vectors, mRNA, and transposons systems. Strengths and weaknesses are listed for each technology.

Figure 3

Genome editing exploitation for adoptive T cell therapy. To eliminate the expression of T cell genes, meganucleases, transcription activator-like effector nucleases (TALENs), and zinc-finger nucleases (ZFNs), the CRISPR/Cas9 system can be employed. A summary of the genes edited in the context of adoptive T cell therapy (TCR- or CAR-T cell immunotherapies) is reported, together with the specific nuclease system used. CAR, chimeric antigen receptor; TCR, T cell receptor.

Figure 4

The interplay between T cells and tumor microenvironment. When adoptively transferred T cells (either tumor-infiltrating lymphocytes, Chimeric Antigen Receptor or T cell Receptor-redirected T cells) infiltrate the tumor, they interact with a complex environment, in which a combination of intracellular signals compete. When inflammatory signals dominate, T cells can perform effector functions and potentially eradicate cancer cells; else, they may become exhausted, have limited survival and fail in killing tumor cells. CAR, chimeric antigen receptor; TCR, T cell receptor.