Genetically engineered T cells for cancer immunotherapy

Abstract

T cells in the immune system protect the human body from infection by pathogens and clear mutant cells through specific recognition by T cell receptors (TCRs). Cancer immunotherapy, by relying on this basic recognition method, boosts the antitumor efficacy of T cells by unleashing the inhibition of immune checkpoints and expands adaptive immunity by facilitating the adoptive transfer of genetically engineered T cells. T cells genetically equipped with chimeric antigen receptors (CARs) or TCRs have shown remarkable effectiveness in treating some hematological malignancies, although the efficacy of engineered T cells in treating solid tumors is far from satisfactory. In this review, we summarize the development of genetically engineered T cells, outline the most recent studies investigating genetically engineered T cells for cancer immunotherapy, and discuss strategies for improving the performance of these T cells in fighting cancers.

Keywords: Drug development; Molecular medicine.

Fig. 1. Immunosuppressive microenvironment in solid tumors.

MDSC myeloid-derived suppressor cell, Treg regulatory T cell, TAM tumor-associated macrophage, TAF tumor-associated fibroblast

Fig. 2. Intracellular costimulatory domain of a CAR construct used in CAR-T cells tested in clinical trials.

The data were obtained from https://clinicaltrials.gov, which was accessed on January 30, 2019. a Diagram of clinical trials of CAR-T cells from different generations. There are 342 registered trials categorized as CAR-T cell trials (second generation: 133, third generation: 20, fourth generation: 5, NA, not available). b Diagram of clinical trials of CAR-T cells using different costimulatory molecules. A total of 156 available CAR constructs with different costimulatory molecules were specifically indicated, and a pie diagram is presented that shows the percentages of trials using cells with different costimulatory domains (4-1BB: 64.7%, CD28: 19.2%, CD28+4-1BB: 9%, CD28+OX40: 2%, CD28+TLR2: 0.6%, CD28+4-1BB+CD27: 2%, CD27: 0.6%, iMyD88/CD40: 0.6%, NKG2D and DAP10: 1.2%)