CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

Abstract

The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

Keywords: CAR-T cell; Chimeric antigen receptor (CAR); gastrointestinal cancer; hepatic carcinoma; immunotherapy.

Figure 1.

The generations of CARs and armored CAR-T cells for improved antitumor therapy. (A) First-generation CARs, including activating receptors, such as CD3ζ; second-generation CARs combine activating and costimulatory signals, such as CD28; third-generation CARs combined two costimulatory and activating signals, such as 4-1BB, etc.; fourth-generation CAR-T cells, also called “TRUCK” cells, are engineered with additional inducible cytokines, which can secrete cytokines upon the activation of CARs. (B) Modified CAR-T cells recognize tumor cells by their tumor-associated antigen in a non-MHC restrictive manner. CAR signaling activates T cells, and the T cells then secrete cytokines, which kill tumor cells and induce them to attack other tumor cells. (C) The fourth-generation CAR-T cells have the additional advantage of activating the innate immune system, which recruits innate immune cells (macrophages or DCs) to attack tumor cells and regulate the tumor microenvironment.