CAR-T cells for Colorectal Cancer: Target-selection and strategies for improved activity and safety

Abstract

Chimeric antigen receptor-T (CAR-T) cell immunotherapy is a novel method that is genetically engineered to recruit T cells against malignant disease. Administration of CAR-T cells has led to progress in hematological malignancies, and it has been proposed for solid tumors like colorectal cancer (CRC) for years. However, this method was not living up to expectations for the intrinsic challenges posed to CAR-T cells by solid tumors, which mainly due to the lacking of tumor-restricted antigens and adverse effects following treatment. New approaches are proposed to overcome the multiple challenges to alleviate the difficult situation of CAR-T cells in CRC, including engineering T cells with immune-activating molecules, regional administration of T cell, bispecific T cell engager, and combinatorial target-antigen recognition. In this review, we sum up the current stage of knowledge about target-selection, adverse events like on/off-tumor toxicity, the preclinical and clinical studies of CAR-T therapy, and the characteristics of strategies applied in CRC.

Keywords: chimeric antigen receptor-T (CAR-T) cell; colorectal cancer; strategies; toxicity; tumor associated antigens.

Figure 1

Summarized strategies for CAR-T cells to overcome toxicity in CRC. A: CAR-T cells were engineered to express CARs that do not directly recognize antigens on target cells, but are recruited to effector cells through bifunctional small molecule “switch”. B: CAR-T cell are transduced with optimized constructions include the CAR structures that provide inefficient activation signals of T cells when bind to one antigen and chimeric costimulatory receptors(CCR) recognize another antigen.

Figure 2

Summarized strategies for CAR-T cells to enhance efficacy in CRC. A: Engineering T cells to secrete inducible IL-12(iIL-12) which are driven by the CAR in tumor site. The interleukins delivered by CAR-T cells deposit in the tumor lesion could attract innate immune cells, like NK cells ,endogenous T cells, dendritic cells and macrophages modulating the tumor microinvironment. B: Furnishing CAR-T cells with genes of chemokine-corresponding receptors to chemokines secreted by solid tumors improves the homing of T cells and the capability of migration and achieving access to tumor site.