Identification of Targets to Redirect CAR T Cells in Glioblastoma and Colorectal Cancer: An Arduous Venture

Abstract

The chimeric antigen receptor (CAR) is an artificial molecule engineered to induce cytolytic T cell reactions in tumors. Generally, this molecule combines an extracellular single-chain variable fragment (scFv) able to recognize tumor-associated epitopes together with the intracellular signaling domains that are required for T cell activation. When expressed by T cells, the CAR enables the recognition and subsequent destruction of cancer cells expressing the complementary antigen on their surface. Although the clinical application for CAR T cells is currently limited to some hematological malignancies, researchers are trying to develop CAR T cell-based therapies for the treatment of solid tumors. However, while in the case of CD19, or other targets restricted to the hematopoietic compartment, the toxicity is limited and manageable, the scarcity of specific antigens expressed by solid tumors and not by healthy cells from vital organs makes the clinical development of CAR T cells in this context particularly challenging. Here we summarize relevant research and clinical trials conducted to redirect CAR T cells to surface antigens in solid tumors and cancer stem cells with a focus on colorectal cancer and glioblastoma. Finally, we will discuss current knowledge of altered glycosylation of CSCs and cancer cells and how these novel epitopes may help to target CAR T cell-based immunotherapy in the future.

Keywords: CAR T cells therapy; CRC (colorectal cancer); CSCs; GBM; MAbs; solid tumor.

Figure 1

The figure illustrates the hurdles of solid tumor targeting as well as potential strategies to overcome these limitations. Upper panel: The major hurdles are: Antigen escape, tumor cells that lose the expression of the antigen; Heterogeneity due to the expression of different TAAs on solid cancers; On-target/off-tumor toxicity in the case that antigens are also highly expressed in healthy cells. In the lower panel, the strategies to optimize CAR T cell function in solid tumors are illustrated: Targeting the T cells with Tandem CARs, universal CARs, or BiTEs. Targeting alternative antigens, Affinity tuning, and the regulation of the CAR expression levels.