Multi-antigen-targeted chimeric antigen receptor T cells for cancer therapy

Abstract

The approval of two chimeric antigen receptor-modified T cell types by the US Food and Drug Administration (FDA) for the treatment of hematologic malignancies is a milestone in immunotherapy; however, the application of CAR-T cells has been limited by antigen escape and on-target, off-tumor toxicities. Therefore, it may be a potentially effective strategy to select appropriate targets and to combine multi-antigen-targeted CAR-T cells with "OR", "AND" and "NOT" Boolean logic gates. We summarize the current limitations of CAR-T cells as well as the efficacy and safety of logic-gated CAR-T cells in antitumor therapy. This review will help to explore more optimized strategies to expand the CAR-T cell therapeutic window.

Keywords: Antigen escape; Chimeric antigen receptor T cells; Logic gate; Off-tumor toxicities; On-target.

Fig. 1

“OR” logic-gated CAR-T cells for preventing tumor antigen escape. a Dual CAR-T cells: “OR” logic gate. Each CAR contains a complete signal domain that activates the antitumor effect of CAR-T cells in the presence of either cognate antigen. b Tandem CAR-T cells: “OR” logic gate. One CAR coexpresses two distinct antigen-binding domains in tandem, using the “OR” logic gate to activate T cell. c Trivalent CAR T cells: “OR” logic gate. Three CARs in one T cell utilize the “OR” logic gate to kill tumor cells in the presence of either validated antigen

Fig. 2

“AND” and “NOT” logic-gated CAR-T cells for alleviating on-target, off-tumor toxicities. a Dual CAR-T cells: “AND” logic gate. Two distinct CARs are coexpressed with complementary signaling domains in one T cell that fully activates the T cell only in the presence of both cognate antigens. b Synthetic Notch Receptor System: “AND” logic gate. In the presence of cognate antigen of CAR1, SynNotch receptor induces the conditional expression of CAR2 in a transcriptional manner, thereby targeting to the second antigen, and finally achieving highly specific activation of T cell. c Trivalent CAR T cells: “AND” logic gate. Trivalent CAR-T cell response to tumor-specific expression patterns to overcome the immunosuppression of TME, rather than adding additional CARs targeting TAAs. d Dual CAR-T cells: “NOT” logic gate. iCAR-T cells selectively kill target cells only expressing one antigen, whereas off-target cells co-expressing another inhibitory ligand recognized by iCAR were protected from attack, allowing T cells to distinguish target cells from the off-target cells