Combinatorial Antigen Targeting: Ideal T-Cell Sensing and Anti-Tumor Response

Abstract

T cells expressing chimeric antigen receptors (CARs) are a formidable platform for the study and application of synthetic biology approaches to study customized and flexible control of cellular functions. Recent reports in the journal Cell provide a new twist on combinatorial antigen targeting, profiting from the singular cleavage and signaling of the Notch receptor to conditionally express CARs.

Figure 1. Combinatorial Antigen Targeting Strategies for CAR Therapy

A) The CAR/CCR approach: Full T cell activation requires the combination of CAR-mediated recognition of antigen A and CCR-mediated costimulation conferred by the engagement of antigen B. CAR and CCR signaling must be designed in such a way as to fail initiating T cell activation alone, but at the same time, be able to rescue each other upon simultaneous binding of both target antigens [9]. B) The synNotch/CAR approach: T cell activation requires binding of the synNotch receptor to antigen B, triggering proteolysis of the intracellular transcriptional effector and transcriptional induction of expression of the antigen A-specific CAR [11].