The quest for spatio-temporal control of CAR T cells

Abstract

Chimeric antigen receptors (CARs) are synthetic receptors capable of directing potent antigen-specific anti-tumor T cell responses. A recent report by Wu et al. extends a series of strategies aiming to curb excessive T cell activity, utilizing in this instance a chemical dimerizer to aggregate antigen-binding, T cell-activating and costimulatory domains.

Figure 1

Building controls into engineered T cells. (a) The small molecule AP1903 can dimerize the suicide switch iCasp9 to induce T cell apoptosis. (b) Bifunctional small molecule bridging the binding between antigen and CAR or antibody mediating the interaction between antigen and synthetic Fc receptor can be remote controls of CAR T cells. (c) iCAR can inhibit CAR function in the presence of an antigen present in normal cells but not tumor cells. (d) CCR binding to a second antigen in tumor cells is required for full T cell activation. (e) The small molecule AP21976 can dimerize two independent signaling entities through an FKBP-FRB module to control T cell activation. (a, b, e) Strategies employing one remote control (antibody or small molecule) in addition to one autonomous control (antigen A). (c, d) Strategies with two autonomous controls (antigen A and antigen B). Negative regulation involves inducing apoptosis (a) or turning off T cell activation (c) by input 2 while positive regulation (b, d, e) results in T cell activation by input 2.