Sensitive and adaptable pharmacological control of CAR T cells through extracellular receptor dimerization

Abstract

Chimeric antigen receptor (CAR) T cell therapies have achieved promising outcomes in several cancers; however, more challenging oncology indications may necessitate advanced antigen receptor designs and functions. Here we describe a bipartite receptor system composed of separate antigen-targeting and signal transduction polypeptides, each containing an extracellular dimerization domain. We demonstrate that T cell activation remains antigen dependent but can only be achieved in the presence of a dimerizing drug, rapamycin. Studies performed in vitro and in xenograft mouse models illustrate equivalent to superior antitumor potency compared with currently used CAR designs, and at rapamycin concentrations well below immunosuppressive levels. We further show that the extracellular positioning of the dimerization domains enables the administration of recombinant retargeting modules, potentially extending antigen targeting. Overall, this regulatable CAR design has exquisite drug sensitivity, provides robust antitumor responses, and is flexible for multiplex antigen targeting or retargeting, which may further assist the development of safe, potent, and durable T cell therapeutics.