Direct control of CAR T cells through small molecule-regulated antibodies
Spencer Park, Edward Pascua, Kevin C. Lindquist, Christopher R. Kimberlin, Xiaodi Deng, Yvonne S.L. Mak, Zea Melton, Theodore Johnson, Regina Lin, Bijan Boldajipour, Robert T. Abraham, Jaume Pons, Barbra J. Sasu, Thomas Van Blarcom, Javier Chaparro‐Riggers
Abstract
Antibody-based therapeutics have experienced a rapid growth in recent years and are now utilized in various modalities spanning from conventional antibodies, antibody-drug conjugates, bispecific antibodies to chimeric antigen receptor (CAR) T cells. Many next generation antibody therapeutics achieve enhanced potency but often increase the risk of adverse events. Antibody scaffolds capable of exhibiting inducible affinities could reduce the risk of adverse events by enabling a transient suspension of antibody activity. To demonstrate this, we develop conditionally activated, single-module CARs, in which tumor antigen recognition is directly modulated by an FDA-approved small molecule drug. The resulting CAR T cells demonstrate specific cytotoxicity of tumor cells comparable to that of traditional CARs, but the cytotoxicity is reversibly attenuated by the addition of the small molecule. The exogenous control of conditional CAR T cell activity allows continual modulation of therapeutic activity to improve the safety profile of CAR T cells across all disease indications.