Authors: Thomas J. Gardner, J. Peter Lee, Christopher M. Bourne, Dinali Wijewarnasuriya, Nihar Kinarivala, Keifer G. Kurtz, Broderick C. Corless, Megan M. Dacek, Aaron Y. Chang, George Mo, Kha M. Nguyen, Renier J. Brentjens, Derek S. Tan, David A. Scheinberg
Summary: Chimeric antigen receptor (CAR)-T cells represent a major breakthrough in cancer therapy, wherein a patient’s own T cells are engineered to recognize a tumor antigen, resulting in activation of a local cytotoxic immune response. However, CAR-T cell therapies are currently limited to the treatment of B cell cancers and their effectiveness is hindered by resistance from antigen-negative tumor cells, immunosuppression in the tumor microenvironment, eventual exhaustion of T cell immunologic functions and frequent severe toxicities. To overcome these problems, we have developed a novel class of CAR-T cells engineered to express an enzyme that activates a systemically administered small-molecule prodrug in situ at a tumor site. We show that these synthetic enzyme-armed killer (SEAKER) cells exhibit enhanced anticancer activity with small-molecule prodrugs, both in vitro and in vivo in mouse tumor models. This modular platform enables combined targeting of cellular and small-molecule therapies to treat cancers and potentially a variety of other diseases.
Source: Nature Chemical Biology, 2021