Engineering CAR-T cells to activate small-molecule drugs in situ

Nat Chem Biol. 2022 Feb;18(2):216-225. doi: 10.1038/s41589-021-00932-1. Epub 2021 Dec 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Drug Delivery Systems
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms / therapy
  • Neoplasms, Experimental
  • Prodrugs
  • Receptors, Chimeric Antigen
  • T-Lymphocytes
  • Tumor Microenvironment
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Prodrugs
  • Receptors, Chimeric Antigen