Engineering CAR-T cells to activate small-molecule drugs in situ Journal Article
| Authors: | Gardner, T. J.; Lee, J. P.; Bourne, C. M.; Wijewarnasuriya, D.; Kinarivala, N.; Kurtz, K. G.; Corless, B. C.; Dacek, M. M.; Chang, A. Y.; Mo, G.; Nguyen, K. M.; Brentjens, R. J.; Tan, D. S.; Scheinberg, D. A. |
| Article Title: | Engineering CAR-T cells to activate small-molecule drugs in situ |
| Abstract: | 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. [Figure not available: see fulltext.]. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc. |
| Keywords: | antineoplastic agents; antineoplastic agent; neoplasm; neoplasms; t lymphocyte; t-lymphocytes; mouse; animal; animals; mice; drug screening; xenograft model antitumor assays; mice, inbred c57bl; c57bl mouse; drug delivery systems; chemistry; neoplasms, experimental; experimental neoplasm; drug delivery system; prodrug; prodrugs; tumor microenvironment; hek293 cells; humans; human; male; female; hek293 cell line; receptors, chimeric antigen |
| Journal Title: | Nature Chemical Biology |
| Volume: | 18 |
| Issue: | 2 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2022-02-01 |
| Start Page: | 216 |
| End Page: | 225 |
| Language: | English |
| DOI: | 10.1038/s41589-021-00932-1 |
| PUBMED: | 34969970 |
| PROVIDER: | scopus |
| PMCID: | PMC9152922 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2022 -- Source: Scopus |
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