Engineering CAR-T Cells to Activate Small-molecule Drugs in Situ

Overview

Journal Nat Chem Biol

Specialties Biochemistry
Biology
Chemistry

Date 2021 Dec 31

PMID 34969970

Citations 30

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Strategies to Overcome Antigen Heterogeneity in CAR-T Cell Therapy.

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Carcopino C, Erdogan E, Henrich M, Kobold S Immunooncol Technol. 2024; 24:100739.

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Theoretical basis, state and challenges of living cell-based drug delivery systems.

Liu W, Cheng G, Cui H, Tian Z, Li B, Han Y Theranostics. 2024; 14(13):5152-5183.

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Augmenting CAR T-cell Functions with LIGHT.

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