Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

Authors

Michael S. Magee, Bluebird Bio; Thomas Jefferson UniversityFollow
Tara S. Abraham, Thomas Jefferson UniversityFollow
Trevor R. Baybutt, Thomas Jefferson UniversityFollow
John C. Flickinger, Thomas Jefferson UniversityFollow
Natalie A. Ridge, Thomas Jefferson University
Glen P Marszalowicz, Drexel University
Priyanka Prajapati, Thomas Jefferson University
Adam R. Hersperger, Thomas Jefferson University
Scott A. Waldman, Thomas Jefferson UniversityFollow
Adam E. Snook, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

5-1-2018

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Cancer Immunology Research, Volume 6, Issue 5, May 2018, Pages 509-516.

The published version is available at https://doi.org/10.1158/2326-6066.CIR-16-0362. Copyright © American Association for Cancer Research

Abstract

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer.

Recommended Citation

Magee, Michael S.; Abraham, Tara S.; Baybutt, Trevor R.; Flickinger, John C.; Ridge, Natalie A.; Marszalowicz, Glen P; Prajapati, Priyanka; Hersperger, Adam R.; Waldman, Scott A.; and Snook, Adam E., "Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases." (2018). Department of Pharmacology and Experimental Therapeutics Faculty Papers. Paper 109.
https://jdc.jefferson.edu/petfp/109

PubMed ID

29615399

Language

English