GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity.

Authors

• Michael S Magee
• Crystal L Kraft
• Tara S Abraham
• Trevor R Baybutt
• Glen P Marszalowicz
• Peng Li
• Scott A Waldman
• Adam E Snook

Publication/Presentation Date

1-1-2016

Abstract

Adoptive T-cell therapy (ACT) is an emerging paradigm in which T cells are genetically modified to target cancer-associated antigens and eradicate tumors. However, challenges treating epithelial cancers with ACT reflect antigen targets that are not tumor-specific, permitting immune damage to normal tissues, and preclinical testing in artificial xenogeneic models, preventing prediction of toxicities in patients. In that context, mucosa-restricted antigens expressed by cancers exploit anatomical compartmentalization which shields mucosae from systemic antitumor immunity. This shielding may be amplified with ACT platforms employing antibody-based chimeric antigen receptors (CARs), which mediate MHC-independent recog-nition of antigens. GUCY2C is a cancer mucosa antigen expressed on the luminal surfaces of the intestinal mucosa in mice and humans, and universally overexpressed by colorectal tumors, suggesting its unique utility as an ACT target. T cells expressing CARs directed by a GUCY2C-specific antibody fragment recognized GUCY2C, quantified by expression of activation markers and cytokines. Further, GUCY2C CAR-T cells lysed GUCY2C-expressing, but not GUCY2C-deficient, mouse colorectal cancer cells. Moreover, GUCY2C CAR-T cells reduced tumor number and morbidity and improved survival in mice harboring GUCY2C-expressing colorectal cancer metastases. GUCY2C-directed T cell efficacy reflected CAR affinity and surface expression and was achieved without immune-mediated damage to normal tissues in syngeneic mice. These observations highlight the potential for therapeutic translation of GUCY2C-directed CAR-T cells to treat metastatic tumors, without collateral autoimmunity, in patients with metastatic colorectal cancer.

Volume

5

Issue

10

First Page

1227897

Last Page

1227897

ISSN

2162-4011

Published In/Presented At

Magee, M. S., Kraft, C. L., Abraham, T. S., Baybutt, T. R., Marszalowicz, G. P., Li, P., Waldman, S. A., & Snook, A. E. (2016). GUCY2C-directed CAR-T cells oppose colorectal cancer metastases without autoimmunity. Oncoimmunology, 5(10), e1227897. https://doi.org/10.1080/2162402X.2016.1227897

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

27853651

Department(s)

Administration and Leadership

Document Type

Article