CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy.

Authors

• Trevor R Baybutt
• Ariana A Entezari
• Adi Caspi
• Ross E Staudt
• Robert D Carlson
• Scott A Waldman
• Adam E Snook

Publication/Presentation Date

12-31-2024

Abstract

Despite success in treating some hematological malignancies, CAR-T cells have not yet produced similar outcomes in solid tumors due, in part, to the tumor microenvironment, poor persistence, and a paucity of suitable target antigens. Importantly, the impact of the CAR components on these challenges remains focused on the intracellular signaling and antigen-binding domains. In contrast, the flexible hinge and transmembrane domains have been commoditized and are the least studied components of the CAR. Here, we compared the hinge and transmembrane domains derived from either the CD8ɑ or CD28 molecule in identical GUCY2C-targeted third-generation designs for colorectal cancer. While these structural domains do not contribute to differences in antigen-independent contexts, such as CAR expression and differentiation and exhaustion phenotypes, the CD8ɑ structural domain CAR has a greater affinity for GUCY2C. This results in increased production of inflammatory cytokines and granzyme B, improved cytolytic effector function with low antigen-expressing tumor cells, and robust anti-tumor efficacy

Volume

25

Issue

1

First Page

2398801

Last Page

2398801

ISSN

1555-8576

Published In/Presented At

Baybutt, T. R., Entezari, A. A., Caspi, A., Staudt, R. E., Carlson, R. D., Waldman, S. A., & Snook, A. E. (2024). CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy. Cancer biology & therapy, 25(1), 2398801. https://doi.org/10.1080/15384047.2024.2398801

Disciplines

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

PubMedID

39315411

Department(s)

Administration and Leadership

Document Type

Article