The Identification of IL-4 as a Regulator of Chimeric Antigen Receptor T Cell Exhaustion

• DOI: 10.1101/2023.09.28.560046
• Publication Date: 2023-10-01T05:05:14Z
• Authors: Carli M. Stewart; Elizabeth L. Siegler; R. Leo Sakemura; Michelle J. Cox; Truc Huynh; Brooke Kimball; Long Mai; Ismail Can; Claudia Manriquez...; Kun Yun; Olivia Sirpilla; James H. Girsch; Ekene Ogbodo; Wazim Ismail; Alexandre Gaspar ...; Justin Budka; Jenny Kim; Nathalie Scholler; Mike Mattie; Simone Filosto; Saad S. Kenderian
• Keywords: Cart

Abstract Durable response to chimeric antigen receptor T (CART) cell therapy remains limited in part due CART exhaustion. We investigated the regulation of exhaustion with three independent approaches including: a genome-wide CRISPR knockout screen using validated vitro model for exhaustion, RNA and ATAC sequencing on baseline chronically stimulated cells, pre-infusion products from responders non-responders ZUMA-1 clinical trial. Each these identified IL-4 as key regulator dysfunction. Further, when cells were treated IL-4, they developed signs but an monoclonal antibody, showed improved antitumor efficacy reduced preclinical models. Therefore, our study both novel role improvement through neutralization. Statement Significance Identifying regulators will not only enhance field’s understanding therapeutic failure, it also provide avenues efficacy. This reveals strategy improve activity