Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models

Yanping Yang, Huan Yang, Yago Alcaina, Janusz Puc, Alyssa Birt, Yogindra Vedvyas, Michael Gallagher, Srinija Alla, Maria Cristina Riascos, Jaclyn E. McCloskey, Karrie Du, Juan Gonzalez-Valdivieso, Irene M. Min, Elisa de Stanchina, Matt Britz, Eric von Hofe and Moonsoo M. Jin ()
Additional contact information
Yanping Yang: Weill Cornell Medicine
Huan Yang: AffyImmune Therapeutics, Inc.
Yago Alcaina: Weill Cornell Medicine
Janusz Puc: AffyImmune Therapeutics, Inc.
Alyssa Birt: AffyImmune Therapeutics, Inc.
Yogindra Vedvyas: Weill Cornell Medicine
Michael Gallagher: AffyImmune Therapeutics, Inc.
Srinija Alla: AffyImmune Therapeutics, Inc.
Maria Cristina Riascos: Weill Cornell Medicine
Jaclyn E. McCloskey: Weill Cornell Medicine
Karrie Du: AffyImmune Therapeutics, Inc.
Juan Gonzalez-Valdivieso: Weill Cornell Medicine
Irene M. Min: Weill Cornell Medicine
Elisa de Stanchina: Memorial Sloan Kettering Cancer Center
Matt Britz: AffyImmune Therapeutics, Inc.
Eric von Hofe: AffyImmune Therapeutics, Inc.
Moonsoo M. Jin: Weill Cornell Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract The limited number of targetable tumor-specific antigens and the immunosuppressive nature of the microenvironment within solid malignancies represent major barriers to the success of chimeric antigen receptor (CAR)-T cell therapies. Here, using epithelial cell adhesion molecule (EpCAM) as a model antigen, we used alanine scanning of the complementarity-determining region to fine-tune CAR affinity. This allowed us to identify CARs that could spare primary epithelial cells while still effectively targeting EpCAMhigh tumors. Although affinity-tuned CARs showed suboptimal antitumor activity in vivo, we found that inducible secretion of interleukin-12 (IL-12), under the control of the NFAT promoter, can restore CAR activity to levels close to that of the parental CAR. This strategy was further validated with another affinity-tuned CAR specific for intercellular adhesion molecule-1 (ICAM-1). Only in affinity-tuned CAR-T cells was NFAT activity stringently controlled and restricted to tumors expressing the antigen of interest at high levels. Our study demonstrates the feasibility of specifically gearing CAR-T cells towards recognition of solid tumors by combining inducible IL-12 expression and affinity-tuned CAR.

Date: 2023
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DOI: 10.1038/s41467-023-37646-y

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