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

2023; Nature Portfolio; Volume: 14; Issue: 1 Linguagem: Inglês

10.1038/s41467-023-37646-y

2041-1723

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 González‐Valdivieso, Irene M. Min, Elisa de Stanchina, Matt Britz, Eric von Hofe, Moonsoo M. Jin,

Advancements in Semiconductor Devices and Circuit Design

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 EpCAM high 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.