Academic Journal
Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models
| العنوان: | Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models |
|---|---|
| المؤلفون: | Yang, Yanping, Yang, Huan, Alcaina, Yago, Puc, Janusz, Birt, Alyssa, Vedvyas, Yogindra, Gallagher, Michael, Alla, Srinija, Riascos, Maria Cristina, McCloskey, Jaclyn E., Du, Karrie, Gonzalez-Valdivieso, Juan, Min, Irene M., de Stanchina, Elisa, Britz, Matt, von Hofe, Eric, Jin, Moonsoo M. |
| المساهمون: | Sponsored research grant (AffyImmune), and institutional grant (MI3, Weill Cornell Medicine). |
| المصدر: | Nature Communications ; volume 14, issue 1 ; ISSN 2041-1723 |
| بيانات النشر: | Springer Science and Business Media LLC |
| سنة النشر: | 2023 |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| DOI: | 10.1038/s41467-023-37646-y |
| الاتاحة: | http://dx.doi.org/10.1038/s41467-023-37646-y https://www.nature.com/articles/s41467-023-37646-y.pdf https://www.nature.com/articles/s41467-023-37646-y |
| Rights: | https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| رقم الانضمام: | edsbas.A9CEAF85 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-023-37646-y |
|---|