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

Autor: Yang Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Yang H; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Alcaina Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Puc J; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Birt A; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Vedvyas Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Gallagher M; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Alla S; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Riascos MC; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA., McCloskey JE; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Du K; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Gonzalez-Valdivieso J; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Min IM; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Britz M; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., von Hofe E; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Jin MM; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu.; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2023 Apr 12; Vol. 14 (1), pp. 2068. Date of Electronic Publication: 2023 Apr 12.
DOI: 10.1038/s41467-023-37646-y
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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