Chlorotoxin Redirects Chimeric Antigen Receptor T Cells for Specific and Effective Targeting of Glioblastoma

Author:

Wang Dongrui,Starr Renate,Chang Wen-Chung,Aguilar Brenda,Alizadeh Darya,Wright Sarah L.,Yang Xin,Brito Alfonso,Sarkissian Aniee,Ostberg Julie R.,Shi Yanhong,Gutova Margarita,Aboody Karen,Badie Behnam,Forman Stephen J.,Barish Michael E.,Brown Christine E.

Abstract

AbstractWhile chimeric antigen receptor (CAR) T cells have demonstrated antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To more effectively target heterogeneous GBMs, we report the development of a novel peptide-based CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). CLTX bound a greater proportion of tumor cells than GBM-associated antigens EGFR, HER2 and IL13Rα2. CAR T cells bearing CLTX as the targeting domain (CLTX-CAR), mediated potentin vitroandin vivoanti-GBM activity, and efficiently targeted tumors lacking expression of other GBM-associated antigens. Importantly, CLTX-CAR T cells exhibited no observable off-target effector activity against normal cells, or when adoptively transferred into mice. Effective targeting by CLTX-CAR T cells required cell surface expression of matrix metalloproteinase-2 (MMP-2). Our results are the first demonstration of a peptide toxin utilized as a CAR targeting domain, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.One Sentence SummaryChimeric antigen receptors incorporating chlorotoxin as the tumor targeting domain recognize and kill glioblastoma with high specificity and potency.

Publisher

Cold Spring Harbor Laboratory

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