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Wang, Dongrui; Starr, Renate; Chang, Wen-Chung; Aguilar, Brenda; Alizadeh, Darya; Wright, Sarah L; Yang, Xin; Brito, Alfonso; Sarkissian, Aniee; Ostberg, Julie R; Li, Li; Shi, Yanhong; Gutova, Margarita; Aboody, Karen; Badie, Behnam; Forman, Stephen J; Barish, Michael E; Brown, Christine E
Science translational medicine, 03/2020, Volume: 12, Issue: 533Journal Article
Although chimeric antigen receptor (CAR) T cells have demonstrated signs of antitumor activity against glioblastoma (GBM), tumor heterogeneity remains a critical challenge. To achieve broader and more effective GBM targeting, we developed a peptide-bearing CAR exploiting the GBM-binding potential of chlorotoxin (CLTX). We find that CLTX peptide binds a great proportion of tumors and constituent tumor cells. CAR T cells using CLTX as the targeting domain (CLTX-CAR T cells) mediate potent anti-GBM activity and efficiently target tumors lacking expression of other GBM-associated antigens. Treatment with CLTX-CAR T cells resulted in tumor regression in orthotopic xenograft GBM tumor models. CLTX-CAR T cells do not exhibit observable off-target effector activity against normal cells or after adoptive transfer into mice. Effective targeting by CLTX-CAR T cells requires cell surface expression of matrix metalloproteinase-2. Our results pioneer a peptide toxin in CAR design, expanding the repertoire of tumor-selective CAR T cells with the potential to reduce antigen escape.
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