Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma
Dongrui Wang, Renate Starr, Wen-Chung Chang, Brenda Aguilar, Darya Alizadeh, Sarah Wright, Xin Yang, Alfonso Brito, Aniee Sarkissian, Julie R. Ostberg, Li Li, Yanhong Shi, Margarita Gutova, Karen S. Aboody, Behnam Badie, Stephen J. Forman, Michael E. Barish, Christine E. Brown
Abstract
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.