Chlorotoxin-directed CAR T cells for specific and effective targeting of glioblastoma

Dongrui Wang, Renate Starr, Wen-Chung Chang, Brenda Aguilar, Darya Alizadeh, Sarah L. Wright, Xin Yang, Alfonso Brito, Aniee Sarkissian, Julie R. Ostberg, Li Li, Yanhong Shi (+6 others)
2020 Science Translational Medicine  
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
more » ... iate 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.
doi:10.1126/scitranslmed.aaw2672 pmid:32132216 fatcat:lr7sle55jje6nk7kojgdpchhla