Research ArticleCancer

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

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Science Translational Medicine  04 Mar 2020:
Vol. 12, Issue 533, eaaw2672
DOI: 10.1126/scitranslmed.aaw2672

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Stinging glioblastoma

Chlorotoxin derived from scorpion venom has previously been shown to bind glioblastoma cells. Wang et al. designed a chimeric antigen receptor (CAR) based on chlorotoxin to surmount limitations of other glioblastoma-targeted CARs that have not been able to overcome tumor heterogeneity and antigen escape. They demonstrated that chlorotoxin binding captures a broader array of primary tumors than staining for previously identified antigenic targets. Chlorotoxin-directed CAR T cells were safe in mice and induced regression of orthotopic glioblastoma xenografts with no evidence of antigen escape. These toxin-based CAR T cells are distinct from conventional CAR design and could one day be used to deliver a poisonous blow to glioblastoma.


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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