Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 12, Issue 533, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw2672
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Funding
- Ben and Catherine Ivy Foundation
- NIH [P30CA33572]
- NCI fellowship [5F99CA234923-02]
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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. CART 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-CART cells resulted in tumor regression in orthotopicxenograft 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 CART cells with the potential to reduce antigen escape.
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