期刊
CELL REPORTS MEDICINE
卷 2, 期 6, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.xcrm.2021.100297
关键词
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资金
- NIH, NCI, Center for Cancer Research (CCR) [Z01 BC010891]
- Cancer Moonshot program through the NCI CCR Center for Cell-based Therapy
- NCI CCR FLEX Program Synergy Award
The study utilized RNA sequencing analysis to identify high expression of GPC2 exons 3 and exons 7-10 in cancer but minimal expression in normal tissues. A monoclonal antibody CT3 was discovered and used to design CAR T cells for treating neuroblastoma. Genomic sequencing of T cells recovered from mice revealed potential CAR integration sites contributing to CART cell proliferation and persistence.
Targeting solid tumors must overcome several major obstacles, in particular, the identification of elusive tumor-specific antigens. Here, we devise a strategy to help identify tumor-specific epitopes. Glypican 2 (GPC2) is overexpressed in neuroblastoma. Using RNA sequencing (RNA-seq) analysis, we show that exon 3 and exons 7-10 of GPC2 are expressed in cancer but are minimally expressed in normal tissues. Accordingly, we discover a monoclonal antibody (CT3) that binds exons 3 and 10 and visualize the complex structure of CT3 and GPC2 by electron microscopy. The potential of this approach is exemplified by designing CT3-derived chimeric antigen receptor (CAR) T cells that regress neuroblastoma in mice. Genomic sequencing of T cells recovered from mice reveals the CAR integration sites that may contribute to CART cell proliferation and persistence. These studies demonstrate how RNA-seq data can be exploited to help identify tumor-associated exons that can be targeted by CAR T cell therapies.
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