CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice

Author:

Li, Nan

Torres, Madeline B.

Spetz, Madeline R.

Wang, Ruixue

Peng, Luyi

Tian, Meijie

Dower, Christopher M.

Nguyen, Rosa

Sun, Ming

Tai, Chin-Hsien

de Val, Natalia

Cachau,Raul

Wu, Xiaolin

Hewitt, Stephen M.

Kaplan, Rosandra N.

Khan, Javed

St Croix,Brad

Thiele, Carol J.

Ho, Mitchell
Author Address

NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NCI, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA.NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.NCI, Ctr Mol Microscopy, Ctr Canc Res, NIH, Frederick, MD 21702 USA.Leidos Biomed Res Inc, Canc Res Technol Program, Frederick, MD 21702 USA.Leidos Biomed Res, Data Sci & Informat Technol Program, Frederick, MD 21702 USA.NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA.

Abstract:

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.

See More

Author Address