2. Academic Validation
  3. CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice

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

  • Cell Rep Med. 2021 Jun 1;2(6):100297. doi: 10.1016/j.xcrm.2021.100297.
Nan Li 1,  Madeline B Torres 1,  Madeline R Spetz 1,  Ruixue Wang 1,  Luyi Peng 1,  Meijie Tian 2,  Christopher M Dower 3,  Rosa Nguyen 4,  Ming Sun 4,  Chin-Hsien Tai 1,  Natalia de Val 5 6,  Raul Cachau 7,  Xiaolin Wu 6,  Stephen M Hewitt 8,  Rosandra N Kaplan 4,  Javed Khan 2,  Brad St Croix 3,  Carol J Thiele 4,  Mitchell Ho 1
Affiliations

Affiliations

  • 1 Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 2 Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 3 Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
  • 4 Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • 5 Center for Molecular Microscopy, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
  • 6 Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick, MD 21702, USA.
  • 7 Data Science and Information Technology Program, Leidos Biomedical Research, Frederick, MD 21702, USA.
  • 8 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
PMID: 34195677 DOI: 10.1016/j.xcrm.2021.100297
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 CAR T 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.

Keywords

antibodies; chimeric antigen receptor (CAR) T cells; electron microscopy; epitopes; glypican 2; heparan sulfate proteoglycans; immunotherapy; neuroblastoma; pediatric cancers; tumor-specific T cells.

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