Journal article
Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases
Cancer immunology research, v 6(5)
30 Apr 2018
PMCID: PMC5932207
PMID: 29615399
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro. GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer.
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Details
- Title
- Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases
- Creators
- Michael Magee - Thomas Jefferson UniversityTara S Abraham - Thomas Jefferson UniversityTrevor R. Baybutt - Thomas Jefferson UniversityJohn C Flickinger - Thomas Jefferson UniversityNatalie A Ridge - Thomas Jefferson UniversityGlen P Marszalowicz - Drexel UniversityPriyanka Prajapati - Thomas Jefferson UniversityAdam R Hersperger - Thomas Jefferson UniversityScott A. Waldman - Thomas Jefferson UniversityAdam E Snook - Thomas Jefferson University
- Publication Details
- Cancer immunology research, v 6(5)
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000431295700002
- Scopus ID
- 2-s2.0-85047770430
- Other Identifier
- 991021864001504721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Immunology
- Oncology