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Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases
Open accessPublished version of a preprint
Abstract
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. Cancer Immunol Res; 6(5); 509–16. ©2018 AACR.
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“Several antigens being evaluated as candidates for anti-CRC CAR-T cell therapy have shown efficacy in CRC preclinical models, including carcinoembryonic antigen and guanylyl cyclase 2C [227,228].”
From Mechanisms and Strategies to Overcome Drug Resistance in Colorectal Cancer (2025) · cites this paper as [227]
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Metadata
- Authors
- Magee, M. S., Abraham, T. S., Baybutt, T. R., Flickinger, J. C., Ridge, N. A., Marszalowicz, G. P., Prajapati, P., Hersperger, A. R., Waldman, S. A., & Snook, A. E.
- Affiliations
- Thomas Jefferson University (US)
- Drexel University (US)
- Corresponding author
- Snook, Adam E.
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2018-04-30
- Volume
- 6
- Issue
- 5
- Pages
- 509-516
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC5932207
- OpenAlex
- W2796020321
- Cited by
- 143
- References
- 31
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 15 · 2023: 23 · 2022: 31 · 2021: 22 · 2020: 14 · 2019: 10 · 2018: 5
- FWCI
- 4.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Medicine Forum (submittedVersion)
- Funders
- NIH (P30 CA56036, R01 CA204881, R01 CA206026, F31 CA171672)
- Pennsylvania Department of Health (SAP #4100059197, SAP #4100051723)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Bacterial Cancer Therapy
- Keywords
- GUCY2C, chimeric antigen receptor T cells, CAR T-cell therapy, colorectal cancer metastasis, lung metastasis, scFv, tumor antigen targeting, intestinal epithelium, xenograft models, adoptive T cell therapy
- MeSH terms
- Receptors, Enterotoxin, Receptors, Chimeric Antigen, Animals, Cells, Cultured, Cytotoxicity, Immunologic, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Transgenic, Neoplasm Metastasis, Receptors, Antigen, T-Cell, T-Lymphocytes, Colorectal Neoplasms, Immunotherapy, Adoptive, Xenograft Model Antitumor Assays, Mice, HEK293 Cells
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