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GUCY2C-targeted chimeric antigen receptor expressing T cells extend survival in a therapeutic mouse model of metastatic colorectal cancer
© Magee et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
Adoptive T cell therapy (ACT) is an emerging cancer treatment paradigm with success in early phase clinical trials in melanoma and B cell leukemia. However, ACT has been unsuccessful in tumors arising from the colorectum, in part due to antigen-dependent “on-target off-tumor” toxicities producing damage to normal tissues. These adverse events reflect the use of affinity-enhanced T cell receptors which increase the risk of T cell-mediated damage to normal tissues expressing the target antigen, an effect which is amplified for antigens broadly expressed by different tissues. In that context, we have generated an antibody-based chimeric antigen receptor (CAR) targeting the cancer mucosa antigen guanylyl cyclase C (GUCY2C), a membrane-bound cyclase selectively produced on apical surfaces of intestinal epithelial cells (IECs) in small and large intestine, whose expression is maintained by >95% of metastatic colorectal tumors. We hypothesized that anatomical compartmentalization of GUCY2C, normally limited to luminal surfaces of intestine but conserved on all colorectal cancer cells, would enable GUC2YC-targeted CAR T cells to eliminate metastatic colorectal tumors in the absence of intestinal damage. Here, CARs specific for mouse or human GUCY2C were inserted into murine CD8+ T cells by retroviral-mediated gene transfer. GUCY2C-specific CAR T cells induced GUCY2C-dependent T cell activation quantified by staining CD25 and CD69 surface markers and intracellular accumulation of IFNγ, TNFα, and MIP1α. Further, GUCY2C-specific CAR T cells lysed CT26 mouse colon cancer cells, quantified by release of β–galactosidase, in a GUCY2C-dependent fashion. Moreover, these CAR T cells extended median and overall survival in therapeutic mouse models of GUCY2C-expressing colorectal cancer metastatic to lung. Importantly, the therapeutic effects of GUCY2C-CAR T cells were not associated with antigen-dependent clinical toxicity, including diarrhea, rectal bleeding, or rectal prolapse, or gross pathology, including hemorrhage or ulceration, in intestine. Together, these observations establish proof-of-principle that adoptive T cell therapy using GUCY2C-targeted CARs is therapeutically effective, in the absence of “on-target off-tumor” normal tissue destruction, in metastatic colorectal cancer.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.