GUCY2C-targeted cancer immunotherapy: past, present and future
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CURRENT IMMUNOLOGY RESEARCH AT JEFFERSON
GUCY2C-targeted cancer immunotherapy: past, present and future Adam E. Snook • Michael S. Magee • Scott A. Waldman
Published online: 30 October 2011 Ó Springer Science+Business Media, LLC 2011
Adam E. Snook
Abstract For the last decade, we have focused on guanylyl cyclase C (GUCY2C) as a potentially ideal target antigen for colorectal cancer immunotherapy. GUCY2C is expressed only in intestinal epithelial cells and by nearly 100% of colorectal cancers. We have developed and tested a recombinant adenoviral vector possessing GUCY2C (Ad5-GUCY2C) as a candidate vaccine for colorectal cancer patients. Murine studies have revealed that this vaccine is safe and effective against GUCY2C-expressing targets, and Ad5-GUCY2C is poised for phase I clinical testing in colorectal cancer patients with minimal residual disease. Moreover, we are developing second-generation GUCY2C-targeted therapeutics, including the use of chimeric antigen receptor (CAR)-expressing T cells, for treatment of patients with advanced colorectal cancer for whom Ad5-GUCY2C immunization is not appropriate. Thus, a family of GUCY2C-targeted immunotherapeutics may bridge the gap in effective treatments for the 500,000 patients worldwide who die annually from colorectal cancer. Keywords
Guanylyl cyclase C GUCY2C Immunotherapy Adoptive cell therapy Cancer
Adenocarcinoma of the colon and rectum (colorectal cancer) is the third most frequent cause of cancer and second leading cause of cancer mortality in the United States [1]. Furthermore, colorectal cancer is the third most frequent cancer and fourth most common cause of cancer mortality in the world, resulting in *1 million cases and *500,000 deaths annually [2, 3]. Colorectal cancer prognosis reflects progression of the disease upon diagnosis. Patients with localized disease (stages I and II) have a favorable prognosis, and surgery is presumptively curative—indeed, these patients do not receive adjunct chemotherapy. Patients with metastases in regional
Disclosures: SAW is the Chair of the Data Safety Monitoring Board for the C-Cure TrialTM sponsored by Cardio Biosciences and the Chair (uncompensated) of the Scientific Advisory Board to Targeted Diagnostics and Therapeutics, Inc., which provided research funding that, in part, supported this work and has a license to commercialize inventions related to this work. A. E. Snook (&) M. S. Magee S. A. Waldman Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1020 Locust Street, JAH 348A, Philadelphia, PA 19107, USA e-mail: [email protected]
lymph nodes (stage III) have a less-favorable prognosis, and approximately 50% survive 5 years following standard chemotherapy regimens. Patients with distant metastases have a poor prognosis, and most succumb to the disease. Importantly, among the stage I and stage II patients, who are ostensibly free of metastases in regional lymph nodes (pN0), approximately 33% develop metastases during the course of their disease [4]. This
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