Guanylyl Cyclase C Vaccines for Secondary Prevention of Metastatic Colorectal Cancer
Abstract
Over the last decade, it has become evident that the immune system can be leveraged in the fight against cancer. Indeed, engaging the immune system through immune checkpoint inhibitor therapy has generated unprecedented results and revolutionized cancer drug development. However, effective therapies for many cancers, such as metastatic colorectal cancer (CRC), are still lacking. In this context, we have developed a vaccine against metastatic CRC for individuals with a high-risk of developing this disease. This vaccine targets the tumor-associated antigen guanylyl cyclase c (GUCY2C, GCC), an antigen that is near universally expressed in CRC. A phase I clinical trial testing an adenovirus-based GUCY2C vaccine (Ad5-GUCY2C-PADRE) recently demonstrated the ability to safely induce GUCY2C-specific immune responses in patients. While promising, this trial also indicated that the vaccine is hindered in two capacities. The trial showed that 1) some patients possess pre-existing antibodies that neutralize the adenovirus vaccine vector and prevent the induction of GUCY2C-specific immune responses and 2) many patients fail to mount CD4+ T-cell responses to the CD4+ helper T-cell epitope, PADRE, which is necessary for effective GUCY2C-specific immune responses. Here, we evaluate a novel GUCY2C immunization regimen utilizing the chimeric adenovirus Ad5.F35 and the bacterium Listeria monocytogenes (Lm) as vaccine vectors. We demonstrate that this combination induces potent antitumor immunity and is not limited by pre-existing Ad5 or Lm immunity. Moreover, through defining the utility of this vaccination regimen, we uncover novel findings concerning the role of CD4+ helper T-cells during CD8+ T-cell responses and reveal limitations of the popular vaccine vector, Lm. These studies carry implications for the design of GUCY2C vaccines as well as designs for vaccines targeting other cancer or infectious disease antigens.
Subject Area
Oncology|Genetics|Pharmacology|Molecular biology
Recommended Citation
Flickinger, John C., "Guanylyl Cyclase C Vaccines for Secondary Prevention of Metastatic Colorectal Cancer" (2023). ProQuest ETD Collection - Thomas Jefferson University. AAI28418286.
https://jdc.jefferson.edu/dissertations/AAI28418286
