John Flickinger

Colorectal cancer is the second leading cause of cancer death and the fourth most common cancer in the United States. Previous work has focused on developing a vaccine for metastatic colorectal cancer utilizing the intestinal receptor and tumor antigen guanylate cyclase C (GCC) as a target. A recent phase I clinical trial demonstrated that a previous version of this vaccine safely induces GCC immune responses in patients. However, this trial also revealed a limitation of current GCC vaccines. Specifically, this project found that 50% of patients possessed pre-existing neutralizing antibodies against the adenovirus vaccine vector, which resulted in a lack of GCC immune responses in these patients. To directly address limitations of antibody neutralization observed in the clinical trial, the project is leveraging the unique biology of the bacterium Listeria monocytogenes. While other vaccine vectors induce neutralizing antibodies that limit responses upon re-exposure, Listeria monocytogenes does not generate neutralizing antibody responses, thereby making it possible to repeatedly administer vaccine and induce antitumor immunity. Moreover, this project is studying fundamental mechanisms of how Listeria monocytogenes induces therapeutic immune responses with a focus on enhancing antitumor properties of these vaccines. Ultimately, it is anticipated these studies will lay a framework for metastatic colorectal cancer vaccination that can hopefully one day be translated to the clinic.