Novel Vaccine Targeting Colonic Adenoma: a Pre-clinical Model

BackgroundColorectal cancer (CRC) is the second leading cause of cancer-related mortality in the USA. Over 80% of CRC develop from adenomatous polyps. Hence, early treatment and prevention of adenomas would lead to a significant decrease of disease burden for CRC. MYB is a transcription factor that is overexpressed in both precancerousadenomatous polyps and colorectal cancer, and hence an ideal immunotherapeutic target. We have developed a cancer vaccine, TetMYB, that targets MYB and aim to evaluate its efficacy in the prophylactic and therapeutic management of adenomatous polyps.Material and MethodsSix- to eight-week-old Apc(min/+) (Familial Adenomatous Polyposis model) and Apc580S (sporadic model) C57BL/6 mice were used. The Apc(min/+) mice are carried a germline mutation of one Apc allele whereas the Apc580S model has an inducible silencing of one Apc allele, when exposed to tamoxifen, via the Cre-Lox recombination enzyme system.In the prophylactic treatment group, Apc(min/+) and Apc580S C57BL/6 mice were vaccinated and surveyed for clinical signs of distress. Number ofadenoma and survival were measured. In the therapeutic cohort, Apc580S C57BL/6 mice were given tamoxifen-laced food to activate Cre-Lox recombinase mediated silencing of one Apc allele and thus inducing adenoma development. Following adenoma detection, mice were vaccinated with TetMYB and treated with anti-PD-1 antibody and were analyzed for overall survival.ResultsIn both the prophylactic and therapeutic setting, mice vaccinated with TetMYB had a significantly improved outcome, with the vaccinated Apc(min/+) mice having a median survival benefit of 70days(p = 0.008) and the vaccinated Apc580S mice having a mean survival benefit of 134days (p = 0.01)over the unvaccinated mice. In the prophylactic cohort, immunofluorescence confirmed a stronger cytotoxic CD8(+) T cellinfiltrate in the vaccinated group, implying an anti-tumor immune response. In the therapeutic cohort, vaccinated Apc580S mice showed significantly reduced adenoma progression rate compared to the unvaccinated mice (p = 0.0005).ConclusionTetMYB vaccine has shown benefit in a prophylactic and therapeutic setting in the management of colonic adenoma in a murine model. This will form the basis for a future clinical trial to prevent and treat colonic adenomatous polyps.