Abstract 1472: Novel vaccine targeting colonic adenoma: A pre-clinical model
Authors: Pham Toan D. , Carpinteri Sandra , Sampurno Shienny , Pereira Lloyd , Roth Sara , Narasimhan Vignesh , Wilson Kasmira , Darcy Phillip , Desai Jayesh , Heriot Alexander G. , Ramsay Robert G. 
Published: August 2019

Background

Colorectal cancer (CRC) is the second leading cause of cancer related mortality. 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 over-expressed in both adenomatous polyp precursors 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 Methods

Six to eight-week-old Apcmin/+ (Familial Adenomatous Polyposis model) and Apc580S (sporadic model) C57BL/6 mice were used. The Apcmin/+ 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, Apcmin/+ and Apc580S C57BL/6 mice were vaccinated and then surveyed for clinical signs of distress according to animal ethical endpoints. Number of adenoma 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 using mouse colonoscopy, mice were vaccinated with TetMYB and treated with anti-PD-1 antibody and were analyzed for adenoma growth rate.

Results

In both the prophylactic and therapeutic setting, mice vaccinated with TetMYB had a significantly improved outcome.

In the prophylactic treatment group, the vaccinated Apcmin/+ mice had a median survival benefit of 70 days (p = 0.008) and the vaccinated Apc580S mice having a mean survival benefit of 134 days (p = 0.01) over the unvaccinated mice.

In the prophylactic cohort, immunofluorescence confirmed a stronger cytotoxic CD8+ T-cell infiltrate in the vaccinated group, implying an anti-tumor immune response. In the therapeutic cohort, vaccinated Apc580S mice showed significantly reduced adenoma growth rate compared to the unvaccinated mice (p = 0.0005).

Conclusion

TetMYB 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, and perhaps colorectal cancer prevention.

Citation Format: Toan D. Pham, Sandra Carpinteri, Shienny Sampurno, Lloyd Pereira, Sara Roth, Vignesh Narasimhan, Kasmira Wilson, Phillip Darcy, Jayesh Desai, Alexander G. Heriot, Robert G. Ramsay. Novel vaccine targeting colonic adenoma: A pre-clinical model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1472.