Novel Vaccine Targeting Colonic Adenoma: a Pre-clinical Model
- 40 Downloads
Colorectal 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 precancerous adenomatous 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 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 surveyed for clinical signs of distress. 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, mice were vaccinated with TetMYB and treated with anti-PD-1 antibody and were analyzed for overall survival.
In both the prophylactic and therapeutic setting, mice vaccinated with TetMYB had a significantly improved outcome, with the vaccinated Apcmin/+ mice having 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 progression rate compared to the unvaccinated mice (p = 0.0005).
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.
KeywordsColorectal adenoma Colorectal cancer Immunotherapy Vaccination Checkpoint inhibition blockade Mouse model
TP, SC, SS, JD, AGH, and RGR produced the study concept and design. TP, SC, and SS performed the scientific literature search and summarized all relevant studies. LP, SC, and TP manufactured the vaccines. TP, SC, and SS were involved in the data collection and analysis. PD provided the anti-PD-1 antibody. All authors were involved in refining the study design and data interpretation. TP, SC, SS, JD, PD, AGH, and RGR wrote the initial draft, with all authors involved in the editing process and final version of the manuscript. TP, SC, SS, and RGR compiled the tables, figures, and supplementary protocols and data.
- 10.Pages, F., et al. (2018). “International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.” Lancet 391(10135): 2128–2139.Google Scholar