Novel Vaccine Targeting Colonic Adenoma: a Pre-clinical Model

  • Toan PhamEmail author
  • Sandra Carpinteri
  • Shienny Sampurno
  • Lloyd Pereira
  • Sara Roth
  • Vignesh Narasimhan
  • Phillip Darcy
  • Jayesh Desai
  • Alexander G. Heriot
  • Robert G. Ramsay
SSAT Plenary Presentation 2018 SSAT Plenary Presentation



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.


Colorectal adenoma Colorectal cancer Immunotherapy Vaccination Checkpoint inhibition blockade Mouse model 


Author Contribution

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.


  1. 1.
    Jass, J.R., Serrated adenoma and colorectal cancer. J Pathol, 1999. 187(5): p. 499–502.CrossRefGoogle Scholar
  2. 2.
    Vogelstein, B., et al., Genetic alterations during colorectal-tumor development. N Engl J Med, 1988. 319(9): p. 525–32.CrossRefGoogle Scholar
  3. 3.
    Fearon, E.R. and B. Vogelstein, A genetic model for colorectal tumorigenesis. Cell, 1990. 61(5): p. 759–67.CrossRefGoogle Scholar
  4. 4.
    Church, J.M., et al., Teenagers with familial adenomatous polyposis: what is their risk for colorectal cancer? Dis Colon Rectum, 2002. 45(7): p. 887–9.CrossRefGoogle Scholar
  5. 5.
    Warrier, S.K. and M.F. Kalady, Familial adenomatous polyposis: challenges and pitfalls of surgical treatment. Clin Colon Rectal Surg, 2012. 25(2): p. 83–9.CrossRefGoogle Scholar
  6. 6.
    Galon, J., et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science, 2006. 313(5795): p. 1960–4.CrossRefGoogle Scholar
  7. 7.
    Galon, J., W.H. Fridman, and F. Pages, The adaptive immunologic microenvironment in colorectal cancer: a novel perspective. Cancer Res, 2007. 67(5): p. 1883–6.CrossRefGoogle Scholar
  8. 8.
    Le, D.T., et al., PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med, 2015. 372(26): p. 2509–20.CrossRefGoogle Scholar
  9. 9.
    Bindea, G., et al., The immune landscape of human tumors: Implications for cancer immunotherapy. Oncoimmunology, 2014. 3(1): p. e27456.CrossRefGoogle Scholar
  10. 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
  11. 11.
    Pham, T., et al., An Update on Immunotherapy for Solid Tumors: A Review. Ann Surg Oncol, 2018. 25(11): p. 3404–3412.CrossRefGoogle Scholar
  12. 12.
    Kimura, T., et al., MUC1 vaccine for individuals with advanced adenoma of the colon: a cancer immunoprevention feasibility study. Cancer Prev Res (Phila), 2013. 6(1): p. 18–26.CrossRefGoogle Scholar
  13. 13.
    Ali, O.A., et al., Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication. Cancer Immunol Res, 2016. 4(2): p. 95–100.CrossRefGoogle Scholar
  14. 14.
    Cross, R.S., et al., Therapeutic DNA vaccination against colorectal cancer by targeting the MYB oncoprotein. Clin Transl Immunology, 2015. 4(1): p. e30.CrossRefGoogle Scholar
  15. 15.
    Ramsay, R.G. and T.J. Gonda, MYB function in normal and cancer cells. Nat Rev Cancer, 2008. 8(7): p. 523–34.CrossRefGoogle Scholar
  16. 16.
    Biroccio, A., et al., c-Myb and Bcl-x overexpression predicts poor prognosis in colorectal cancer: clinical and experimental findings. Am J Pathol, 2001. 158(4): p. 1289–99.CrossRefGoogle Scholar
  17. 17.
    Cheasley, D., et al., Defective Myb Function Ablates Cyclin E1 Expression and Perturbs Intestinal Carcinogenesis. Mol Cancer Res, 2015. 13(8): p. 1185–96.CrossRefGoogle Scholar
  18. 18.
    Shibata, H., et al., Rapid colorectal adenoma formation initiated by conditional targeting of the Apc gene. Science, 1997. 278(5335): p. 120–3.CrossRefGoogle Scholar
  19. 19.
    Williams, B.B., et al., Induction of T cell-mediated immunity using a c-Myb DNA vaccine in a mouse model of colon cancer. Cancer Immunol Immunother, 2008. 57(11): p. 1635–45.CrossRefGoogle Scholar
  20. 20.
    Kanei-Ishii, C., et al., The tryptophan cluster: a hypothetical structure of the DNA-binding domain of the myb protooncogene product. J Biol Chem, 1990. 265(32): p. 19990–5.PubMedGoogle Scholar
  21. 21.
    Gerloni, M., et al., Functional cooperation between T helper cell determinants. Proc Natl Acad Sci U S A, 2000. 97(24): p. 13269–74.CrossRefGoogle Scholar
  22. 22.
    Dove, W.F., et al., The adenomatous polyposis coli gene of the mouse in development and neoplasia. Cold Spring Harb Symp Quant Biol, 1994. 59: p. 501–8.CrossRefGoogle Scholar
  23. 23.
    Dalgleish, A.G. and M.A. Whelan, Cancer vaccines as a therapeutic modality: The long trek. Cancer Immunol Immunother, 2006. 55(8): p. 1025–32.CrossRefGoogle Scholar
  24. 24.
    Ott, P.A., et al., An immunogenic personal neoantigen vaccine for patients with melanoma. Nature, 2017. 547(7662): p. 217–221.CrossRefGoogle Scholar
  25. 25.
    Sahin, U., et al., Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature, 2017. 547(7662): p. 222–226.CrossRefGoogle Scholar
  26. 26.
    Kanwar, R.K., et al., Targeting hepatitis B virus and human papillomavirus induced carcinogenesis: novel patented therapeutics. Recent Pat Antiinfect Drug Discov, 2011. 6(2): p. 158–74.CrossRefGoogle Scholar
  27. 27.
    Zuber, J., et al., An integrated approach to dissecting oncogene addiction implicates a Myb-coordinated self-renewal program as essential for leukemia maintenance. Genes Dev, 2011. 25(15): p. 1628–40.CrossRefGoogle Scholar
  28. 28.
    Hanahan, D. and R.A. Weinberg, The hallmarks of cancer. Cell, 2000. 100(1): p. 57–70.CrossRefGoogle Scholar
  29. 29.
    Hanahan, D. and R.A. Weinberg, Hallmarks of cancer: the next generation. Cell, 2011. 144(5): p. 646–74.CrossRefGoogle Scholar
  30. 30.
    Millen, R., et al., Immunomodulation by MYB is associated with tumor relapse in patients with early stage colorectal cancer. Oncoimmunology, 2016. 5(7): p. e1149667.CrossRefGoogle Scholar
  31. 31.
    Anitei, M.G., et al., Prognostic and predictive values of the immunoscore in patients with rectal cancer. Clin Cancer Res, 2014. 20(7): p. 1891–9.CrossRefGoogle Scholar
  32. 32.
    Galon, J., et al., Validation of the Immunoscore (IM) as a prognostic marker in stage I/II/III colon cancer: Results of a worldwide consortium-based analysis of 1,336 patients. Journal of Clinical Oncology, 2016. 34(15_suppl): p. 3500–3500.CrossRefGoogle Scholar
  33. 33.
    Corley, D.A., et al., Adenoma detection rate and risk of colorectal cancer and death. N Engl J Med, 2014. 370(14): p. 1298–306.CrossRefGoogle Scholar
  34. 34.
    Winawer, S.J., et al., Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med, 1993. 329(27): p. 1977–81.CrossRefGoogle Scholar
  35. 35.
    Abdel-Rahman, O., Risk of Subsequent Primary Kidney Cancer After Another Malignancy: A Population-based Study. Clin Genitourin Cancer, 2017. 15(5): p. e747-e754.CrossRefGoogle Scholar

Copyright information

© The Society for Surgery of the Alimentary Tract 2019

Authors and Affiliations

  • Toan Pham
    • 1
    • 2
    • 3
    • 4
    Email author return OK on get
  • Sandra Carpinteri
    • 1
  • Shienny Sampurno
    • 1
  • Lloyd Pereira
    • 1
  • Sara Roth
    • 1
  • Vignesh Narasimhan
    • 2
    • 3
    • 4
  • Phillip Darcy
    • 1
  • Jayesh Desai
    • 3
  • Alexander G. Heriot
    • 1
    • 2
    • 3
    • 4
  • Robert G. Ramsay
    • 1
    • 5
  1. 1.Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneAustralia
  2. 2.Division of Cancer SurgeryPeter MacCallum Cancer CentreMelbourneAustralia
  3. 3.Sir Peter MacCallum Department of OncologyThe University of MelbourneMelbourneAustralia
  4. 4.Department of SurgeryThe University of MelbourneMelbourneAustralia
  5. 5.Department of PathologyThe University of MelbourneMelbourneAustralia

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