THE PRECLINICAL DEVELOPMENT OF ONCOLYTIC VIRAL IMMUNOTHERAPY FOR EPITHELIAL CANCER

Abstract

HPV-associated cancer and carcinoma of the prostate are responsible for significant worldwide morbidity and mortality. The viral transforming proteins E6 and E7 make human papilloma virus positive (HPV+) malignancies an attractive target for cancer immunotherapy however, therapeutic vaccination exerts limited efficacy in the setting of advanced disease. In prostatic carcinoma therapeutic vaccination shows some therapeutic activity but is infrequently curative.

A strategy to induce substantial specific immune responses against multiple epitopes of E6 and E7 proteins based on an attenuated transgene from HPV serotypes 16 and 18, that is incorporated into MG1-Maraba virotherapy (MG1-E6E7), was designed. MG1-E6E7 is able to boost specific immunity following priming with either an adenoviral vector (Ad-E6E7) or customised synthetic peptide vaccines resulting in multifunctional CD8+ T cell responses of an enormous magnitude. MG1-E6E7 vaccination in the HPV+ murine model TC1 is curative against large tumours in a CD8+ dependent manner and results in durable immunologic memory. Using the same adenoviral prime and MG1 boosting strategy targeting the prostatic antigen, STEAP, immunity against multiple CD8+ STEAP epitopes was induced. In a murine prostate cancer model, STEAP specific oncolytic virotherapy significantly improved the survival of mice bearing advanced TRAMP-C2 tumours.

One significant obstacle to therapeutic cancer vaccination is an immunosuppressive tumour microenvironment. MG1 Maraba is able to lethally infect HPV-associated and prostate cancer cells, increase the immunologic activity within the tumour microenvironment in vivo and exploit molecular hallmarks of HPV-positive cancer and prostatic carcinoma enabling infection of bulky tumours.

Pre-clinical data generated within this thesis has been instrumental in securing funding for future clinical trials assessing the safety and activity of MG1 Maraba virotherapy for HPV-associated cancer and prostatic carcinoma. This promising approach has the potential to be directly translatable to human clinical oncology to tackle these two highly prevalent and frequently lethal groups of epithelial neoplasia.