Improving the Potency of a Melanoma Vaccine by Using a Third Co-Stimulatory Molecule

Melanoma is the third most commonly diagnosed form of cancer amongst Australians and Australia has the highest incidence of melanoma in the world. At present, there are no vaccines that are approved for the treatment of melanoma. Previous research performed in the laboratory resulted in the development of a syngeneic, whole cell melanoma vaccine engineered to express high levels of the B7.1 T cell co-stimulatory molecule, in addition to using high doses of interferons to upregulate MHC Class I molecules on the surface of the vaccine cells. Results from extensive mouse trials determined that the incorporation of B7.1 into the vaccine cell model directly stimulated CD8+ T cells to effectively kill melanoma cells in CTL assays and protect mice from developing tumours following injection with live tumour cells expressing intermediate levels of B7.1, thereby replacing the requirement for CD4+ T cells. Subsequently, the vaccine technology was translated into a human allogeneic, whole cell vaccine that completed testing in 2011 on stage IV melanoma patients in a Phase I clinical trial at the Princess Alexandra Hospital, Brisbane. The purpose of this thesis was to extend this anticancer vaccine technology by investigating whether the addition of a second co-stimulatory molecule, 4-1BBL, onto the surface of the vaccine cells could replace or reduce the requirement for DCs in the stimulation and activation of CD8+ T cells targeting the cancer cells.