Investigation into the use of an oncolytic virus expressing a melanoma cDNA library to induce adaptive anti-tumour immunity in a human in vitro system and the ability of Coley's toxin to enhance the therapeutic efficacy of this response in vivo

Oncolytic viruses are an emerging therapy for cancer. Their efficacy was initially thought to be due to direct tumour cytotoxicity but recent research has highlighted the role that tumour-specific immune responses play in effective therapy. Repeat i.v. injections of vesicular stomatitis virus (VSV) encoding a human melanoma cDNA library cures up to 60% of mice bearing established melanomas. The therapy is immune-mediated and dependent on the presence of CD4+ T cells and IL-17. Within the VSV-cDNA library, three seperate clones were identified which when used together (but not singly) had similar therapeutic efficacy to the whole VSV-cDNA library. However, it is not known whether a VSV-cDNA library can generate immune responses in a human system, nor whether any such responses are analogous to those seen in mice, i.e. IL-17 and CD4+ T cell-dependent. In order to investigate this, human melanoma lines will be infected with the VSV-cDNA library before being loaded onto DC and co-cultured with autologous T cells. The nature of any anti-tumour immune responses generated will be assessed by re-stimulation of the T cells with human melanoma cell lysates and detection of the cytokines produced (IFN-gamma, IL-17). In addition, T cell cytotoxicity towards infected and non-infected melanoma cell lines will be measured along with the relative involvement of CD4+ and CD8+ T cells. The specific clones identified as therapeutically effective in mice will be investigated in the human in vitro system using donors with differing HLA types. This will compare the potential of therapy using a defined set of limited antigens versus a broader whole cDNA library approach, within the genetically diverse human population . Induction of specific anti-tumour immunity plays an important role in successful cancer therapy but it is not usually sufficient for the eradication of disease as tumour-specific cytotoxic T cells can be inactivated on encountering the immune-suppressive environment within a tumour. During the early 1900s William Coley developed a bacterial immunotherapy for the treatment of cancer (Coley’s toxin) that appeared effective in some types of tumour. Later studies showed that this endotoxin-mediated therapy was dependent on pre-existing anti-tumour T cell mediated immunity. VSV-cDNA therapy is immune-mediated which, when given alone, is effective in up to 60% of melanoma-bearing mice. However, its efficacy might be improved by the administration of Coley’s toxin after the anti-tumour immunity has been established; this strategy will be investigated.