Cancer immunotherapies for the treatment of localised and metastatic prostate cancer

This project investigated the potential of interleukin (IL)-18 alone or in combination with regulatory T cell (Treg) interventions as cancer immunotherapies for localised and/or metastatic prostate cancer (PCa). RM1 mouse prostate carcinoma cells and a bone metastatic variant, RM1(BM), engineered to constitutively express varying levels of biologically active IL-18, were used to examine the effects of IL-18 on tumour growth and metastasis in vivo. The IL18-neutralising antibody, SK113AE4, was used to confirm that observed effects were indeed due to the cytokine. In an orthotopic (intraprostatic) tumour model, tumour secretion of IL-18 resulted in tumour growth inhibition; an effect dependent on IFN-γ and mediated via adaptive and innate immune mechanisms. IL-18 also correlated with significant tumour infiltration of CD8+ T cells, CD4+ T cells, macrophages and neutrophils but not NK cells. In a tumour metastasis model involving intracardiac injection of tumour cells, initial tumour establishment followed by complete regression was observed when IL-18 was expressed by tumour cells at high levels (500 ng of IL-18 secreted per 106 cells in 48 hours in in vitro in culture), while lower levels of IL-18 (25 ng per 106 cells) resulted in fewer and smaller bone metastases compared to control mice, but did not prolong survival. In RAG1-/- mice, high IL-18 expression resulted in longer survival and fewer tumours than control mice, confirming that the cell line is indeed tumourigenic. We also showed using a subcutaneous tumour model that intratumoural injection of IL-18 into pre-established tumours results in tumour growth inhibition while intravenous injection did not. We further demonstrated that targeting Tregs, which mediate immune suppression, with the monoclonal antibodies DTA-1 (agonistic for glucocorticoid-induced tumour necrosis factor-related protein (GITR)) or PC61 (for depleting CD25+ cells) at specific time points inhibits the growth of orthotopic tumours. Both treatments also correlated with significant tumour infiltration of macrophages but not T cells. In the tumour metastasis model, αCD25 and αGITR also prolonged mice survival. However, in combination immunotherapy experiments involving IL-18 with αCD25 or αGITR, only the former enhanced the anti-metastatic effects of IL-18 alone. These results collectively indicate that IL-18 and anti-Treg strategies have strong potential for the treatment of PCa