Induction of immunogenic cell death by associating gene transfer and chemotherapy in human prostate carcinoma cells

Abstract

Prostate cancer is among the most common cancers in men worldwide. Despite treatment options, patients with metastatic disease have a five-year survival rate of only 29%, so development of new therapeutic strategies is needed in order to achieve long-term benefits. Treatment resistance mechanisms such as tumor heterogeneity and an immunosuppressive microenvironment prevent the establishment of an effective immune response and a survival improvement of patients. Consequently, great efforts have been directed towards the usage of combination therapies. The research group led by Professor Bryan Strauss (ICESP) has developed adenoviral vectors for the transfer of genes that were able to induce cytotoxicity and immunomodulation in melanoma models. For prostate cancer, previous results demonstrated a cytotoxic potential of p53 gene transfer, which mutation or inactivation has been associated with cases of resistance to chemotherapy and hormone treatments. Therefore we aim to find a therapeutic combination of the p53 gene transfer with a chemotherapeutic agent (cabazitaxel, docetaxel, mitoxantrone or cyclophosphamide) or another viral vector (carrying p14ARF or IFN²) by assessing its potential to induce immunogenic death in vitro. The cytotoxic effect will be evaluated in a xenographic model and the potential to generate an antitumor immune response will be investigated ex vivo using dendritic cells and human T lymphocytes. We then expect to pave the way for prostate cancer immunotherapy.