Enhancing oncolytic adenovirus targeting and efficacy in pancreatic and prostate cancer models.

Oncolytic adenoviruses are engineered to replicate in and lyse cancer cells. Efficacy is also attributed to induction of tumour specific immune responses. Virus-mediated lysis causes release of tumour antigens and activate immune responses. Pancreatic ductal adenocarcinomas (PDAC) and prostate cancers (PCa), are both cancers of unmet clinical needs. A major reason for the poor treatment outcomes is the dense impenetrable stroma surrounding the tumours that prevent access of immune factors and therapeutic drugs to the cancer cells. While our recently engineered oncolytic adenovirus targets the surrounding supporting stroma in addition to the cancer cells, further enhancement of adenoviral delivery and spread within the tumour microenvironment would boost anti-tumour immune responses.
Aims: We will identify drugs that increase viral infection, replication, cell lysis and spread to enhance anti-cancer immune responses in the tumour microenvironment, targeting both cancer and supportive stromal cells.
Strategy: Three-dimensional organoid co-cultures of PCa cells with cancer-associated fibroblasts will be developed for screening of small molecule compounds. The readout will be viral genome amplification to identify drugs that promote viral replication. Hits will be further screened and verified using RNAi or CRISPR/Cas9 and investigated in combination with virus for activation of the host immune system in murine immune competent, tumour-bearing animals. Innate and adaptive immune responses will be determined. In parallel, we will modify the viral mutant to optimise systemic delivery using genetic and chemical tools.
Expected outcomes: A set of drugs will be identified and validated to enhance viral replication in PCa cell lines grown under conditions that mimic the tumour microenvironment in patients. Activation of potent anti-cancer immune responses that target both cancer and stromal cells will be delineated, and efficacy and safety determined. These data will support future clinical translation of the novel virus-drug combinations.