Development of an optimized oncolytic virus-mediated therapy for modulation of the extracellular matrix in pancreatic ductal adenocarcinoma

• Applicant: Privatdozentin Dr. Jennifer Altomonte
• Subject Area: Gastroenterology ; Hematology, Oncology ; Immunology ; Virology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 519840568

Oncolytic viruses (OVs) represent a novel class of therapeutic agents for cancer treatment, due to their intrinsic ability to selectively replicate in and kill tumor cells, while sparing the surrounding normal tissue. OVs exert their effects through multiple mechanisms, including direct killing of susceptible tumor cells, modulation of the tumor microenvironment (TME), and the induction of immune responses against the tumor. Due to the many challenges associated with treatment of pancreatic ductal adenocarcinoma (PDAC), oncolytic virus-based approaches have emerged as promising alternatives to the more traditional therapies, representing an ideal strategy to counteract the stromal-rich and highly immunosuppressive TME and to potentially sensitize these resistant tumors to other therapies. The proposed work program involves three main objectives aimed at developing an optimized and translational oncolytic virus-based approach to address the specific challenges of the complex PDAC tumor microenvironment. In the first objective, PDAC cell lines and primary patient-derived PDAC material will be screened for their susceptibility to the oncolytic effects of the chimeric virus, rVSV-NDV. This information will be compared with their corresponding genome and transcriptome data, in order to identify common mutations or gene expression patterns that correlate to rVSV-NDV susceptibility or resistance. Infection of PDAC cells and cancer-associated fibroblasts, as well as the impact of cross-talk between the two cell types, will also be investigated in order to predict interactions of rVSV-NDV therapy with the tumor microenvironment. Next, the OV therapy will be investigated in in vivo models of PDAC, both to characterize therapeutic effects and the mechanisms of action. Finally, optimized rVSV-NDV vectors, which encode for extracellular matrix (ECM)-degrading proteins will be engineered and characterized and evaluated in a combination approach with immune checkpoint blockade in a clinically-relevant genetic model of orthotopic PDAC. Together, this work will provide mechanistic insights into the therapeutic potential of oncolytic rVSV-NDV for PDAC and pave the way for clinical translation of this promising approach.

• DFG Programme: Research Grants