Combination of proton radiations and oncolytic viruses to eradicate cancer

• Applicant: Professor Dr. Guy Ungerechts, Ph.D.
• Subject Area: Nuclear Medicine, Radiotherapy, Radiobiology ; Hematology, Oncology ; Immunology ; Virology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490994668

Glioblastoma (GBM) and pancreatic ductal adenocarcinoma (PDAC) both have dismal prognoses and urgently require the development of novel and more efficacious therapies. Both tumor entities are characterized by an immunosuppressive (“cold”) tumor microenvironment (TME) impeding immune-mediated recognition and clearance of cancer cells. Current anti-tumor immunotherapies including immune checkpoint inhibition, albeit highly successful in many tumor entities, have thus far failed to deliver therapeutic benefits in GBM or PDAC. These data underline the urgent need for alternative therapeutic approaches that reshape the immunosuppressive TME towards an inflamed phenotype in order to re-establish immune surveillance and cancer cell clearance.Oncolytic viruses (OVs) are emerging anti-tumor immunotherapies and have shown promising results against GBM and PDAC in pre-clinical and clinical studies. Besides direct tumor cell killing, these treatments trigger an immunogenic cell death (ICD) through the activation of PAMP- or DAMP-sensing receptors as well as the release of tumor antigens (TA) from disrupted malignant cells. These processes represent potent stimuli for critical immune cell populations including T cells, DCs and NK cells, instrumental for mounting an effective anticancer immunity. Importantly, OV treatment frequently leads to the production of antiviral and immunostimulatory cytokines, such as type-I interferons (IFNs), a feature correlated with favorable disease outcome for most anticancer immunotherapies. Here, we hypothesize that the combination of an OV (PV, MeV, or both) with proton-based radiotherapy (RT), a complementary treatment modality able to induce inflammation and IFN-production through engagement of the cGAS-Sting pathway, represents a unique and promising treatment approach for GBM and PDAC. Our multi-disciplinary team consisting of virologists, biologists, physicists, radiochemists, oncologists and radiotherapists has a long-standing expertise in developing, characterizing and translating oncolytic viruses as well as in proton-based radiotherapy and high-resolution imaging techniques. Based upon our hypothesis mentioned above and encouraging preliminary data obtained during the last months, we propose to answer three major question within this research proposal: 1. Do the individual viruses (PV and MeV) synergize with proton-based RT in various models of GBM and PDAC? 2. Based on their different abilities to induce and be affected by IFN-signaling, do PVs and MeVs synergize in a sequential treatment schedule of GBM or PDAC tumors? 3. Can we combine this dual virotherapy approach with proton-based radiotherapy to overcome the immunosuppressive TME and induce a robust and durable anti-tumor immune response?With this study, we aim at providing the basis for a near-term clinical translation of a combination radiovirotherapy for treatment of GBM and PDAC.

• DFG Programme: Research Grants
• International Connection: France
• Co-Investigator: Dr. Mathias Leber
• Cooperation Partner: Professor Dr. Laurent Daeffler