Circumventing Barriers to Effective Oncolytic Virotherapy of Malignant Gliomas

OVERALL PROJECT SUMMARY Glioblastoma (GBM) and recurrent GBM (rGBM) is arguably one of the most fatal of cancers: it remains impervious to treatment with the current standard of care (SOC) therapies and numerous clinical trials (including immunotherapy) have failed to meet end points for FDA approval. This makes GBM/rGBM an unmet medical need. The unresolved problem we are trying to solve is that the rGBM tumor microenvironment (TME) is highly immunosuppressive. To revert this immunosuppression, we and others have been utilizing direct intra- tumoral administration of oncolytic viruses (OVs), based on herpes simplex virus type 1 (HSV1). During the current funding cycle (2018-2023), the Principal Investigators of this P01 have contributed several discoveries both in preclinical models of GBM and in a 50 subject phase 1 clinical trial of recurrent GBM (rGBM). Major findings relate to how human subject rGBMs change in response to oHSV (Project 2/ Chiocca), how Notch signaling of myeloid cells in the GBM TME impedes oHSV function (Project 3/Kaur) and how to further immune- stimulate oHSVs by “arming” with immune-stimulatory genes (Project 1/Glorioso and Project 4/Caligiuri). Lessons learned informs the overall hypothesis for this P01: oHSVs induce a rapid and persistently inflamed rGBM microenvironment, correlating with efficacy in human subjects and informing further therapeutic exploitation by arming oHSVs with additional immunostimulatory genes. To test this overall hypothesis, the four Projects will address the following overall aims: Overall Aim 1 – Validate the findings that improved survival for human subjects treated with oHSV correlates with rGBM and peripheral blood biologic transcriptomic and proteomic signatures (Projects 2, 3 and 4); and Overall Aim 2- Engineer and preclinically test the “next-generation” oHSVs “armed” with selected immune-activating genes, focusing on clinical translation for a new phase 1 trial (Projects 1, 3, and 4) To support the efforts of these 4 Projects, we will continue to utilize the services of the oHSV Production Core (Core 1/ Goins), of the GBM Biorepository Core (Core 2/Ligon) and of the Biostatistics and Bioinformatics Core (Core 3/Mo & Zhang). The proposed timeline for the successful completion of the overall aims is 5 years. The principal investigators of this P01 espouse the principle of “from the lab to the clinic and back to the lab”, where the lessons from our treated patients can be applied to build more efficacious therapies for this fatal cancer. The potential impact of this research is that we are proposing to not only test preclinically and clinically potentially impactful oncolytic immunotherapies for an incurable cancer, but we have shown commitment to analyze the biologic and immunologic effects in treated human subjects, so that we can iteratively learn possible pitfalls and devise solutions for patients with GBM.