Project 3: Circumventing extracellular Adenosine barrier to oncolytic virotherapy

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PROJECT SUMMARY – PROJECT 3 Oncolytic viral (OV) therapy is a promising biological approach for treating solid tumors, with oncolytic herpes simplex virus-1 (oHSV) being the most advanced. Indeed, the FDA has approved the use of the oHSV Imlygic® for metastatic melanoma and more recently, G47Δ, marketed by Daiichi Sankyo, gained conditional approval for GBM treatment in Japan. As a result of the close collaborations developed between the PIs on this program project grant, we have recently made an oHSV that encodes for PTENα (oHSV-P10). This virus shows significant antitumor efficacy against intracranial glioma in mice and has recently been licensed by Mesoblast for GMP production and IND enabling studies for Phase 1 clinical testing. Recent investigations into metabolic changes upon oHSV-P10 treatment led to the discovery of increased ATP production and release into the tumor microenvironment. While the extracellular ATP (eATP) can act as a stimulator of the immune system, its breakdown (via the ectoenzymes CD39 and CD73) produces adenosine (eAd) which eventually dampens anti-tumor immunity. CD73 activity represents a significant rate limiting step in this process by converting ATP to adenosine. The overall goal of this application is to evaluate how oHSV antitumor activity may be improved by suppressing the conversion of extracellular ATP (immune stimulatory) to eAd (immune suppressive) through CD73 blockade. In preliminary results we have identified a novel human antibody that can recognize and functionally block human CD73 activity. While we are pursuing the translational development of this antibody outside of this grant, here we propose to evaluate the impact of CD73 blockade using this antibody on oHSV anti-tumor efficacy. In this project proposal, we hypothesize that CD73 inhibition will synergistically combine with oHSV therapy by enhancing anti-tumor efficacy. This research will elucidate the role of the ATP/adenosine balance in the tumor microenvironment. In Aim 1 we will identify the human antibody fragment that efficiently inhibits CD73 function in combination with oHSV-P10. In Aim 2: we will evaluate the impact of newly generated oHSV-P10-αCD73 on anti tumor efficacy. In Aim 3 we will evaluate the impact of oHSV-P10-αCD73 alone and in combination with Avastin (anti-VEGF, frequently given to recurrent GBM patients) on efficacy and anti-tumor immunity.