Oncolytic virus therapeutic responses occur from changes in the glioblastoma immune microenvironment

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Abstract Glioblastoma (GBM) is a fatal brain cancer that recurs after standard of care almost 100 % of the time. There has been great interest in immunotherapy because it has shown recent success against many types of cancers, but recent randomized clinical trials in GBM using immune checkpoint inhibitors, peptide vaccines, or dendritic cell therapies have not been successful. A major reason for the lack of immunotherapy success is likely due to the highly immunosuppressive microenvironment of GBMs which leads this tumor to be immunologically “cold”. We are utilizing an oncolytic HSV1 (oHSV) for its dual properties of direct GBM replicative cytotoxicity and of potent in situ immunostimulation in a phase 1 clinical trial in recurrent GBM. As we begin to analyze data from this trial, questions arise related to the dose of oHSV and to commonly used concomitant treatments, such as steroids or bevacizumab. Answers to these questions will help in design of the next steps in clinical trials of this oHSV. To answer these questions, we have developed pilot data in mouse models of GBM to show how changes in the immune cell TME affect GBM progression or regression when treated with oHSV. Specifically, our studies appear to show that anti-GBM responses from oHSV therapy are characterized by an expansion of activated TILs against a model tumor antigen, whereas GBM progression is characterized by a lack of this expansion. We thus hypothesize that observed oHSV-mediated anti-GBM responses depend on TIL expansion against tumor antigen and that factors such as oHSV dose and other concomitant treatments such as steroids and bevacizumab modulate this. We plan to test these hypotheses by evaluating the kinetics of expansion of TILs against a model GBM antigen (aim 1) and by determining if standard of care treatments, such as dexamethasone and/or bevacizumab change TIL expansion against a model GBM antigen (aim 2). The overall impact of these aims if successful would thus allow us to understand why some GBM patients appear to respond to oHSV therapy and improve our ability to increase the percentage of responders.