Oncolytic Virus Therapeutic Responses Occur from Changes in the Glioblastoma Immune Microenvironment

PROJECT SUMMARY Glioblastoma (GBM), the most common malignant brain tumor and one of the most fatal of cancers, remains impervious to treatment with the current standard of care (SOC) therapies. Even immunotherapies like immune checkpoint inhibitors (ICI) have failed for GBM despite their success with other cancers. One critical reason for this failure is that the brain’s GBM tumor microenvironment (TME) is highly immunosuppressive. To change the GBM microenvironment, over the last period of funding we have been exploring the use of oncolytic viruses (OV), based on herpes simplex virus type 1 (oHSV). Of relevance, we have completed a “first-in-human” clinical trial in subjects with GBM. Recovery of the brain tumors after therapy revealed persistence of the oHSV in some patients, highly significant infiltration of CD8+ and CD4+ T cells with an effector transcriptomic signature, and a significant correlation between subject survival and changes in T cell metrics. Very interestingly, pre-existent and/or seroconverted HSV1 serology was a highly significant independent predictor of subject survival, suggesting the existence of anti-HSV1 T cell memory that could be stimulated by tumor injection with the oHSV to differentiate into effector T cells that would then aid in the anticancer effect. In fact, we have found that patients with pre-existent HSV1 immunity or that seroconverted were the ones who were more likely to clear HSV1 antigen from injected GBMs. Two questions arise from these findings: 1- what is the role of antiviral HSV1 “bystander” T cells in therapy efficacy, and 2- what is the significance of oHSV antigen persistence in injected GBMs? Our overall hypothesis, informed by our clinical trial data, is that oHSV’s antiGBM effectiveness is based on expansion from “bystander” anti-HSV1+ memory T cells into effector T cells, whose activity is marked by infiltration and “clearance’ of replicating oHSV previously injected into the GBM. To test thus hypothesis, we plan to pursue the following aims: Aim 1- Determine if a pre-existent anti-HSV1 memory T cell population differentiating into an effector T cell population infiltrates syngeneic murine GBMs infected with oHSV; Aim 2- Determine if antiviral bystander T cells aid antitumor T cells in tumor rejection upon oHSV administration, and Aim 3- Characterize whether oHSV persistence in tumors stimulates further effector antitumor T cell responses or leads to terminal exhaustion of T cells. The impact from these studies will be to significantly inform whether oncolytic immunotherapy depends on pre-existent immunity to the cognate OV, leaving to avenues for improvements in the next phase of clinical trials for this modality.