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

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $458,847

## Abstract

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.

## Key facts

- **NIH application ID:** 10879618
- **Project number:** 2R01NS110942-06
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** E. Antonio Chiocca
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $458,847
- **Award type:** 2
- **Project period:** 2019-09-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879618

## Citation

> US National Institutes of Health, RePORTER application 10879618, Oncolytic Virus Therapeutic Responses Occur from Changes in the Glioblastoma Immune Microenvironment (2R01NS110942-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879618. Licensed CC0.

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