# Circumventing barriers to effective oncolytic virotherapy of malignant gliomas

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $1,777,058

## Abstract

PROJECT SUMMARY - OVERALL
We propose preclinical and clinical studies of oncolytic Herpes simplex viruses (oHSVs) for the therapy of
glioblastoma (GBM), a deadly and incurable neoplasm. This class of biologic agents (recently approved by the
FDA for melanoma) are thought to exert their effects through two mechanisms: there is an initial phase of OV
infection of tumor cells, followed by serial rounds of viral progeny production and spread of the infection to
adjacent tumor cells. This first phase results in direct tumor cytotoxicity, produces inflammatory responses and
release of tumor antigens that activate a second phase of cytotoxic T cell responses, responsible for the durable
anticancer activity of virotherapy.
During the current cycle, we discovered that the initial phase of oHSV action is hindered by rapid and premature
clearance of oHSVs by cells of the innate immune system, i.e., natural killer (NK) cells and macrophages. Our
overall hypothesis is that NK cells and macrophages are called into the GBM microenvironment to
rapidly remove oHSV-infected tumor cells, before sufficient viral replication and tumor cytotoxicity
occurs. Recognizing that this hypothesis requires broadening based on the clinical success of immune
checkpoint (IC) blockade, a corollary is that oHSV-mediated immunostimulation and GBM inflammation
when coupled with restoration of T cell activation (via immune checkpoint blockade) leads to a durable
“anti-GBM” effect.
Our four projects propose two overall approaches to test these hypotheses: (a) direct inhibition of NK cell receptor
activation against viral antigens on tumor cell surfaces (Project 4-Dr. Caligiuri; The Ohio State University
Comprehensive Cancer Center, OSUCCC) and/or inhibition of oHSV-infected tumor cell signaling that activate
NK cells (Project 1-Dr. Glorioso; University of Pittsburgh Medical Center, UPMC) and macrophages (Project
3- Dr. Kaur, University of Texas Health Sciences, UTHealth), and (b) addition of immune checkpoint inhibition
to oHSV therapy (Project 2-Dr. Chiocca, Brigham and Women's Hospital/Dana Farber Cancer Institute,
BWH/DFCI).
Further, this PPG will perform a “first-in-man” clinical trial in recurrent GBM patients using an oHSV
whose development was completed during the current funding period. Project 2 will provide the clinical
samples to the other Projects and Cores to allow for the clinical validation of experimental outcomes. Three
Cores provide oHSV preparation (Core 1- Dr. Goins, UPMC), mouse and human GBM cells (Core 2-Dr. Ligon,
DFCI) and biostatistical analyses (Core 3-Dr. Fernandez, OSUCCC). Our group comprises experts in virology,
cancer biology, immunology, and clinical trials with biologic therapies and is uniquely positioned to assess the
preclinical and clinical efficacy of oHSV therapy for patients with recurrent GBM.

## Key facts

- **NIH application ID:** 10019334
- **Project number:** 5P01CA163205-08
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** MICHAEL A CALIGIURI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,777,058
- **Award type:** 5
- **Project period:** 2013-02-07 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019334

## Citation

> US National Institutes of Health, RePORTER application 10019334, Circumventing barriers to effective oncolytic virotherapy of malignant gliomas (5P01CA163205-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10019334. Licensed CC0.

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