# Project 3  Gene Mediated Cytotoxic Immmunotherapy for GBM

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $290,642

## Abstract

Overall Summary – Project 3
There is resurgent interest in immunotherapy approaches against glioblastoma multiforme (GBM), a brain
cancer with dismal prognosis. We have pioneered the utilization of Gene-Mediated Cytotoxic Immunotherapy
(GMCI), consisting of tumor injection of aglatimagene besadenovec (AdV-tk) a non-replicating adenovirus
expressing the Herpes virus thymidine kinase gene followed by an oral anti-herpetic prodrug (valacyclovir),
combined with standard of care (SOC) in humans with newly diagnosed GBM. Mature phase II data appears
to show encouraging, albeit not definite, results in terms of possible efficacy based on the extent of residual
tumor burden. Our pilot data shows that efficacy may be limited by immune checkpoint signaling networks,
such as PD-1/ PD-L1. Therefore, our overarching hypothesis is that a combination of GMCI-based
intratumoral immunostimulation with inhibition of immune checkpoint signaling will provide increased
effectiveness in animal models of glioma and in a planned prospective randomized clinical trial. In addition, we
hypothesize that extracellular vesicles (EVs) and their contents released by glioma cells provide
immunomodulatory signals in the GBM microenvironment. These will be further studied in an integrated mode
with the other Project 1 and 2 of this PO1. Core B and C will be utilized as well for animal models and sample
procurement/storage. These hypotheses will be tested by accomplishing the following specific aims:
Aim 1: Characterize the impact of GBM tumor burden on the efficacy of GMCI alone and in combination
with immune checkpoint inhibition. Hypothesis: GBM tumor burden mitigates the impact of GMCI due to
cytotoxic T cell exhaustion. Significance: Our preclinical and clinical data suggests that GMCI is most
effective with minimal tumor. However, the impact of Immune checkpoint inhibition on this effectiveness is not
known. Impact: This knowledge would help in the design of our planned clinical trial for GBM.
Aim 2: Determine if GMCI can sensitize resistant GBMs to immune checkpoint inhibition. Hypothesis:
The response of different GBMs to GMCI depends on their mutational load and/or differing expression of
immune checkpoint activating ligands. Significance: Since our preclinical data shows that not GBM models
differ in response to PD-1 immune checkpoint inhibition, these experiments would determine what other
immune checkpoint signals may be operative and/or whether altering the mutation load in different GBM cells
may lead to different efficacy responses. Impact: This knowledge would also help in clinical trial design and
provide mechanistic evidence of possible resistance mechanisms.
Aim 3: Determine the significance of immune checkpoint inhibitory protein expression in extracellular
vesicles (EVs) released by GSCs after GMCI in vitro and in vivo. Hypothesis: Immune checkpoint
inhibitory proteins in EVs are a novel mechanism of glioma immuno-evasion after therapy and may help
identify pat...

## Key facts

- **NIH application ID:** 9939475
- **Project number:** 5P01CA069246-23
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** E. Antonio Chiocca
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $290,642
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939475

## Citation

> US National Institutes of Health, RePORTER application 9939475, Project 3  Gene Mediated Cytotoxic Immmunotherapy for GBM (5P01CA069246-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9939475. Licensed CC0.

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