# Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $648,944

## Abstract

Project Summary/Abstract
Glioblastoma multiforme (GBM) is a dreadful cancer with a median survival of 14 months due to a lack of
effective therapy. Checkpoint blockade immunotherapies have shown promising clinical outcomes for several
cancers, and as such there are now many early stage clinical trials for GBM. Trials are designed for both newly
diagnosed and recurrent GBMs and in both cases, checkpoint blockade is administered on the background of
standard of care (SOC) therapy for GBM, which consists of surgical debulking, followed by fractionated
radiation (XRT) with concomitant and adjuvant temozolomide (TMZ) alkylating chemotherapy. In addition, most
patients are subjected to steroid use (dexamethasone-Dex)) to alleviate post surgery neurological symptomatic
relief. There is a critical deficiency in our understanding on how XRT/TMZ and steroid exposure affect the
tumor microenvironment (TME), specifically the immune cells component. Therefore there is a pressing need
to understand how the efficacy of checkpoint immunotherapies is affected by XRT/TMZ/Dex and delineate a
clinical strategy that will maximize treatment effectiveness. In addition, we demonstrate that the composition
and activation status of GBM immune infiltrates is influenced by the driver genotype of the GBM cells. Our
proposal will fill a knowledge gap regarding the type and activation status of the immune infiltrate vis-à-vis
tumor driver genotypes.
The central hypotheses of our proposal are: 1) the immune landscape of GBM is related to the type of driver
mutations (genotype) of the tumor and 2) the SOC for GBM will affect its immune component and function,
both of which will directly influence the efficacy of PD-1 and CTLA-4 checkpoint blockade immunotherapies.
We need to delineate those effects and understand them in order to modify GBM management protocols to
take full advantage of the power of immunotherapy. We propose to use EGFR- and PDGFR-driven
genetically engineered mouse models, which accurately recapitulate human GBM, to determine the effects of
tumor genotype on the immunofauna, to unveil the consequences of SOC on immune function and to relate
those findings to clinical practice. Our project will deliver on an effective translational use of genetically cutting
edge models of GBM that accurately recapitulate human disease to inform the conduct of clinical trials and to
mechanistically interpret their outcomes.

## Key facts

- **NIH application ID:** 9949669
- **Project number:** 5R01CA229784-03
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** VASSILIKI A BOUSSIOTIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $648,944
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9949669

## Citation

> US National Institutes of Health, RePORTER application 9949669, Advancing treatment outcomes in malignant glioma by integrating immunotherapy and standard of care using genetically engineered mice that recapitulate molecular feature of human glioma (5R01CA229784-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9949669. Licensed CC0.

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