# Proj. 1 Targeting Tumor-Specific Neoepitopes for Glioblastoma Immunotherapy

> **NIH NIH P01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $503,520

## Abstract

Catherine J. Wu, MD and David A. Reardon, MD
Project 1: Personalized Neoantigen Vaccination and Anti-PD-1 Therapy for Glioblastoma
Summary
Current therapies for glioblastoma (GBM), the most common malignant primary brain cancer,
remain palliative. These tumors have responded poorly to single agent immunotherapy
approaches due to several factors including the fact that GBM is an immunologically cold tumor
with a paucity of effector T cells infiltrating the tumor microenvironment. We have developed a
personalized tumor neoantigen-targeting vaccine strategy (NeoVax) based on robust analytic
sequencing pipelines and have demonstrated marked CD4+ and CD8+ T cell responses to
vaccinated neoepitope peptides among patients with high-risk melanoma (Ott & Hu, Nature, 2017)
and with newly diagnosed GBM (Reskin et al., Nature 2019). Furthermore, in collaboration with
investigators from Project 3, we demonstrated that NeoVax induced a marked influx of
intratumoral immune effector cells, including CD4+ T cells with specificity to an immunizing
neoepitope into the GBM tumor microenvironment. We now extend this work by conducting a
second trial in which NeoVax will be combined with anti-PD-1 therapy for GBM patients based on
our observation that anti-PD-1 therapy broadened anti-tumor immune responses among our
melanoma patients treated with NeoVax. We have designed our trial to address the key question
whether timing of PD-1 blockade relative to neoantigen priming with NeoVax affects T cell memory
responses, based on recent work by Dr. Sharpe (Project 2) demonstrating that PD-1 signaling
critically regulates long-term T cell memory. We hypothesize anti-PD-1 therapy will improve
outcome for GBM patients undergoing NeoVax therapy and that timing of PD-1 blockade
relative to tumor neoantigen priming with NeoVax will critically influence the generation of
polyfunctional, long-term memory T cell responses. We will evaluate these hypotheses in
work organized into three specific aims. In Aim 1, we will evaluate the administration of PD-1
blockade either before or after NeoVax priming in a phase 1b trial for newly diagnosed GBM
patients who are treated with standard radiotherapy. We will evaluate the strength, breadth and
state of circulating neoantigen-specific T cell responses relative to timing of PD-1 blockade
including long-term T cell memory responses among patients treated on this trial in Aim 2. We will
similarly interrogate the composition and functional states of tumor infiltrating immune cells before
and after NeoVax plus anti-PD-1 therapy in Aim 3. T cell immune responses for Aims 2 and 3 will
be analyzed in Core 1, while Core 2 will perform the computational and statistical analyses of
these data.

## Key facts

- **NIH application ID:** 10876406
- **Project number:** 5P01CA236749-05
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAVID A REARDON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,520
- **Award type:** 5
- **Project period:** 2020-07-03 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10876406

## Citation

> US National Institutes of Health, RePORTER application 10876406, Proj. 1 Targeting Tumor-Specific Neoepitopes for Glioblastoma Immunotherapy (5P01CA236749-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10876406. Licensed CC0.

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