# Neoadjuvant anti-PD-1 immunotherapy and Stereotactic Radiation in Patients with Recurrent Glioblastoma

> **NIH NIH R21** · CEDARS-SINAI MEDICAL CENTER · 2023 · $229,533

## Abstract

Project Summary/Abstract
Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults and has a dismal
prognosis. Tumor heterogeneity and immune suppression (via the PD-1/PDL-1 mechanism) are likely reasons
why GBMs almost always recur after treatment. Neo-adjuvant anti-PD-1 immunotherapy has recently been
shown to have a modest benefit. Radiation therapy promotes a pro-inflammatory tumor microenvironment and
can work synergistically with immunotherapy. Therefore, we propose an early phase clinical trial to compare the
anti-tumor immune response before and after the novel combination of neoadjuvant anti-PD-1 immunotherapy
and stereotactic radiation (SRT). Ten adult subjects with pathologically confirmed WHO Grade IV, recurrent
glioblastoma multiforme that are planning to undergo surgical resection will be recruited. All subjects will have
pre-treatment biopsy tissue available. Patients will be administered a single dose of anti-PD-1 immunotherapy
followed by SRT followed by surgical resection and then continue on anti-PD-1 until disease progression. In our
first aim, we propose to measure the changes in the T cell response against GBM following treatment. We
hypothesize that the pre-surgical administration of anti-PD-1 combined with SRT will lead to an increase in the
anti-tumor immune response. The primary immune biomarkers will be T cell receptor clonality and CD8+ T cell
activation. We will perform single-cell RNA sequencing to study the changes in the T cell and macrophage
populations after treatment and interrogate their functional phenotypes. In our second aim, we will assess the
changes in intra-tumoral heterogeneity following treatment and identify genomic correlates of immune resistance.
Our hypothesis is that treatment will reduce the number of distinct GBM clones as assessed by single cell RNA
sequencing. We will also compare the expression profiles of cancer pathways between immune responders
versus non-responders using differential enrichment analysis. This will allow us to identify the little-known
genomic correlates of anti-PD-1 immune resistance in GBM. Knowledge of these correlates can assist in better
selection of GBM patients that are likely to benefit from PD-1 blockade as well as inform us on future
combinatorial treatment strategies. Successful completion of our specific aims will deepen our understanding of
the changes in the immune response and GBM heterogeneity. Encouraging findings from our study would lead
us to pursue a phase II RCT of neoadjuvant anti-PD-1 immunotherapy plus SRT versus best available standard
of care.

## Key facts

- **NIH application ID:** 10536628
- **Project number:** 5R21CA256421-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Chirag Gadkary Patil
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $229,533
- **Award type:** 5
- **Project period:** 2021-12-08 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536628

## Citation

> US National Institutes of Health, RePORTER application 10536628, Neoadjuvant anti-PD-1 immunotherapy and Stereotactic Radiation in Patients with Recurrent Glioblastoma (5R21CA256421-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10536628. Licensed CC0.

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