# Effects of FLASH Radiation on Cancer and the Immune Response

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $493,013

## Abstract

Project Summary/Abstract
Background: Radiation therapy (RT) is a core treatment modality that benefits patients with many types of
cancer and can synergize with immune checkpoint blockade therapy. However, delivery of maximally effective
doses of radiation to tumors is limited by collateral damage to normal tissues. We are developing a next-
generation clinical RT platform called PHASER that will deliver ultra-rapid and precise radiation (FLASH) to
decrease damage to normal tissues dramatically. Using a unique preclinical FLASH irradiator we developed for
mice, our preliminary data show enhanced tumor control with FLASH vs. conventional dose rate irradiation as
well as increased infiltration of immune cells into the tumor, suggestive of an immune mediated mechanism.
Hypothesis and objective: We hypothesize that FLASH will demonstrate a superior therapeutic index by
comparison to conventional dose rate RT for multiple cancers, based not only on its precision but also on the
induction of more potent anti-tumor immunity. We will test this hypothesis in experimental models of cancer.
Specific Aims and Study Design: Aim 1: Compare the anti-tumor potency, safety and immunological
effects of FLASH vs conventional dose rate RT in primary tumors: We will evaluate different doses of
FLASH and compare its effects with maximally tolerated doses of conventional dose rate RT in both syngeneic
and patient derived xenograft mouse models. In addition to assessing tumor growth, we will analyze the effects
of FLASH on the immune response, both locally and systemically through the use CyTOF and our
SCAFFOLDS algorithms. This approach will reveal where and which immune cell subsets become activated in
successfully treated animals. We will also assess the immunologic correlates of reduced toxicity from FLASH.
Aim 2: Analyze the therapeutic effects of FLASH alone and in combination with immune checkpoint
antibodies in metastatic disease. To assess our hypothesis that FLASH in combination with PD-1 blockade
will exhibit synergistic anti-tumor effects due to an enhanced system-wide immune response, we will study the
effects of FLASH, alone and in combination with anti-PD-1, on tumors outside the radiation field, and assess
the immune response as in Aim 1. Aim 3: Identify the immune cellular and molecular basis of FLASH
efficacy. We will test the hypothesis that efficacy is dependent on T cells as well as antigen presenting
dendritic cells (DCs) by treating tumors in Rag-2 KO and BATF3 KO mice, respectively, and will elucidate the
role for these cells by transferring T cells or DCs from successfully treated mice to naive mice challenged with
tumor. The specific subsets required for efficacy are expected to be those shown to expand in multiple tissues
in Aim 1. Lastly, we will explore the role of Type I interferon and its receptor on DCs in the efficacy of FLASH.
Expected Results and Impact: These experiments are expected to demonstrate that FLASH in combination
with check...

## Key facts

- **NIH application ID:** 10188463
- **Project number:** 5R01CA233958-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** EDGAR G. ENGLEMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $493,013
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188463

## Citation

> US National Institutes of Health, RePORTER application 10188463, Effects of FLASH Radiation on Cancer and the Immune Response (5R01CA233958-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10188463. Licensed CC0.

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