# The role of extracellular vesicles in regulating response to immunotherapy

> **NIH NIH F32** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $71,734

## Abstract

Summary
 There are an estimated 12,390 cases of glioblastoma (GBM) in the United States with a median survival rate
of only 14.6 months despite advances in surgery, chemotherapy, and radiation therapy. The microenvironment
of these tumors is often highly infiltrated with immunosuppressive cells, including tumor-associated macrophages
(TAMs). Checkpoint blockade therapies rely on the infiltration of tumors with cytotoxic T cells to be effective, and
therefore some GBM patients may not respond well to them. Therefore, GBM has been an attractive target for
treatment with chimeric antigen receptor (CAR) T cell therapy to overcome immune evasion often observed in
GBM patients by producing T cells that respond to the GBM tumor neo-antigen epidermal growth factor receptor
(EGFR) variant III (EGVRvIII). Despite some advances in response, the microenvironment can play an important
role in modulating the response of tumors to immune modulatory therapies. GBM patients that do not respond
to checkpoint blockade therapy often have high levels of TAM infiltration, which might limit the efficacy of CAR
T therapy. Previous work has shown that tumor derived extracellular vesicles (EVs) can modulate the
microenvironment toward a pro-tumor, immune inhibitory environment. Specifically, they can be taken up by
macrophages to drive them toward a pro-tumor, immune-suppressive phenotype. Numerous studies have
outlined the ability of exosomes to directly bind T cells and block cytotoxic activity against tumors. A blood-based
‘liquid biopsy’ is ideal to determine which patients will respond to immunotherapy without the need for invasive
biopsies. I therefore hypothesize that tumor derived EVs transmit cargo to the immune system regulating
therapeutic response to immunotherapy and this cargo can serve as prognostic biomarkers.
 In the first aim, I will determine the impact of tumor EV secretion on immune infiltrate and immunotherapy
efficacy by reducing EV secretion using Rab27a KO. These models will be tested in both humanized mice as
well as syngeneic models to test the impact of EV secretion of CAR T cell efficacy and checkpoint blockade
therapy (respectively). In the second aim I will use novel microfluidics to capture tumor EVs, measure mRNAs,
test if any of these differentially expressed mRNAs are prognostic or predictive biomarkers. I will additionally
compare these markers to immune infiltrate in the same patients using multispectral imaging.
 My proposal focuses on one major question: How EVs regulate the immune system and the tumor response
to immunotherapy. Insights into EV mRNA cargo, will both identify patients that will respond to immunotherapy
as well as help identify alternative treatments to overcome an immunosuppressive environment.

## Key facts

- **NIH application ID:** 10299629
- **Project number:** 5F32CA236417-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Daniel Christopher Rabe
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $71,734
- **Award type:** 5
- **Project period:** 2019-12-24 → 2022-12-23

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299629

## Citation

> US National Institutes of Health, RePORTER application 10299629, The role of extracellular vesicles in regulating response to immunotherapy (5F32CA236417-03). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10299629. Licensed CC0.

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