# Determining the role of gas metabolite in response to immunotherapy

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2021 · $204,531

## Abstract

Project Summary
Lung cancer is a leading cause of death and the second most common cancer in the United States.
Application of immunotherapies has led to significant improvement in survival of cancer patients. However,
there is further need to achieve better responses to current immunotherapies. The most promising results had
been achieved when combining anti-PD-L1/PD-1 with treatments that activate immune function.
We propose that exogenous carbon monoxide (COex) applied at low non-toxic doses is a potential
adjuvant for patients with lung cancer treated with immunotherapy. CO is generated endogenously by heme
oxygenase-1 (HO-1) that acts during homeostasis to break down heme to three active metabolites. We have
demonstrated that COex applied at 250 ppm for 1 hour per day (that corresponds to the dose of CO obtained
from burning 2 cigarettes) blocks progression of lung and prostate cancers. COex can block tumor growth via
targeting metabolism of cancer cells. However, since COex blocks growth of different tumor types and at
various metabolic rates as well as is more efficient in vivo than in vitro in inducing apoptosis of cancer cells, we
reasoned COex has a broader effect in the TME that includes immune cells. Our preliminary data suggest that
COex promotes more ‘immuno-receptive’ tumor microenvironment (TME). We propose that reprograming of the
TME by regulating heme metabolism regulates responses to immunotherapy.
Our aim is to:
To determine the role of COex in redirecting immune responses to increase efficacy of immunotherapy.
Specifically, we intent to:
i) Determine effectiveness of the combination of COex and anti-CTLA-4, anti-PD-L1 or anti-PD-1 treatment in a
mouse model of lung cancer.
ii) Determine COex-mediated induction of CD86 via mTOR-Notch1 signaling during response to immunotherapy
in the lung cancer model.
iii) Define the importance of endogenous HO-1-derived CO during response to immunotherapy.
The investigations proposed in this application will delineate the role of CO and HO-1 in activation of the host
immune responses via selective signaling pathways leading to increase in myeloid function in the TME. Our
findings will have fundamental and therapeutic implications for patients with lung cancer, especially that COex is
in clinical trials. This study is well-aligned with the mission of the NCI and this RFA “NCI Clinical and
Translational Exploratory/Developmental Studies (R21 Clinical Trial Optional)” (PAR-19-356).

## Key facts

- **NIH application ID:** 10118733
- **Project number:** 1R21CA256720-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Barbara Wegiel
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $204,531
- **Award type:** 1
- **Project period:** 2020-12-09 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118733

## Citation

> US National Institutes of Health, RePORTER application 10118733, Determining the role of gas metabolite in response to immunotherapy (1R21CA256720-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10118733. Licensed CC0.

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