# Long-Term Cardiovascular Sequelae of Cancer Immunotherapies

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $606,001

## Abstract

Project Summary/Abstract
In this proposal, we will study the long-term cardiovascular sequelae of immune checkpoint inhibitors (ICI),
therapies that have revolutionized cancer treatment. We will use both mouse models and cancer survivors
treated with ICI. We have defined acute, T cell mediated cardiac complications of ICI, including myocarditis,
pericarditis, and vasculitis as a significant clinical concern in these patients. Our preliminary data suggest a
role for programmed death-1/ligand-1 (PD-1/PD-L1) in preventing myocardial injury and other cardiovascular
disease. Clinically, we have observed patients with subacute cardiac injury following ICI treatment. We
hypothesize that PD-1/PD-L1 blockade through ICI therapy, in conjunction with other cardiac insults, worsens
long-term cardiovascular health. To address this, we will first utilize two mouse models that we have developed
that recapitulate ICI-cardiopulmonary toxicities: a model (MRL/MpJ) treated with combination ICI therapy, and
a genetic knockout model (PD1-/-; CTLA+/-). In Aim 1, we will test the hypothesis that cardiac ischemia
potentiates increased immune infiltration and inflammation in our pharmacologic and genetic mouse models
(compared to appropriate controls), performing in-depth physiologic and immune profiling in these mouse
models. We leverage these mechanistic and pre-clinical models with translational endpoints for Aim 2, where
we will utilize a large retrospective cohort of long-term survivors treated with ICI (200 patients) to assess the
impact of ICI on cardiac risk factors, including blood pressure, weight, body composition, and coronary artery
calcification. A prospective cohort (150 patients) will be accrued for longitudinal clinical phenotyping to identify
and validate clinical endpoints and to extend and validate these findings. We will perform intensive cardiac
(echocardiography, cardiac MRI, high-sensitivity troponin, C-reactive protein) and metabolic (fasting lipids and
glucose) monitoring, specifically testing the hypothesis that troponin elevation early in treatment with ICI
correlates with ventricular remodeling, inflammation, and fibrosis. In patients who die following recovery from
myocarditis, we will perform rapid autopsies to determine the extent of inflammation, fibrosis, structural
changes, and residual immune cell populations.
The overwhelming success of ICI has led to a dramatic increase of long-term survivors treated with these
agents. This proposal will allow us to characterize the effects of ICI on long-term cardiovascular health, thus
enabling development of appropriate screening, treatment, and prevention strategies.

## Key facts

- **NIH application ID:** 10868773
- **Project number:** 5R01HL155990-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Douglas B Johnson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,001
- **Award type:** 5
- **Project period:** 2021-05-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868773

## Citation

> US National Institutes of Health, RePORTER application 10868773, Long-Term Cardiovascular Sequelae of Cancer Immunotherapies (5R01HL155990-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10868773. Licensed CC0.

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