# Exploring the immunomodulatory effects of anti-FAP CAR T cells in cardiac fibrosis

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2024 · $34,623

## Abstract

Project Summary
 Cardiovascular disease is the leading cause of death worldwide and despite efforts to preserve
cardiac function in heart failure patients, preventing adverse remodeling and fibrosis remains a challenging
task. Cardiac fibrosis can negatively impact cardiac compliance and function, and is associated with
worsened outcomes in heart failure patients. Recent sequencing technology advancements hav e allowed
for the identification of fibroblast activation protein (FAP) as a marker of pathologically activated fibroblasts
present in failing hearts but not in healthy controls. This has raised the possibility of selectively depleting
FAP+ cells for heart failure therapy. One proposed strategy is to use chimeric antigen receptor (CAR) T
cells that are engineered to express a surface receptor directed against FAP. Initial studies utilizing these
FAP CAR T cells in a mouse model of hypertensive cardiac injury have been promising, but the effects of
CAR T cells on the myocardial environment are not understood.
 The proposed project aims to investigate the feasibility of T cell engaging therapies as a strategy of
targeted cell depletion in cardiac fibrosis, and also investigate the modes of crosstalk between FAP CAR T
cells and other cell populations in the heart. These questions have broad implications for this novel cardiac
application of cellular immunotherapy. Preliminary data demonstrate that FAP CAR T cells can actually
worsen the development of fibrosis in an angiotensin II/phenylephrine mouse model of cardiac injury.
Importantly, expression of interferon gamma (IFN) and its targets is elevated in the hearts of FAP CAR T
cell treated mice compared to those of control T cell treated mice. IFN has been shown to worsen fibrosis
in other models of cardiac injury. We hypothesize that FAP CAR T cells can deplete activated fibroblasts,
and that this has an anti-fibrotic effect, but it is offset by pro-inflammatory, pro-fibrotic crosstalk between
FAP CAR T cells and other immune cells in the myocardium. Aim 1 of this proposal focuses on delineating
the feasibility of T cell engaging therapies in cardiac fibrosis. Specifically, it compares FAP CAR T cells to
other T cell-based therapies such as bispecific T cell engagers (BiTE®) in target cell depletion, IFN
activation, and fibrosis modulation. Aim 2 studies how blocking IFN signaling in FAP CAR T cell treated
mice affects the cellular and transcriptional landscape of the heart. It also investigates which cells are the
sources of IFN, which cells are responding to this signal during FAP CAR T cell treatment, and what
effects these signaling axes have on myocardial inflammation and fibrosis. Together these aims seek to
understand the effects and mechanisms of FAP CAR T cell cross talk with other myocardial immune
populations, and can potentially inform the field of strategies to refine T cell engaging therapies to
maximize efficacy and improve safety in the cardiac setting.

## Key facts

- **NIH application ID:** 10825258
- **Project number:** 1F30HL172583-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Steven Yang
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,623
- **Award type:** 1
- **Project period:** 2024-02-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825258

## Citation

> US National Institutes of Health, RePORTER application 10825258, Exploring the immunomodulatory effects of anti-FAP CAR T cells in cardiac fibrosis (1F30HL172583-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10825258. Licensed CC0.

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