# Project 4: Activity of CAR T cell Therapy for Patients with Metastatic TNBC

> **NIH NIH P50** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $356,676

## Abstract

PROJECT 4: Activity of Car T Cell Therapy for Patients With Metastatic TNBC - Abstract
Triple negative breast cancer (TNBC) remains a tumor with dismal prognosis even in the era of immune
checkpoint inhibitors (ICIs). Here we propose to develop chimeric antigen receptor T cells (CAR-Ts) to target
TNBC. Specifically, we will target the B7-H3 antigen that is aberrantly expressed in several solid tumors
including TNBC, but has limited expression in normal tissues. In Aim 1, we will conduct a Phase I clinical study
infusing autologous B7-H3.CAR-Ts in patients with TNBC.
Solid tumors including TNBC are characterized by heterogeneity of antigen expression and can escape
immune targeting directed against a single antigen. Furthermore, brain metastases of TNBC remain difficult to
treat due to the presence of the blood-brain-barrier (BBB) that poses physical impediment to both drugs and
immune cells.
In Aim 2 we propose to develop preclinical models of TNBC to test dual CAR-Ts targeting B7-H3 and
chondroitin sulphate proteoglycan 4 (CSPG4) using a novel dual CAR design and to engineer dual CAR-Ts to
express the CCR2b chemokine receptor, which we found to promote CAR-T cell trafficking through the BBB
when brain metastases produces the CCL2 chemokine.
The inhibitory TME contributes to attenuating CAR-T cell functions. We implemented a model of CAR-Ts in
immunocompetent mice and demonstrated that Th/Tc17 polarized CAR-Ts combined with STING agonists
prompted superior tumor control compared to conventional CAR-Ts. Furthermore, STING agonist 2'3' cGAMP
leads to significant enrichment of T cells with stem cell (TSCM) and central-memory (TCM) characteristics both in
vitro and in vivo. In Aim 3, we will assess the mechanism and antitumor activity of Th/Tc17 CAR-Ts activated
by cGAMP in modulating the breast cancer TME and enhancing the expansion of CAR-Ts in the TME.

## Key facts

- **NIH application ID:** 10935477
- **Project number:** 2P50CA058223-29A1
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Gianpietro Dotti
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $356,676
- **Award type:** 2
- **Project period:** 1997-08-05 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935477

## Citation

> US National Institutes of Health, RePORTER application 10935477, Project 4: Activity of CAR T cell Therapy for Patients with Metastatic TNBC (2P50CA058223-29A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10935477. Licensed CC0.

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