# Radiation and CSPG4-specifc CAR T cell based combinatorial therapy for the in vivo treatment of TNBC

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $83,660

## Abstract

Project Summary/Abstract
Effective treatment options for triple negative breast cancer (TNBC) are lacking due to chemotherapy and
radiation resistance and low therapeutic efficacy of novel targeted therapies. Because of these disappointing
clinical results, we have assessed the potential therapeutic clinical application of a CSPG4-specific chimeric
antigen receptor (CAR) T cell-based therapy for the treatment of TNBC. CSPG4 has been selected as the target,
since this tumor antigen (TA) is expressed in about 70% of primary and metastatic TNBC tumors. Furthermore,
CSPG4 is expressed on TNBC cancer initiating cells (CICs), which are believed to play a role in metastatic
spreading and disease recurrence, the two major causes of patients' morbidity and mortality. Lastly, CSPG4 is
not detectable on normal cells with the exception of activated pericytes in the tumor microenvironment (TME).
We have shown that CSPG4 CAR T cells are effective in eliminating differentiated TNBC cells and TNBC CICs
in vitro, but are not able to completely eradicate TNBC tumors grafted in immunodeficient mice. This discrepancy
may reflect the negative impact of TME on CSPG4-specific CAR T cell-TNBC cell interactions as well as poor
T cell infiltration of the tumor. To counteract these obstacles to the successful application of CAR T cell therapy,
we will combine CSPG4-specific CAR T cells with radiation. This combinatorial strategy is based on our
preliminary results, which in combination with the information in the literature show that tumor radiation can
enhance the antitumor activity of CSPG4-specific CAR T cells with TNBC cells. This effect appears to be
mediated by multiple mechanisms, of which, a significant upregulation of CSPG4 expression on TNBC cells,
modulation of molecules involved in cell apoptosis and increased T cell infiltration and persistence seem to be
involved. The specific aims of this proposal are to i) evaluate whether tumor radiation enhances the ability of
CSPG4-specific CAR T cells to eradicate human TNBC cells orthotopically grafted in NRG mice and ii) assess
the molecular mechanism(s) underlying the increased ability of CSPG4-specific CAR T cells in combination with
radiation to eradicate human TNBC cells orthotopically grafted in NRG mice. These results will contribute to
optimize a combinatorial radiation and CSPG4-specific CAR T cell-based strategy for the treatment of TNBC.

## Key facts

- **NIH application ID:** 10447683
- **Project number:** 5R03CA256764-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Dan Gabriel Duda
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $83,660
- **Award type:** 5
- **Project period:** 2021-07-08 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447683

## Citation

> US National Institutes of Health, RePORTER application 10447683, Radiation and CSPG4-specifc CAR T cell based combinatorial therapy for the in vivo treatment of TNBC (5R03CA256764-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10447683. Licensed CC0.

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