# Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2020 · $316,411

## Abstract

PROJECT SUMMARY
Although several lines of evidence support the use of immunotherapy in triple-negative breast cancer (TNBC),
the modest clinical efficacy achieved in current clinical trials suggests that the immunosuppressive
microenvironment cannot be overcome by PD-1/PD-L1 blockade alone. In order to improve outcomes, this
project will investigate the immunologic effects of two emerging classes of targeted breast cancer therapies, poly
(ADP-ribose) polymerase (PARP) and BET bromodomain (BBD) inhibitors, and will test the hypothesis that
combinations of these agents with immunotherapies will be effective therapeutic strategies for BRCA-mutated
and sporadic TNBC. The rationale for this work is based on our preliminary data indicating that PARP inhibition
can activate the STING pathway, alter tryptophan metabolism and stimulate the infiltration and activation of
cytotoxic T cells, and that BBD inhibitors synergize with paclitaxel and PD-L1 blockade in preclinical models.
Two specific aims are proposed. In Aim 1, the effects of PARP inhibition alone and in combination with PD-1
blockade on the immune microenvironment and on tumor growth will be assessed in an animal model of BRCA-
associated TNBC and in a clinical trial. Experiments will be conducted in mice bearing TNBCs derived from the
K14Cre;BRCA1f/f;p53f/f genetically-engineered mouse model, and will translate to a phase 2 trial in the
neoadjuvant setting using niraparib or combined niraparib/PD-1 therapy, in which changes in T cell infiltrate and
pathologic complete response (pCR) rate will be defined. Preclinically, combined PARP inhibition and PD-1
blockade will also be investigated in BRCA wild-type syngeneic TNBC models, including EMT-6 and JC. In Aim
2, the effects of the BBD inhibitor JQ1 alone and in combination with PD-L1 blockade will be evaluated in the
same syngeneic and genetically-engineered mouse models of TNBC used in Aim 1, as well as in a clinical trial.
Changes in the composition and activation of components of the immune microenvironment will be assessed
following JQ1 or JQ1 and PD-L1 treatment, with or without paclitaxel. Finally, a Phase 1 dose-escalation trial
combining the JQ1 derivative RO6870810 and atezolizumab as a doublet, or with paclitaxel as a triplet, will be
performed using concomitant and sequential schedules, in which tumor biopsies will be studied to document
changes in the immune microenvironment and in copy number and expression of CD274, encoding PD-L1. The
successful completion of this project will improve our understanding of the immune effects of these targeted
therapies and may identify biomarkers to aid the selection of patients most likely to benefit.

## Key facts

- **NIH application ID:** 9973095
- **Project number:** 5P50CA168504-07
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** KORNELIA POLYAK
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,411
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973095

## Citation

> US National Institutes of Health, RePORTER application 9973095, Project 4: Combined use of immunotherapy and targeted treatments for triple negative breast cancer (5P50CA168504-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9973095. Licensed CC0.

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