# Project 2: Combination immunotherapy approaches to overcome therapeutic resistance in HER2-positive breast cancer

> **NIH NIH P50** · DANA-FARBER CANCER INST · 2020 · $473,960

## Abstract

PROJECT SUMMARY
Despite significant advances in the management of metastatic HER2+ breast cancer (BC), it remains incurable.
The reason for this is that cancers invariably develop resistance to standard therapies – both cytotoxic
chemotherapies and those that specifically target HER2. Modern attempts to improve upon standard therapies
have largely focused on agents that inhibit HER2 downstream signaling more potently, but these have yielded
only incremental benefits. Therefore, new treatment approaches are urgently needed. Recently it has become
clear that HER2+ BCs are immunogenic. HER2 is a strong tumor antigen, and a proportion of HER2+ BCs
harbor a lymphocytic infiltrate, which predicts for improved outcomes. In addition, anti-HER2 antibodies exert
their effects in part by stimulating immune effector cells. Collectively, these facts provide rationale for testing
immunotherapy in HER2+ metastatic BC. Our co-investigator Dr. Loi recently conducted a phase II study of
trastuzumab and pembrolizumab (a PD-1 inhibitor) in patients with HER2+ metastatic BC (PANACEA). The
study met its primary endpoint and thus provides proof-of-principle for the use of immunotherapy in HER2+
disease – however, only a small minority of patients benefited. In Project 2, we will therefore study two novel
therapeutic approaches designed to boost the anti-tumor immune response against HER2+ BC further: the use
of CDK4/6 inhibitors, given together with trastuzumab and PD-1 blockade (Aim One); and the addition of PD-
L1 blockade and a 4-1BB agonist to chemotherapy and trastuzumab (Aim Two). Both regimens are rationally
designed, based on our convincing preclinical data showing that these approaches markedly amplify anti-tumor
immunity. In each Aim, we will perform a randomized, multicenter phase II clinical trial to determine the efficacy
of these novel approaches. Each Aim will also employ a “co-clinical trial” model, with mouse studies running in
parallel to human trials. The animal experiments will be performed using our state-of-the-art transgenic model
of human HER2- driven mammary carcinoma (MMTV-rtTA/tetO-HER2). Our mouse studies incorporate cutting-
edge technologies to understand the mechanisms of activity for these novel immunotherapy approaches, as
well as detailed studies of resistance mechanisms (including next-generation sequencing and multiplexed
immunofluorescent profiling of tumor tissue). Meanwhile, the trials involve serial collection of tumor biopsies
and blood samples. Biospecimens from mice and patients will be analyzed in parallel, with each informing the
other. Ultimately, these studies will: (1) characterize the immune landscape of advanced HER2-positive BC in
unprecedented detail; (2) determine whether either of the two novel approaches is an effective clinical strategy;
(3) establish cellular mechanisms of activity for each regimen; and (4) explore mechanisms of therapeutic
resistance. This work has the potential to uncover new therapies that enh...

## Key facts

- **NIH application ID:** 9973093
- **Project number:** 5P50CA168504-07
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** IAN E KROP
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $473,960
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9973093

## Citation

> US National Institutes of Health, RePORTER application 9973093, Project 2: Combination immunotherapy approaches to overcome therapeutic resistance in HER2-positive breast cancer (5P50CA168504-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9973093. Licensed CC0.

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