# Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $85,627

## Abstract

Abstract
In our previous studies, we have identified that HER2 monoclonal antibodies (mAb) function to stimulate
antibody dependent cellular phagocytosis (ADCP) through innate pathways, which are critical to establish
effective anti-tumor responses (Tsao et al., JCI-Insight, 2019). In our ongoing funded studies (R01 CA238217-
01A1), we are exploring if HER2-specific ADCP eliciting antibodies could be enhanced by innate ICB (targeting
CD47) and adaptive ICBs (targeting CTLA4/PD1). These studies utilize an endogenous immune-tolerant model
of HER2+ BC (Turpin et al., 2016) driven by an oncogenic human isoform of HER2, HER2Δ16. While this
model is immune-tolerant to HER2 epitopes and generates HER2Δ16-driven tumors in an appropriate
mammary microenvironment, it does not recapitulate the tumor heterogeneity seen clinically in HER2+ BCs, or
permit the development of major resistance mechanisms to HER2 mAb therapies, which often occur in
advanced HER2+ BC patients. To address these shortcomings and further our understanding of HER2 mAb
therapies in HER2+ BC, we propose to utilize a novel HER2BOW mouse developed through the IMAT program
(5R33CA191198;Lubkov et al., Nat. Cell Bio., in review). This model utilizes the stochastic activation of several
different variants of HER2 (HER2-WT, HER2Δ16, and HER2-p95) within the mammary compartment to evolve
heterogeneous HER2+ BCs with disparate pathologies. Critically, these different pathologies stem from the
expression of these alternate HER2 isoforms, which may explain HER2+ tumor heterogeneity observed
clinically. Moreover, this model contains HER2-p95, which lacks the extracellular binding domain for HER2
mAbs to function as a driver of resistance. However, HER2-specific mAbs are able to prime T cell responses
against HER2 intracellular epitopes within the heterogeneous context of clinical HER2+ BCs, thus its
importance in mediating resistance in a heterogeneous context is unclear. Moreover, it is unknown if strategies
to enhance HER2 mAb stimulated immunity could overcome HER2-p95 mediated resistance thorough
enhanced HER2 immune cross-priming. We hypothesize that HER2-p95 expression confers resistance against
HER2 mAb therapies within heterogeneous HER2+ BCs, but that dual (innate and adaptive) ICB-enhanced
HER2 mAb therapies could overcome this resistance through enhance HER2 epitope cross-priming. Guided by
our preliminary data, this hypothesis will be tested by utilizing the HER2BOW model that can be interrogated
with the following combinations that comprise our specific aims: 1) HER2+CD47 mAbs and 2) HER2/CD47
mAbs + CTLA4/PD1 ICB combinations. These studies will determine if responsiveness is due to a lack of local
immunity related to substantial intratumoral heterogeneity, or due to the rapid development of resistance from
alternate HER2 oncogenic isoforms. Critically, they will also validate the therapeutic utility of the HER2BOW
model and the therapeutic potential of HER2 mAb+ICB combinations acros...

## Key facts

- **NIH application ID:** 10271164
- **Project number:** 3R01CA238217-02S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zachary Conrad Hartman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $85,627
- **Award type:** 3
- **Project period:** 2019-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271164

## Citation

> US National Institutes of Health, RePORTER application 10271164, Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers (3R01CA238217-02S1). Retrieved via AI Analytics 2026-06-15 from https://api.ai-analytics.org/grant/nih/10271164. Licensed CC0.

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