# 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 · 2020 · $414,073

## Abstract

Abstract
While immune checkpoint blockade (ICB) has emerged as a validated therapeutic axis in a variety of cancers,
initial monotherapy strategies have proven beneficial only to a subset of patients. These studies have
suggested the importance of T-cells in responsive cancers, thus strategies to improve T-cell stimulation and
infiltration have been prioritized. However, our recent studies (Shuptrine et al., 2017) have identified the
CD47/SIRPα innate pathway, which governs antibody dependent cell phagocytosis (ADCP), as one of the
most critical potential mediators of anti-tumor immunity. This suggests that complementary innate anti-tumor
effector pathways involving antibodies, particularly relating to ADCP, may represent critical pathways to
establish effective anti-tumor responses. Recent positive results from the first clinical study using CD47 innate
ICB (with CD20 mAb in resistant lymphoma) strongly suggest that this may be a clinically effective means to
stimulate immunity in cancers (Advani, NEJM, 2018). This may be best explored in solid cancers in HER2+
Breast Cancer (BC), which are currently treated using HER2 mAbs that we recently determined function
through ADCP (Tsao et al., JCI-Insight, in review). Additionally, we have also recently published positive
responses from a vaccine strategy targeting HER2, documenting the induction of polyclonal antibodies (pAbs)
in HER2+ BC patients (Crosby et al., CCR 2019). We have now identified these HER2 pAbs to elicit anti-
tumor effects through the activation of complement, allowing our study of how pAbs (in contrast to monoclonal
HER2-Abs) may differentially impact tumor immunity. Based on our recent adaptive ICB mechanistic studies,
(Crosby et al., 2018), our central hypothesis is that HER2-targeted mAbs or pAbs elicit antibody dependent
phagocytosis (ADCP) that is enhanced by CD47 blockade to immunologically to recruit and prime effector T-
cells that can be expanded through the use of CTLA4 adaptive ICB mAbs and functionally enhanced by the
use of PD1 ICB mAbs. Guided by our preliminary data, this hypothesis will be tested by utilizing our unique
HER2+ BC models that can be interrogated with the following combinations that comprise our specific aims: 1)
HER2+CD47 mAbs 2) HER2/CD47 mAbs + CTLA4/PD1 ICB combinations and 3) HER2 vaccination + innate
CD47 ICB and CTLA4/PD1 adaptive ICB combinations. These studies will be the first to determine how these
innate and adaptive ICB combinations impact Ab-mediated anti-tumor immunity and mechanistically alter
tumor-specific and non-specific adaptive responses, as well as determine how the HER2 pAb activation of
complement and direct T-cell stimulation can alter anti-tumor immunity in an endogenous HER2 immune-
competent model that possesses few neoepitopes and is αPD1 resistant. The proposed research is significant,
because if fundamental mechanisms and synergies are identified with minimal toxicities, these approaches
could be utilized with targeted m...

## Key facts

- **NIH application ID:** 9886858
- **Project number:** 1R01CA238217-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Zachary Conrad Hartman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $414,073
- **Award type:** 1
- **Project period:** 2019-12-06 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886858

## Citation

> US National Institutes of Health, RePORTER application 9886858, Enabling effective anti-tumor immunity from targeted antibodies through dual innate and adaptive immune checkpoint blockade in non-immunogenic cancers (1R01CA238217-01A1). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9886858. Licensed CC0.

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