# Nano immunoconjugates to treat primary and metastatic HER2 positive breast cancer

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2020 · $637,908

## Abstract

PROJECT SUMMARY / ABSTRACT
Breast cancer (BC) is the second cause of cancer death among women in the United States The
development of brain metastases is qualified as the most advanced stage of the HER2+ expressing BC with
survival rate from 3-6 months. Recently, a blocking antibody (Ab) to cytotoxic T lymphocyte (CTL)-associated
antigen 4 (CTLA-4), which turns off the inhibitory mechanism to allow CTL and natural killer (NK) cells to
eliminate cancer cells, was approved for cancer treatment. Working through regulatory T (Treg) cells enriched
in tumors, this antibody dramatically activates anti-tumor immune response. An antibody blocking lymphocytic
surface receptor programed cell death protein 1 (PD-1) has a similar activity. The immunotherapy of HER2+
BCs and its response to Treg inhibiting Abs (checkpoint inhibitors) is understudied and poorly understood, in
spite of lymphocytic infiltration of their stroma. Our goal is to introduce new nano immunoconjugates (NIC)
with attached checkpoint inhibitors that boost immune microenvironment of BCs and their brain metastases.
Contrary to free checkpoint inhibitor Abs, our nano drugs will cross a number of bio barriers, including blood-
brain barrier (BBB) and activate local primary breast and metastatic anti-tumor immune system.
We propose to develop novel NICs loaded with the combination of tumor immune stimulators and inhibitors of
cancer-specific marker(s), which is a response to the latest tendency in cancer treatment. As potent immune
stimulators, we will use Abs to CTLA-4 or PD-1/PD-L1, which turn off the inhibitory mechanism allowing CTL to
eliminate cancer cells. The same NIC will also have cytotoxic anti-cancer antisense drugs against (1) c-Myc, a
master signaling regulator of cancer environment that can also suppress the expression of CTLA-4/PD-1,
and/or (2) HER2 that would increase apoptosis of the tumor cells making them more visible to the immune
system. A significant advantage of new NIC is the use of specific peptides to replace monoclonal Abs for the
delivery to the tumor and across BBB. They will also make NIC less immunogenic and smaller in size. Three
specific aims are proposed: Aim 1. Synthesize and characterize the nano immunodrugs; study the physico-
chemical properties of poly(malic acid) (PMLA)-based NIC to optimize the synthesis with preservation of
activity of peptide-based NIC delivery and treatment in comparison to delivery using tumor targeting Abs. Aim
2. Determine the efficacy of primary and metastatic HER2+ breast cancer treatment and mechanism of action
of the nano immunodrugs. Analysis of T cell populations in BC to reveal reduced Treg (CD4+FOXP3+) fraction
and increased CTL by nanopolymer conjugates and combinations. Aim 3. Define the pharmacokinetics and
toxicity of the nano immunodrugs; study the pharmaceutical characteristics (half-life, PK), bio distribution, and
toxicity of different NIC versions. The premedication against therapeutic Abs immuno toxicity will be...

## Key facts

- **NIH application ID:** 9831149
- **Project number:** 5R01CA230858-02
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Eggehard Holler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $637,908
- **Award type:** 5
- **Project period:** 2018-12-03 → 2020-08-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9831149

## Citation

> US National Institutes of Health, RePORTER application 9831149, Nano immunoconjugates to treat primary and metastatic HER2 positive breast cancer (5R01CA230858-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9831149. Licensed CC0.

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