# Targeted immuno-nanoparticles for directing antitumor immune response against breast cancer metastasis

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $591,007

## Abstract

PROJECT SUMMARY
First-line chemotherapy is the standard of care for patients with triple-negative breast cancer (TNBC). While
short-term response is achievable, most patients succumb to recurrence due to metastasis. Micrometastasis
encompasses a small population of dormant disseminated tumor cells (dDTCs) that survive in
quiescent/senescent states prior to initiating their ‘explosive’ metastatic outgrowth. Standard chemotherapy is
completely ineffective against the slow-dividing dDTCs. In contrast, cancer immunotherapy is based on the
premise of immune-recognition and targeted killing of tumor cells, thus possess the promising power to control
dormant metastatic cancer cells. However, one major hurdle in immunotherapy is to overcome the profound
immunosuppression within the tumor microenvironment (TME). TME is associated with the accumulation of
dysfunctional antigen-presenting cells (APCs). An effective approach to alter TME is to reprogram these
inhibitory APCs into properly activated APCs that stimulate tumor antigen-specific T cells. We designed an
immuno-stimulatory nanoparticle that exploits the unique physiological features of metastatic TME, which
allows the systemic delivery of nanoparticles to achieve a robust immunostimulation within the TME. First, to
drive a sustainable antitumor immune response, we harness two synergistic innate immune pathways by co-
delivering two immune agonists. The immuno-NP is co-loaded with an agonist of the Stimulator of Interferon
Genes (STING) pathway and a Toll-like receptor 4 (TLR4) agonist, which synergize to produce high levels of
Type I interferon (IFN) β. The dual-agonist NP guarantees uptake of both agonists by the same APC, which
elicits functional synergy. Second, the immuno-NP facilitates proficient presentation of each agonist to the
appropriate intracellular location of APCs. Third, the immuno-NP is designed for systemic administration
targeting the APC-rich perivascular areas of metastasis, leading to uptake predominantly by APC cells. As a
result, high levels of IFNβ produced within the tumor site lead to the activation of APC and NK cells that
consequently drive the recruitment of additional immune cells as well as the activation of tumor-reactive
cytotoxic CD8+ T cells. Any immuno-NP-associated toxicity was minimal and reversible. Our central
hypothesis is that the dual-agonist cargo (STING and TLR4 agonists) of the immuno-NP targeted to the
perivascular regions of metastasis will produce a strong IFNβ-driven antitumor immune response.
Aim 1: Optimize an immuno-NP design that targets the metastatic TME with high efficiency and mediates co-
delivery of the dual-agonist cargo at the ratio of STING/TLR4 agonists for optimal functional synergy.
Aim 2: Evaluate the short and long-term safety profile of the immuno-NP and characterize the mechanism of
antitumor immune responses associated with dosage and frequency of immuno-NP administration.
Aim 3: Evaluate the therapeutic efficacy of the immuno-...

## Key facts

- **NIH application ID:** 10058872
- **Project number:** 1R01CA253627-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Efstathios Karathanasis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $591,007
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10058872

## Citation

> US National Institutes of Health, RePORTER application 10058872, Targeted immuno-nanoparticles for directing antitumor immune response against breast cancer metastasis (1R01CA253627-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10058872. Licensed CC0.

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