# Dual action immunostimulatory nanoparticles for treatment of aggressive cancers

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $77,121

## Abstract

PROJECT SUMMARY: Cancer immunotherapy is based on the premise of immune-recognition and targeted
killing of tumor cells, thus possesses the promising power to eradicate aggressive disease. Notably to date,
immunotherapy with immune checkpoint inhibitors significantly prolongs the survival of patients. Unfortunately,
recurrent and metastatic disease occurs to a significant portion of patients within 5 years largely due to
resistance to the immune checkpoint inhibitor. This largely stems from the local immunosuppressive tumor
microenvironment (TME), which is enriched with immunosuppressive myeloid cells. To reprogram the TME into
a “hot” environment enriched with functional myeloid cells, we designed a dual action immunostimulatory
nanoparticle (dual-NP) that triggers a highly potent activation of the dysfunctional tumor-resident myeloid cells.
The premise of our strategy is based on three key components: (1) Our previous studies showed that V domain
Immunoglobulin Suppressor of T cell Activation (VISTA) is a novel myeloid cell-intrinsic immune checkpoint
protein, which controls antitumor immunity. We showed VISTA is highly expressed on immunosuppressive
myeloid cells and blocking VISTA can synergize with TLR9 agonist to reprogram the immunosuppressive
myeloid cells to boost antitumor immunity. (2) The dual-NP is co-loaded with a VISTA siRNA and the TLR9
agonist CpG. Upon intratumoral administration, the dual-NP ensures the simultaneous uptake of its synergistic
cargoes by the same tumor-resident myeloid cells and proficient intracellular delivery of each cargo, thus
achieving optimal effects to activate these cells. Our recent studies show that simultaneous silencing of the
VISTA gene and stimulation of TLR9 leads to a synergistic T cell-mediated tumor clearance and curative
responses with protective immunological memory against tumor recurrence. (3) We developed a simple and
controllable method to generate ionizable lipid dual-NPs of different sizes (i.e., 30, 40 or 60 nm) with high
degree of uniformity and consistency. Our studies show that small dual-NPs achieve widespread distribution
and predominant uptake by myeloid cells throughout the tumor volume upon intratumoral administration.
Innovation: To our knowledge, this is the first effort to combine advanced nanoparticle design, simultaneous
delivery of siRNA and a TLR agonist, and silencing of a gene related to an immune checkpoint protein specific
to myeloid cells.
AIM 1: Optimize the design of the dual-NP and test the ex vivo and in vivo efficacy in reprograming
tumorassociated myeloid cells.
AIM 2: Evaluate the short and long-term safety profile of the dual-NP and characterize the mechanism of
antitumor immune responses associated with dosage and frequency of dual-NP administration.
AIM 3: Evaluate the therapeutic efficacy of the dual-NP as a monotherapy and in combination with standard
immune checkpoint inhibitors in murine models of advanced melanoma and metastatic breast cancer.

## Key facts

- **NIH application ID:** 11043505
- **Project number:** 3R01CA278633-02S1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Efstathios Karathanasis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,121
- **Award type:** 3
- **Project period:** 2023-06-26 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11043505

## Citation

> US National Institutes of Health, RePORTER application 11043505, Dual action immunostimulatory nanoparticles for treatment of aggressive cancers (3R01CA278633-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11043505. Licensed CC0.

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