# Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy

> **NIH NIH R37** · OKLAHOMA STATE UNIVERSITY STILLWATER · 2022 · $345,260

## Abstract

Summary
Malignant melanoma in advanced stages is a highly lethal form of cancer, refractory to chemo- and radio-therapy,
and the median survival is typically less than 4years. To improve response rates, antibodies that target CTL-4,
PD1, and PDL1 has gained prominence, and can achieve a response rate of ~50% in metastatic cases. This is
promising but a large proportion of patients still do not respond to immune therapies due to the absence of
infiltrating T-cells, and presence of aberrant and suppresive signaling pathways that blunt the expression of
checkpoint proteins (e.g. CD47, PDL1). To promote inflamed melanoma microenvironment, recent studies
indicate that image-guided focused ultrasound (FUS) can i) mediate precise mechanical perturbation and
elevation of tumor temperature to induce tumor antigen release and ii) upregulate calreticulin (CRT), a protein
that is key to the activation of local and systemic anti-immunity. However, the exact mechanisms and how to
translate this approach for clinical treatment of malignant melanoma is poorly understood.
The goal of this project is to combine ultrasound guided FUS with novel CRT-NP, a liposome-plasmid
nanoparticle agent that transfects melanoma cells to induce expression of CRT. Our in vitro and in vivo data in
murine melanoma suggest that combined local treatment with CRT-NP/FUS (CFUS) enhances expression of
CRT and modulates innate (CD47) and adaptive checkpoint proteins (PDL1); all of which significantly enhance
the local and systemic immune priming and anti-tumor responses. Based on this premise, our central hypothesis
is that CFUS targeted optimization of the CRT/CD47/PDL1 axis will provide powerful immune priming and
generation of systemic immunity against malignant melanoma.
To test our hypothesis, we will mechanistically dissect and understand CFUS-mediated immune priming in a B16
orthotopic and genetically-engineered mouse melanoma model (Aim 1 & 2) and translate this approach to clinical
use in trials using client-owned dogs with spontaneous oral melanoma (Aims 3). Specifically, we will evaluate
the impact of the CFUS treatment sequence, FUS exposures, and CRT-activation mechanisms in murine
melanoma and translate this information to improve efficacy of checkpoint blockage in murine and canine tumor
models.
We expect that the successful optimization of local CFUS in this project will liberate tumors from their immune-
suppressive state, achieve consistent and predictable clonal expansion of cytotoxic immune cells, and improve
immunotherapy efficacy independent of cancer complexity. If successful, this method will provide a promising
new avenue for treating melanoma and other types of solid tumor (e.g., breast, prostate) by significantly
overcoming current immunotherapy barriers.

## Key facts

- **NIH application ID:** 10434835
- **Project number:** 5R37CA239150-04
- **Recipient organization:** OKLAHOMA STATE UNIVERSITY STILLWATER
- **Principal Investigator:** Ashish Ranjan
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $345,260
- **Award type:** 5
- **Project period:** 2019-06-04 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434835

## Citation

> US National Institutes of Health, RePORTER application 10434835, Novel focused ultrasound enhanced calreticulin-nanoparticle for immune primed melanoma immunotherapy (5R37CA239150-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10434835. Licensed CC0.

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