# HIFU-immunotherapy in pancreatic cancer

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $608,025

## Abstract

HIFU-immunotherapy in pancreatic cancer
Most importantly, we find that the combination of ultrasound, TLR7/8 agonists with aCD40 and checkpoint
inhibition (building on a protocol in emerging human studies) efficiently eliminated implanted multisite invasive
KPC murine pancreatic tumors. Recent studies have provided compelling evidence as to the utility of agonist
CD40 (aCD40) antibodies within multicomponent protocols to treat pancreatic cancer, and studies combining
aCD40 with checkpoint modulators and chemotherapy have shown highly encouraging data. CD40 is expressed
on a subset of pancreatic cancer cells and the overwhelming majority of peritumoral lymphocytes. For PDAC,
the aCD40 monoclonal antibody also promotes stromal degradation, dendritic cell maturation and alters
macrophage phenotype, and therefore is an attractive approach for immunotherapy. While NCT03214250
(combining gemcitabine and Abraxane with aCD40 and aPD-1 immunotherapy) yielded very promising results
in which all patients receiving all components demonstrated regression of metastatic pancreatic cancer, T cell
activation was not observed and patients were not cured. Reliably delivering these treatments in human
pancreatic cancer is challenging due to the dense stroma and limited vascular supply. Initial studies of MR
guided focused ultrasound (MRgFUS) to ablate human pancreatic tumors are scheduled to begin in early 2020
at Stanford. Here, we will combine MRgFUS with an aCD40+checkpoint inhibitor strategy. We will immediately
work to translate such a strategy if results are promising. Further, recent work has also demonstrated that toll
like receptor (TLR)7/8 agonists have therapeutic utility, particularly in pancreatic cancer. TLR7/8 agonists are
desirable for translation due to the distribution of receptors on subsets of DCs. Our preliminary data demonstrate
synergy between TLR7/8 and aCD40, and we build on the combination of TLR7/8 agonists and aCD40 in Aim
2. While TLR7/8 agonists can be delivered intradermally, the direct delivery of TLR agonists to tumors yields an
in situ vaccination that facilitates efficacy by exposing activated immune cells to cancer antigen. Our preliminary
data indicate that with 2 treatments (with intravenous injection of TLR7/8 and CP4) up to 100% of directly-treated
tumors and 60% of distant KPC tumors were eliminated. A major challenge for human studies is to deliver
sufficient quantities of TLR7/8 agonists and antibodies to pancreatic cancer without dose-limiting toxicity. We
have developed a temperature-sensitive liposomal (TSL) strategy to assure adequate delivery of TLR7/8
agonists to pancreatic cancer and add this in Aim 2. With such a strategy, it is feasible to deliver 8% or more of
the injected dose to a human tumor (at least 20 fold more than free drug) and limit systemic toxicity. In summary,
within Aim 1, we will incorporate MRgFUS ablation into clinically-relevant aCD40+checkpoint therapy. Within
Aim 2, we will further add TLR7/8 a...

## Key facts

- **NIH application ID:** 10654577
- **Project number:** 5R01CA253316-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Katherine W Ferrara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $608,025
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10654577

## Citation

> US National Institutes of Health, RePORTER application 10654577, HIFU-immunotherapy in pancreatic cancer (5R01CA253316-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10654577. Licensed CC0.

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