# Integration of stromal targeting agents with immune checkpoint therapy

> **NIH NIH P01** · JOHNS HOPKINS UNIVERSITY · 2021 · $344,496

## Abstract

Pancreatic ductal adenocarcinoma (PDA) is enriched with activated stellate cells and hyaluronic acids (HA) that
contribute to the cancer’s poor prognosis. Our recent publication has shown that the PEGylated form of
recombinant hyaluronidase (PEGPH20), which degrades hyaluronic acid in the stroma, enhances the intra-
tumoral trafficking of effector T cells and anti-tumor efficacy of a PDA vaccine. We also demonstrated that the
effect of PEGPH20 is mediated by the CXCL12-CXCR4-CCR7 signaling axis that is transmitted from stromal
fibroblasts to myeloid cells and T cells. Focal adhesion kinase (FAK) also plays an integral role in modulating
pancreatic stellate cells and recruiting myeloid-derived suppressor cells (MDSCs), tumor-associated
macrophages (TAMs) and T regulatory cells (Tregs) into PDA mouse tumors. FAK inhibition can also enhance
antitumor activity when given in combination with immune checkpoint inhibitors (ICIs) that block PD-1. Therefore,
we hypothesize that targeting stromal/myeloid cell signals by FAK and HA-CXCR4 inhibition will enhance
antitumor immune responses by selectively recruiting high-quality effector memory T cells (Tem) into PDA
tumors. First, this project will examine PDA tumor microenvironment (TME) reprogramming following treatment
with stromal/myeloid cell targeting agents and ICIs in PDA mouse models. We will test combinations of
PEGPH20 or anti-CXCR4 antibody, with FAK inhibitor and anti-PD-1 antibody, for enhanced T cell infiltration
and function in murine PDAs. We will compare two different CXCL12/CXCR4 targeting agents: anti-mouse
CXCR4 antibody vs. small molecule inhibitor AMD3100, and evaluate whether lower HA/CXCR4 is associated
with improved response to PD-1 and FAK inhibitors in PDA tumors banked from a clinical trial testing anti-PD-1
and FAK inhibition as neoadjuvant therapy for surgically resectable PDA patients. Second, this project will dissect
mechanisms of cross-talk between FAK and HA-CXCR4 signaling pathways that regulate infiltration and function
of high-quality T cells in murine PDA. We will test the working hypotheses that PEGPH20 inhibits CD44 through
degrading HA; by inhibiting binding of HA to its receptor CD44, PEGPH20 inhibits the phosphorylation of FAK
reducing its inhibitory activity in Tem. Also, HA activates pFAK in CAFs to produce CXCL12, which in turn
activates CXCR4 on suppressive myeloid cells. Third, this project will explore combinations of FAK inhibition
and stroma/myeloid cell targeting agents, with ICIs for enhanced infiltration and function of high-quality
neoepitope-specific effector T cells in murine PDAs. Specifically, we will test the hypothesis that combining neo-
antigen T cell inducing approaches with FAK and HA/CXCR4 inhibitors and ICIs results in enhanced infiltration
and function of high quality, neoepitope-specific T cells in PDAs.

## Key facts

- **NIH application ID:** 10170023
- **Project number:** 1P01CA247886-01A1
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Lei Zheng
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $344,496
- **Award type:** 1
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170023

## Citation

> US National Institutes of Health, RePORTER application 10170023, Integration of stromal targeting agents with immune checkpoint therapy (1P01CA247886-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10170023. Licensed CC0.

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