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Integration of stromal targeting agents with immune checkpoint therapy

基质靶向剂与免疫检查点疗法的整合

基本信息

批准号：
10408084
负责人：
Lei Zheng
金额：
$ 33.8万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408084
关键词：
AMD3100 Address Allogenic Antibodies Ants Bioinformatics Biometry CD44 gene CXCL12 gene CXCR4 Signaling Pathway CXCR4 gene Cells Clinical Trials Collaborations Combination immunotherapy Cytometry Data Desmoplastic Epigenetic Process Epithelial Fibroblasts Flow Cytometry Focal Adhesion Kinase 1 Future GVAX Cancer Vaccine Granulocyte-Macrophage Colony-Stimulating Factor Granzyme Human Hyaluronic Acid Hyaluronic Acid Binding Hyaluronidase Immune Immune System Diseases Immune checkpoint inhibitor Immunohistochemistry Immunotherapy Infiltration Interferon Type II Malignant Neoplasms Malignant neoplasm of pancreas Measures Mediating Memory Modeling Monitor Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoadjuvant Therapy Operative Surgical Procedures Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Phosphorylation Play Production Prognosis Publications Recombinants Regulatory T-Lymphocyte Resectable Role Signal Pathway Signal Transduction T cell receptor repertoire sequencing T memory cell T-Lymphocyte Technology Testing Tumor Bank Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells Vaccines anti-PD-1 anti-PD1 antibodies anti-tumor immune response checkpoint therapy cytotoxic effector T cell exhaustion improved infiltrating duct carcinoma inhibitor kinase inhibitor monocyte mouse model neoantigen vaccine neoantigens neoplastic cell novel novel strategies pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic stellate cell peripheral blood programmed cell death protein 1 receptor recruit response single-cell RNA sequencing small molecule inhibitor stellate cell synergism targeted agent trafficking tumor tumor microenvironment ultrasound

项目摘要

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.

胰腺导管腺癌（PDA）富含活化的星状细胞和透明质酸（HA）