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：
10661808
负责人：
Lei Zheng
金额：
$ 33.76万
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/10661808
关键词：
AMD3100 Allogenic Antibodies Antigen Targeting Ants Bioinformatics Biometry CD44 gene CXCR4 Signaling Pathway CXCR4 gene Cells Clinical Trials Collaborations Combination immunotherapy Cytometry Data Desmoplastic Epigenetic Process Epithelium 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 PD-1 inhibitors Pancreatic Ductal Adenocarcinoma Pathway interactions Patients Phenotype Phosphorylation Inhibition Play Production Prognosis Publications Recombinants Regulatory T-Lymphocyte Resectable Role Signal Pathway Signal Transduction Sorting Stromal Cell-Derived Factor 1 Suppressor-Effector T-Lymphocytes T cell infiltration T cell receptor repertoire sequencing T memory cell T-Lymphocyte Technology Testing Tumor Bank Tumor Immunity Tumor-associated macrophages Vaccines anti-PD-1 anti-PD1 antibodies anti-tumor immune response antigen-specific T cells checkpoint therapy cytotoxic effector T cell exhaustion immunoregulation 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 transmission process 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)，我们最近的出版物表明，聚乙二醇化形式会导致癌症的不良预后。重组透明质酸酶（PEGPH20）可降解基质中的透明质酸，增强内部效应 T 细胞的肿瘤运输和 PDA 疫苗的抗肿瘤功效我们还证明了。 PEGPH20 的作用是由基质传递的 CXCL12-CXCR4-CCR7 信号轴介导的成纤维细胞、骨髓细胞和 T 细胞在调节中也发挥着不可或缺的作用。胰腺星状细胞和招募骨髓源性抑制细胞（MDSC），肿瘤相关巨噬细胞 (TAM) 和 T 调节细胞 (Treg) 进入 PDA 小鼠肿瘤也可以增强 FAK 抑制作用。与阻断 PD-1 的免疫检查点抑制剂 (ICIs) 联合使用时具有抗肿瘤活性。我们发现，通过 FAK 和 HA-CXCR4 抑制来靶向基质/骨髓细胞信号将增强通过选择性地将高质量效应记忆 T 细胞 (Tem) 招募到 PDA 中来产生抗肿瘤免疫反应首先，该项目将检查治疗后 PDA 肿瘤微环境 (TME) 重编程。我们将在 PDA 小鼠模型中测试基质/骨髓细胞靶向剂和 ICI 的组合。 PEGPH20 或抗 CXCR4 抗体，结合 FAK 抑制剂和抗 PD-1 抗体，用于增强 T 细胞浸润以及在鼠 PDA 中的功能我们将比较两种不同的 CXCL12/CXCR4 靶向药物：抗小鼠。 CXCR4 抗体与小分子抑制剂 AMD3100，并评估较低的 HA/CXCR4 是否相关根据抗 PD-1 临床试验，PDA 肿瘤对 PD-1 和 FAK 抑制剂的反应有所改善和 FAK 抑制作为可手术切除的 PDA 患者的新辅助治疗其次，该项目将进行剖析。调节浸润和功能的 FAK 和 HA-CXCR4 信号通路之间的串扰机制我们将测试 PEGPH20 通过抑制 CD44 的工作假设。降解HA；通过抑制HA与其受体CD44的结合，PEGPH20抑制FAK的磷酸化降低 Tem 中的抑制活性此外，HA 还会激活 CAF 中的 pFAK 产生 CXCL12，进而产生 CXCL12。第三，该项目将探索 FAK 抑制的组合。和基质/骨髓细胞靶向剂，具有 ICI，可增强高质量的浸润和功能具体来说，我们将测试结合新表位的假设。使用 FAK 和 HA/CXCR4 抑制剂以及 ICI 诱导抗原 T 细胞的方法可增强浸润以及 PDA 中高质量、新表位特异性 T 细胞的功能。