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

• 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
• 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

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)， 导致癌症预后不良的原因之一。我们最近的出版物表明，聚乙二醇化形式的 重组透明质酸酶(PEGPH20)可以降解基质中的透明质酸，增强基质内的 肿瘤转移效应T细胞和PDA疫苗的抗肿瘤效果。我们还演示了 PEGPH20的作用是由基质传递的CXCL12-CXCR4-CCR7信号轴介导的 成纤维细胞分化为髓系细胞和T细胞。粘着斑激酶(FAK)也在调节中起着不可或缺的作用 胰腺星状细胞和招募髓系来源的抑制细胞(MDSCs)，肿瘤相关 巨噬细胞(TAMs)和T调节细胞(Tregs)进入PDA小鼠肿瘤。抑制FAK还可以增强 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。因此， 我们假设，通过抑制FAK和HA-CXCR4靶向基质/髓系细胞信号将增强 PDA选择性募集高质量效应记忆T细胞(Tem)的抗肿瘤免疫应答 肿瘤。首先，这个项目将检查治疗后PDA肿瘤微环境(TME)的重新编程 在PDA小鼠模型中使用基质/髓系细胞靶向药物和ICIS。我们将测试以下几种组合 PEGPH20或抗CXCR4抗体与FAK抑制剂和抗PD-1抗体一起用于增强T细胞浸润 并在小鼠掌上电脑中发挥作用。我们将比较两种不同的CXCL12/CXCR4靶向制剂：抗鼠 CXCR4抗体与小分子抑制剂AMD3100的比较，并评估低HA/CXCR4是否相关 抗PD-1临床试验证实PDA肿瘤对PD-1和FAK抑制剂的反应有所改善 FAK抑制作为可手术切除的PDA患者的新辅助治疗。其次，本项目将剖析 调节渗透和功能的FAK和HA-CXCR4信号通路之间的串扰机制 在小鼠PDA中获得高质量的T细胞。我们将测试PEGPH20通过以下途径抑制CD44的工作假设 降解HA；PEGPH20通过抑制HA与其受体CD44的结合抑制FAK的磷酸化 降低其在Tem中的抑制活性。此外，HA激活CAF中的pFAK以产生CXCL12，进而 激活抑制髓系细胞上的CXCR4。第三，该项目将探索FAK抑制的组合 和间质/髓系细胞靶向剂，配合ICIS用于增强渗透和功能的高质量 小鼠PDA中新表位特异性效应T细胞。具体地说，我们将测试这一假设，即结合近地天体- FAK、HA/CXCR4抑制剂和ICIS诱导抗原T细胞途径可增强浸润 以及PDA中高质量、新表位特异性T细胞的功能。