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: 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
• 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

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（PEGPH 20），其降解基质中的透明质酸，增强细胞内的 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， PEGPH 20的作用是由CXCL 12-CXCR 4-CCR 7信号轴介导的，该轴从间质 成纤维细胞转化为骨髓细胞和T细胞。粘着斑激酶（FAK）也在调节细胞凋亡中起着不可或缺的作用。 胰腺星状细胞和招募髓源性抑制细胞（MDSC），肿瘤相关 巨噬细胞（TAM）和调节性T细胞（T细胞）移植到PDA小鼠肿瘤中。FAK抑制还可以增强 当与阻断PD-1的免疫检查点抑制剂（ICI）联合给药时，具有抗肿瘤活性。因此，我们认为， 我们假设通过FAK和HA-CXCR 4抑制靶向基质/骨髓细胞信号将增强 通过选择性募集高质量效应记忆T细胞（Tem）进入PDA的抗肿瘤免疫应答 肿瘤的首先，该项目将检查PDA肿瘤微环境（TME）治疗后的重编程 在PDA小鼠模型中使用基质/骨髓细胞靶向剂和ICI。我们将测试 PEGPH 20或抗CXCR 4抗体，与FAK抑制剂和抗PD-1抗体，用于增强T细胞浸润 并在鼠PDA中发挥作用。我们将比较两种不同的CXCL 12/CXCR 4靶向剂： CXCR 4抗体与小分子抑制剂AMD 3100，并评估HA/CXCR 4降低是否与 在PDA肿瘤中对PD-1和FAK抑制剂的反应改善，这些肿瘤来自一项测试抗PD-1的临床试验 和FAK抑制作为可手术切除的PDA患者的新辅助治疗。第二，这个项目将剖析 FAK和HA-CXCR 4信号通路之间的相互作用机制，调节浸润和功能 高质量的T细胞在鼠PDA中的作用。我们将测试PEGPH 20通过以下途径抑制CD 44的工作假设： 通过抑制HA与其受体CD 44的结合，PEGPH 20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CXCL 12，CXCL 12反过来 激活抑制性骨髓细胞上的CXCR 4。第三，本项目将探索FAK抑制的组合， 和基质/骨髓细胞靶向剂，与ICI用于增强高质量的浸润和功能， 新表位特异性效应T细胞在鼠PDA中的表达。具体来说，我们将测试的假设，结合新- 使用FAK和HA/CXCR 4抑制剂和ICI的抗原T细胞诱导方法导致浸润增强 以及PDA中高质量新表位特异性T细胞的功能。