Targeting the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer with a Neoadjuvant Platform Clinical Trial

利用新辅助平台针对胰腺癌免疫抑制肿瘤微环境的临床试验

基本信息

批准号：
10654572
负责人：
ELIZABETH M. JAFFEE
金额：
$ 55.29万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-21 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654572
关键词：
Aftercare Agonist Annexins Antibodies Award Biopsy CD8-Positive T-Lymphocytes Cell physiology Cells Clinical Trials Clonal Expansion Clone Cells Combination immunotherapy Combined Vaccines Complex Data Data Analyses Defect Funding GVAX Cancer Vaccine Goals Granzyme IL8 gene ITGAM gene Immune Immune checkpoint inhibitor Immunohistochemistry Immunologics Immunotherapeutic agent Immunotherapy Impairment Implant Infiltration Lymphoid Malignant neoplasm of pancreas Modeling Modification Myeloid Cells Neoadjuvant Therapy Nivolumab PD-1/PD-L1 Pancreas Pancreatic Ductal Adenocarcinoma Pathologic Patients Phenotype Regulatory T-Lymphocyte Resectable Resected Resistance Serum Signal Transduction Specimen T cell infiltration T cell receptor repertoire sequencing T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tumor Antigens Tumor-infiltrating immune cells Vaccine Therapy Vaccines antagonist anti-PD-1 anti-PD1 antibodies anti-PD1 therapy arm density effector T cell exhaustion genetically modified cells granulocyte immune checkpoint immunogenic mesothelin mouse model neoantigens neoplastic cell neutrophil pancreatic ductal adenocarcinoma model pancreatic neoplasm peptide based vaccine preclinical study prevent programmed cell death protein 1 randomized, clinical trials rational design resistance mechanism response single-cell RNA sequencing trafficking tumor tumor microenvironment tumor-immune system interactions

项目摘要

Pancreatic ductal adenocarcinomas (PDACs) are known to be immunogenically “cold” tumors. To convert PDACs into immune checkpoint inhibitor (ICI) responsive tumors, effective immunotherapy strategies are required at a minimum to: 1) increase antigenicity; 2) enhance effector T cell function, and 3) overcome immunosuppressive signals in the tumor microenvironment(TME). Previously, we demonstrated that the pancreatic cancer GVAX can inflame PDAC tumors with the formation of intratumoral tertiary lymphoid aggregates. Immune checkpoint signals such as PD-L1/PD-1 were induced and potentially primed PDAC for ICI treatments. The concept was subsequently tested in our neoadjuvant clinical trial study in resectable PDACs and supported by the previous R01 award. The addition of anti-PD-1 antibody(aPD1) to GVAX counteracts a T cell exhaustion phenotype, however, did not enhance the effector T cell (Teff) “quality” as indicated by lack of enhanced Granzyme B+ CD8+ T cells. Nevertheless, we noticed that a subset of PDACs that have a higher level of CD137 expression do have a higher density of granzyme B+ CD8+ T cells following treatment with GVAX and aPD1. Second, IL8 expression in CD11b+ myeloid cells positively correlates with tumor-associated neutrophil (TAN) and higher density of TANs is associated with shorter survival following the neoadjuvant therapy with GVAX and aPD1. These results support testing the hypothesis that anti-CD137 agonist antibody(aCD137) and/or anti-IL8 antibody(aIL8) enhances the Teff function and overcomes the immunosuppressive TME in PDACs. Thus, this project will test the hypothesis that increased “quantity” and higher “quality” Teffs are induced, re- invigorated, and activated in PDACs by the triple combination of vaccine, aPD1 antagonist, and aCD137 agonist. To this end, a third arm with this triple combo has been added to the previous R01-funded neoadjuvant clinical trial platform of resectable PDACs. Using a mouse model of PDAC, we will further test the hypothesis that aCD137 agonist expands and enhances the function of neoepitope specific T cells. Next, this project will test the hypothesis that inhibiting the trafficking of TANs will overcome the barriers to high “quantity” and high “quality” Teffs trafficking and function in PDACs. To this end, two new arms will be added to the neoadjuvant platform clinical trial to test the combination of aIL8 and nivolumab with and without GVAX, respectively. Specially, we will test the hypothesis that significantly greater infiltration of CD137+PD-1+ T cells and enhanced expansion of CD8+ T cell clones that express granzyme B are induced by the combination of nivolumab and aIL8. The findings from this study will directly inform the rational design of an immunotherapy combination to be tested in a large randomized clinical trial in locally advanced and metastatic PDAC patients.

胰腺导管腺癌（PDAC）被认为是免疫原性“冷”肿瘤。 PDACs成为免疫检查点抑制剂（ICI）反应性肿瘤，有效的免疫治疗策略是至少需要：1) 增加抗原性；2) 增强效应 T 细胞功能，以及 3) 克服之前，我们证明了肿瘤微环境（TME）中的免疫抑制信号。胰腺癌 GVAX 可以使 PDAC 肿瘤发炎，形成瘤内三级淋巴组织诱导免疫检查点信号（例如 PD-L1/PD-1），并可能为 ICI 启动 PDAC。随后，我们在可切除 PDAC 的新辅助临床试验研究中测试了这一概念。并得到之前R01奖的支持，在GVAX中添加抗PD-1抗体（aPD1）可以抵消T。然而，细胞耗竭表型并没有增强效应 T 细胞 (Teff) 的“质量”，如缺乏增强的颗粒酶 B+ CD8+ T 细胞尽管如此，我们注意到 PDAC 的一个子集具有更高的水平。 GVAX 治疗后，CD137 表达确实具有更高密度的颗粒酶 B+ CD8+ T 细胞其次，CD11b+ 骨髓细胞中的 IL8 表达与肿瘤相关中性粒细胞呈正相关。 (TAN) 且较高密度的 TAN 与新辅助治疗后较短的生存期相关 GVAX 和 aPD1 支持检验抗 CD137 激动剂抗体 (aCD137) 和/或的假设。抗IL8抗体（aIL8）增强Teff功能并克服PDAC中的免疫抑制TME。因此，该项目将检验这样的假设：诱导 Teff 的“数量”增加和“质量”更高，重新通过疫苗、aPD1 拮抗剂和 aCD137 激动剂的三重组合在 PDAC 中增强和激活。为此，在先前 R01 资助的新辅助临床中添加了具有这种三重组合的第三组可切除 PDAC 的试验平台使用 PDAC 小鼠模型，我们将进一步检验以下假设： aCD137激动剂扩大并增强了新表位特异性T细胞的功能，接下来，该项目将进行测试。假设抑制 TAN 贩运将克服高“数量”和高质量“质量”的障碍 Teffs 的运输和 PDAC 中的功能为此，新辅助平台将添加两个新武器。分别测试 aIL8 和 nivolumab 联合使用和不联合使用 GVAX 的临床试验。将检验以下假设：CD137+PD-1+T 细胞的浸润显着增加，并且增强的扩增纳武单抗和 aIL8 联合诱导表达颗粒酶 B 的 CD8+ T 细胞克隆。这项研究将直接指导免疫治疗组合的合理设计，并进行大规模测试局部晚期和转移性 PDAC 患者的随机临床试验。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preclinical mouse models for immunotherapeutic and non-immunotherapeutic drug development for pancreatic ductal adenocarcinoma.

DOI：
10.21037/apc.2020.03.03
发表时间：
2020-07-01
期刊：
Annals of pancreatic cancer
影响因子：
0
作者：
He, Mengni;Henderson, MacKenzie;Zheng, Lei
通讯作者：
Zheng, Lei

Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.

DOI：
10.18632/oncotarget.17237
发表时间：
2017-07-04
期刊：
Oncotarget
影响因子：
0
作者：
Yarchoan M;Myzak MC;Johnson BA 3rd;De Jesus-Acosta A;Le DT;Jaffee EM;Azad NS;Donehower RC;Zheng L;Oberstein PE;Fine RL;Laheru DA;Goggins M
通讯作者：
Goggins M

Cancer-cell-derived sialylated IgG as a novel biomarker for predicting poor pathological response to neoadjuvant therapy and prognosis in pancreatic cancer.