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

• 批准号: 10407582
• 负责人: ELIZABETH M. JAFFEE
• 金额: $ 55.69万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/10407582
• 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; Eragrostis; 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; Randomized Clinical Trials; Regulatory T-Lymphocyte; Resectable; Resected; Resistance; Serum; Signal Transduction; Specimen; 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; base; 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; rational design; resistance mechanism; response; single cell analysis; single-cell RNA sequencing; trafficking; tumor; tumor microenvironment; tumor-immune system interactions

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.

已知胰腺导管腺癌（PDAC）在“冷”肿瘤上已知。转换 PDAC进入免疫粘液抑制剂（ICI）反应性肿瘤，有效的免疫疗法策略是 至少需要：1）增加抗原性； 2）增强效应子T细胞功能，3）克服 肿瘤微环境（TME）中的免疫抑制信号。以前，我们证明了 胰腺癌GVAX会与形成肿瘤内淋巴样形成PDAC肿瘤 聚合。诱导ICI的免疫检查点信号，例如PD-L1/PD-1，并有可能引发PDAC 治疗。随后在我们的Neoadjuvant临床试验研究中对该概念进行了测试。 并得到了先前的R01奖的支持。在GVAX中添加抗PD-1抗体（APD1）可以抵消T 然而，细胞耗尽表型并未增强效应细胞（TEFF）“质量”，如缺乏所示 增强的颗粒B+ CD8+ T细胞。尽管如此，我们注意到一个具有更高级别的PDAC子集 用GVAX和GVAX和 APD1。其次，CD11b+髓样细胞中的IL8表达与肿瘤相关的中性粒细胞正相关 （棕褐色）和较高的棕褐色密度与新辅助治疗后较短的生存有关 GVAX和APD1。这些结果支持检验抗CD137激动剂抗体（ACD137）和/或 抗IL8抗体（AIL8）增强了TEFF功能，并克服了PDAC中的免疫抑制性TME。 这是该项目将检验以下假设，即增加“数量”和更高的“质量” TEFF是被诱导的，重新的 通过疫苗，APD1拮抗剂和ACD137激动剂的三组合在PDAC中激活并激活PDAC。 为此，将具有三重组合的第三臂添加到了先前的R01资助的新辅助临床上 可切除PDAC的试用平台。使用PDAC的小鼠模型，我们将进一步检验以下假设。 ACD137激动剂扩展并增强了Neoeppitope特异性T细胞的功能。接下来，该项目将测试 抑制晒黑人口贩运的假设将克服高“数量”和高质量的障碍 Teffs在PDAC中运输和功能。为此，将在新辅助平台上添加两个新的武器 临床试验分别测试AIL8和Nivolumab分别在有和没有GVAX的情况下结合使用。特别是，我们 将检验以下假设，即CD137+ PD-1+ T细胞的浸润明显更大并增强了 表达颗粒酶B的CD8+ T细胞克隆是由Nivolumab和AIL8的组合诱导的。发现 从这项研究中，将直接告知免疫疗法组合的合理设计，以在大型中进行测试 局部晚期和转移性PDAC患者的随机临床试验。