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

胰腺导管腺癌(PDAC)是已知的免疫原性“冷”瘤。要转换 PDAC进入免疫检查点抑制物(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)增强效应器T细胞功能；3)克服 肿瘤微环境(TME)的免疫抑制信号。在此之前，我们演示了 胰腺癌GVAX可通过瘤内第三级淋巴组织的形成而使PDAC肿瘤炎症 集合体。免疫检查点信号如PD-L1/PD-1被诱导并潜在地为用于ICI的PDAC准备 治疗。这一概念随后在我们对可切除的PDAC进行的新辅助临床试验研究中进行了测试。 并得到了上一届R01奖的支持。在GVAX中加入抗PD-1抗体(APD1)可中和T 然而，细胞耗竭表型并没有提高效应器T细胞(Tef)的质量，这表明缺乏 增强颗粒酶B+CD8+T细胞。然而，我们注意到，具有更高级别的PDAC的子集 GVAX和GVAX治疗后CD137表达的T细胞中颗粒酶B+CD8+T细胞密度较高 APD1.第二，CD11b+髓系细胞中IL8的表达与肿瘤相关的中性粒细胞呈正相关 (TAN)和较高的TAN密度与新辅助治疗后较短的生存期有关 GVAX和aPD1。这些结果支持对抗CD137激动剂抗体(ACD137)和/或 抗IL8抗体(AIL8)可增强PDAC的Tef功能，克服免疫抑制的TME。 因此，这个项目将检验这样的假设，即增加的“数量”和更高的“质量”被诱导，重新- 通过疫苗、aPD1拮抗剂和aCD137激动剂的三重组合在PDAC中激活和激活。 为此，在之前的R01资助的新辅助临床中增加了具有这种三重组合的第三个手臂 可切除PDAC的试验平台。使用PDAC的小鼠模型，我们将进一步检验假设 CD137激动剂可扩增并增强新表位特异性T细胞的功能。接下来，这个项目将测试 限制制革交易将克服高“量”和高“质”障碍的假说 TEFS在PDAC中的贩运和功能。为此，将在新佐剂平台上增加两个新的手臂 临床试验，分别测试aIL8和nivolumab与GVAX和不使用GVAX的组合。特别是，我们 将检验这一假设，即CD137+PD-1+T细胞的显著渗透和增强的扩增 表达颗粒酶B的CD8+T细胞克隆是由nivolumab和aIL8联合诱导的。调查结果 这项研究将直接为免疫疗法组合的合理设计提供信息，并进行大规模试验 局部晚期和转移性PDAC患者的随机临床试验。

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.