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”肿瘤。转换 PDAC进入免疫检查点抑制剂（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，和3）克服 肿瘤微环境（TME）中的免疫抑制信号。之前，我们证明了 胰腺癌GVAX可使PDAC肿瘤发炎，形成肿瘤内三级淋巴样 集料.诱导免疫检查点信号，如PD-L1/PD-1，并可能引发ICI的PDAC 治疗。这个概念随后在我们的可切除PDAC的新辅助临床试验研究中进行了测试 并得到了先前R 01奖项的支持。向GVAX中加入抗PD-1抗体（aPD 1）可以抵消T细胞增殖。 然而，细胞耗竭表型并没有增强效应T细胞（Teff）的“质量”，这是由于缺乏 增强颗粒酶B+ CD 8 + T细胞。然而，我们注意到，一个具有更高水平的PDAC子集 在用GVAX处理后，CD 137表达的人确实具有更高密度的颗粒酶B+ CD 8 + T细胞， aPD 1。其次，CD 11b+髓系细胞中IL 8的表达与肿瘤相关中性粒细胞 (TAN)较高的TAN密度与新辅助治疗后较短的生存期相关， GVAX和aPD 1。这些结果支持测试抗CD 137激动性抗体（aCD 137）和/或抗CD 137激动性抗体（aCD 137）与抗CD 137激动性抗体（aCD 137）结合的假设。 抗IL 8抗体（aIL 8）增强Teff功能并克服PDAC中的免疫抑制性TME。 因此，本项目将检验这一假设，即增加的“数量”和更高的“质量”Teff是诱导的，重新- 在PDAC中，通过疫苗、aPD 1拮抗剂和aCD 137激动剂的三联组合进行扩增和活化。 为此，在之前R 01资助的新辅助治疗临床试验中增加了第三组， 可切除PDAC的试验平台。使用PDAC的小鼠模型，我们将进一步测试以下假设： aCD 137激动剂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 假设抑制TAN的贩运将克服高“量”和高“质”的障碍， TEFF在PDAC中的运输和功能。为此，新辅助治疗平台将增加两个新组 临床试验，以分别测试aIL 8和纳武单抗与和不与GVAX的组合。特别是，我们 将检验CD 137 +PD-1+ T细胞显著更大的浸润和PD-1 + T细胞扩增增强的假设。 通过纳武单抗和aIL 8的组合诱导表达颗粒酶B的CD 8 + T细胞克隆。这些发现 本研究的结果将直接告知在大规模试验中测试的免疫治疗组合的合理设计。 在局部晚期和转移性PDAC患者中进行的随机临床试验。

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.