Integration of neo-antigen vaccines and immune checkpoint therapy

项目1摘要 免疫检查点抑制剂(ICIS)在大约20%的癌症患者中提供了持久的临床反应， 但在缺乏肿瘤内T细胞的癌症中效果甚微。将T细胞耗竭的癌症转化为 需要吸引高质量T细胞的细胞才能使这些对ICIS不敏感的癌症变得敏感。大多数肿瘤 具有编码突变蛋白的体细胞突变，这些突变蛋白是肿瘤特异性的，在正常情况下不表达 细胞(称为新抗原)。具有最高突变负担的癌症更有可能对单个 ICIS探员。然而，大多数癌症，包括胰腺癌(PDA)，突变负荷较低， 导致抗原性较低，内源性T细胞谱系较弱，以及较少的T细胞渗入肿瘤。 PDA还具有由抑制单核细胞组成的免疫抑制肿瘤微环境(TME)， 表达T细胞抑制信号并在TME内排除或抑制T细胞的B细胞和T细胞。 然而，我们发表的数据显示，在基因工程KPC小鼠中表达突变的癌蛋白 KRAS(MKRAS)，当接种mKRAS疫苗时，癌前病变可以防止进展到PDA 是与ICIS一起提供的。最近，我们在小鼠Panc02模型中发表了大约50个新抗原的表达 与人类PDA类似，一种新抗原靶向多肽疫苗(PancVAX)由12种 每20个氨基酸的多肽在佐剂中长期乳化并与ICIS一起给药，可以治疗PancO2肿瘤 老鼠。因此，在本提案中，我们将测试针对共享(MKRAS)或 个性化的新抗原将触发高质量的新抗原特异性效应和效应记忆T细胞， 将变得可供ICIS进一步激活并导致肿瘤排斥。我们将指挥两名人类 临床试验(目标1和目标2)以测试针对mKRAS和患者肿瘤特异性新抗原的疫苗 联合应用ipilimumab和nivolumab治疗PDA切除和转移患者。搬家 从床边到替补席，在目标3中，我们将进一步发展我们的新方法，这些方法来自于我们的 提高新抗原疫苗免疫原性的最新数据。我们新的初步数据显示 MHCⅡ类表位的加入增强了我们的小鼠疫苗PancVAX的CD8+T细胞应答 (主要由MHC第I类表位组成)。我们还将审问其他人 免疫抑制的TME和靶向治疗，可能会重新编程肿瘤相关 巨噬细胞和基质细胞与项目3和4合作。在所有情况下，我们都将评估质量 每种疫苗方法结合免疫调节剂诱导的T细胞。这些研究将 为未来的联合免疫治疗方法提供信息，用于项目3 PDA患者的测试。

Project 1 Summary Immune-checkpoint inhibitors (ICIs) are providing durable clinical responses in about 20% of cancer patients, but have minimal effect in cancers lacking intra-tumoral T cells. Approaches that turn T cell deplete cancers into ones that attract high quality T cells are needed to sensitize these unresponsive cancers to ICIs. Most tumors have somatic mutations that encode for mutant proteins that are tumor–specific and not expressed on normal cells (termed neoantigens). Cancers with the highest mutational burdens are more likely to respond to single agent ICIs. However, most cancers, including pancreatic adenocarcinoma (PDA) have lower mutational loads, resulting in lower antigenicity, weaker endogenous T cell repertoires, and fewer T cells infiltrating the tumor. PDAs also have an immunosuppressive tumor microenvironment (TME) consisting of suppressive monocytes, B cells and T cells that express T cell inhibitory signals and exclude T cells or suppress them within the TME. However, we published data showing in genetically–engineered KPC mice expressing the oncoprotein mutated KRAS (mKRAS), that premalignant lesions can be prevented from progressing to PDA when a mKRAS vaccine is given with ICIs. More recently, we published in the murine Panc02 model that expresses about 50 neoantigens similar to human PDA, that a neoantigen targeted peptide vaccine (PancVAX) consisting of a mixture of 12 peptides each 20 amino acids long emulsed in adjuvant and given with ICIs, can treat PancO2 tumor-bearing mice. Thus, in this proposal we will test the hypothesis that peptide vaccines targeting shared (mKRAS) or personalized neoantigens will trigger high quality neoantigen–specific effector and effector memory T cells, which will become available for further activation by ICIs and result in tumor rejection. We will conduct two human clinical trials (Aims 1 and 2) to test vaccines targeting mKRAS and patient–tumor–specific neoantigens in combination with ipilimumab and nivolumab in patients with resected and metastatic PDA, respectively. Moving from the bedside back to the bench, in Aim 3, we will further develop our novel approaches arising from our current data to enhance the immunogenicity of the neoantigen vaccines. Our new preliminary data has shown that the inclusion of MHC Class II epitopes enhances CD8+ T cell response of our murine vaccine PancVAX (which is composed primarily of MHC Class I epitopes). We will also interrogate the otherwise immunosuppressive TME with targeted therapies that would potentially reprogram tumor-associated macrophages and stromal cells in collaboration with Projects 3 and 4. In all instances, we will assess the quality of T cells induced by each vaccine approach in combination with immune–modulatory agents. These studies will inform future combination immunotherapy approaches for testing in Project 3 patients with PDA.