Integration of neo-antigen vaccines and immune checkpoint therapy

项目1摘要 免疫检查点抑制剂（ICI）在约20%的癌症患者中提供持久的临床反应， 但在缺乏肿瘤内T细胞的癌症中效果最小。将T细胞耗尽的癌症转化为 需要吸引高质量T细胞的细胞来使这些无反应的癌症对ICI敏感。大多数肿瘤 具有编码突变蛋白的体细胞突变，所述突变蛋白是肿瘤特异性的并且在正常细胞上不表达。 细胞（称为新抗原）。突变负担最高的癌症更有可能对单一的 ICI探员然而，包括胰腺癌（PDA）在内的大多数癌症具有较低的突变负荷， 导致较低的抗原性、较弱的内源性T细胞库和较少的T细胞浸润肿瘤。 PDA还具有由抑制性单核细胞组成的免疫抑制性肿瘤微环境（TME）， B细胞和T细胞，其表达T细胞抑制信号并在TME内排除T细胞或抑制T细胞。 然而，我们发表的数据显示，在基因工程KPC小鼠表达突变的癌蛋白， KRAS（mKRAS），当mKRAS疫苗接种时，可以预防癌前病变进展为PDA 与ICIs一起使用。最近，我们发表了表达约50种新抗原的小鼠Panc02模型， 类似于人PDA，由12种抗原的混合物组成的新抗原靶向肽疫苗（PancVAX 在佐剂中长时间乳化并与ICI一起给予的每种20个氨基酸的肽可以治疗携带PancO 2的肿瘤 小鼠因此，在本提案中，我们将测试肽疫苗靶向共享（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， 将可用于进一步被ICI激活并导致肿瘤排斥。我们将进行两个人类 临床试验（目的1和2），以测试靶向mKRAS和患者肿瘤特异性新抗原的疫苗， 分别与伊匹单抗和纳武单抗联合治疗切除和转移性PDA患者。移动 在目标3中，我们将进一步发展我们的新方法， 目前的数据来增强新抗原疫苗的免疫原性。我们新的初步数据显示 包含MHC II类表位增强了我们的鼠疫苗PancVAX的CD8+ T细胞应答， （其主要由MHC I类表位组成）。我们也会审问 免疫抑制性TME与靶向治疗，可能会重新编程肿瘤相关的 巨噬细胞和基质细胞与项目3和4合作。在所有情况下，我们将评估质量 通过与免疫调节剂组合的每种疫苗方法诱导的T细胞。这些研究将 为未来在项目3 PDA患者中进行测试的联合免疫治疗方法提供信息。

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.