Personalized neuroblastoma vaccines

项目总结 这项针对儿科免疫治疗网络的多负责人研究(MPI)项目提案是重点 高危神经母细胞瘤，一种起源于发育中的交感神经的多种神秘的恶性肿瘤 尽管进行了密集的多模式治疗，但50%的患者仍有致命的神经系统。有一件急事 开发新的治疗干预措施以降低复发率的需求未得到满足，总体上增加 存活，并减少与标准治疗相关的破坏性毒性。该项目的主要目标是 为改善高危神经母细胞瘤患者的预后 针对个性化新抗原的个性化疫苗接种策略。中心假设是高风险 神经母细胞瘤，尽管肿瘤突变负荷(TMB)很低，但通过 用于识别、预测和验证最佳新抗原肽的正则和非正则突变 有效的多价个性化神经母细胞瘤疫苗。这项拟议研究的动机是 迫切需要提高高危患者的存活率和降低与治疗相关的发病率 神经母细胞瘤。事实上，大多数高危神经母细胞瘤患者达到了标准的缓解 治疗，在这里，我们寻求利用适应性免疫系统来根除残留病和预防 旧病复发。我们将通过两个具体的目标来检验我们的假设：1)定义高抗原的新图景。 风险神经母细胞瘤患者和基因工程小鼠模型(GEMM)肿瘤；2)开发和测试 易于翻译的个性化疫苗接种策略。在目标1中，我们都将提供概念验证， 由CD4+和CD8+表位组成的多价疫苗对每个高危患者都是可行的，而且 我们的GEMM系统用于AIM 2的临床前疫苗试验。我们将使用整合的蛋白质基因组学 为每个个性化疫苗识别最多八个免疫原肽的方法。在目标2中，我们将对两者进行测试 OUR自组装纳米多价肽疫苗的预防和治疗效果 GEMM系统在CB57BL/6的背景下，然后将该疫苗平台与一种新的脂多肽进行比较 优化的聚合物疫苗系统，可将多肽输送到树突状细胞。该项目提出了一种创新的 识别、优先和验证高危神经母细胞瘤中新抗原的实验策略，以及临床上的 相关神经母细胞瘤GEMM系统用于神经母细胞瘤疫苗的临床前评价。的重要意义。 拟议的项目是创建和验证一种新的免疫治疗方法，该方法具有潜在的 通过提供持久的治疗和减少治疗来彻底改变高危神经母细胞瘤的护理标准- 相关发病率。这个协作性MPI项目的预期结果是建立临床前证据 一项个性化神经母细胞瘤临床试验的概念，我们将寻求在这笔赠款的最后几年推出该试验 考虑到我们已经到位的基础设施。该项目的成功完成还将使个性化 基于新抗原的其他儿童恶性肿瘤疫苗的开发。

PROJECT SUMMARY This Multiple Principal Investigator (MPI) Project proposal for the Pediatric Immunotherapy Network is focused on high-risk neuroblastoma, a diverse and enigmatic malignancy arising from the developing sympathetic nervous system that remains lethal in 50% of patients despite intensive multi-modal therapy. There is an urgent unmet need for developing novel therapeutic interventions to decrease the incidence of relapse, increase overall survival, and reduce devastating toxicities associated with standard therapy. The primary goal of this Project is to achieve improved outcomes for patients with high-risk neuroblastoma through the development of a personalized vaccination strategy targeting individualized neoantigens. The central hypothesis is that high-risk neuroblastomas, despite a low tumor mutation burden (TMB), harbor a sufficient number of neoepitopes through canonical and non-canonical mutations to identify, predict, and validate optimal neoantigen peptides to engineer effective multivalent personalized neuroblastoma vaccines. The motivation for the proposed research is the urgent need to improve survival and to decrease treatment-related morbidities for patients with high-risk neuroblastoma. Indeed, the majority of high-risk neuroblastoma patients achieve a remission with standard therapy, and here we seek to engage the adaptive immune system to eradicate residual disease and prevent relapse. We will test our hypothesis through the two Specific Aims: 1) define the neoantigen landscape of high- risk neuroblastoma patient and genetically engineered mouse model (GEMM) tumors; 2) develop and test a readily translatable personalized vaccination strategy. In Aim 1 we will both provide the proof-of-concept that a multivalent vaccine consisting of both CD4+ and CD8+ epitopes is feasible for each high-risk patient and also credential our GEMM system for preclinical vaccination trials in Aim 2. We will use an integrative proteogenomic approach to identify up to eight immunogenic peptides for each personalized vaccine. In Aim 2, we will test both preventative and therapeutic efficacy of self-assembling nanoparticle multivalent peptide vaccines using our GEMM system on the CB57BL/6 background, and then compare this vaccine platform to a new lipid-peptide polymer vaccine system optimized to deliver peptides to dendritic cells. This Project proposes an innovative experimental strategy to identify, prioritize, and validate neoantigens in high-risk neuroblastoma, and a clinically relevant neuroblastoma GEMM system for preclinical evaluation of neuroblastoma vaccines. The significance of the proposed Project is the creation and validation of a novel immunotherapeutic approach that has the potential to revolutionize high-risk neuroblastoma standard of care by providing durable cures and decreased therapy- related morbidity. The expected outcome of this collaborative MPI Project is to establish the preclinical proof-of- concept for a personalized neuroblastoma clinical trial that we would seek to launch in the out years of this grant given the infrastructure we have in place. The successful completion of this Project will also enable personalized neoantigen-based vaccine development for other pediatric malignancies.