Personalized neuroblastoma vaccines

个性化神经母细胞瘤疫苗

基本信息

批准号：
10713548
负责人：
JOHN M MARIS
金额：
$ 83.91万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10713548
关键词：
Activities of Daily Living Adaptive Immune System Affinity Allografting Antigen Receptors Antigens Biological Models CD8-Positive T-Lymphocytes CD8B1 gene Cancer Burden Cancer Vaccines Cell membrane Childhood Childhood Malignant Brain Tumor Childhood Solid Neoplasm Clinical Trials Combined Modality Therapy Credentialing Data Dendritic Cells Development Disease Disease remission Engineering Epigenetic Process Epitopes Evaluable Disease Exhibits FDA approved Generations Genetic Transcription Genetically Engineered Mouse Goals Grant HLA Antigens Health Human Immune response Immunize Immunotherapeutic agent Immunotherapy In Vitro Incidence Individual Infiltration Infrastructure Lipids MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Methods Mission Monoclonal Antibodies Morbidity - disease rate Motivation Mus Mutation Neoplasm Metastasis Neuroblastoma Oncogenic Oncoproteins Outcome Patient-Focused Outcomes Patients Peptide Vaccines Peptides Phenotype Polymers Prevention Prevention strategy Principal Investigator Proliferating Proteins Public Health Publishing Relapse Research Residual Neoplasm Resistance Sampling Specificity Specimen Survival Rate Sympathetic Nervous System System T cell response T-Cell Receptor Testing Therapeutic Toxic effect Transgenic Mice Treatment Efficacy Tumor Specific Peptide Tumor-infiltrating immune cells United States National Institutes of Health Vaccines Validation adaptive immune response adaptive immunity chimeric antigen receptor clinically relevant density design disorder risk evidence base exome sequencing experience high risk immunogenic immunogenicity improved improved outcome innovation mouse model nanoparticle neoantigens novel novel therapeutic intervention overexpression pre-clinical preclinical evaluation predictive tools proteogenomics relapse prediction relapse prevention response self assembly sialogangliosides standard of care transcriptome sequencing tumor vaccination strategy vaccine development vaccine evaluation vaccine formulation vaccine platform vaccine strategy vaccine trial

项目摘要

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.

项目概要这个针对儿科免疫治疗网络的多位首席研究员 (MPI) 项目提案的重点是高危神经母细胞瘤是一种由发育中的交感神经系统引起的多样化且神秘的恶性肿瘤尽管进行了强化多模式治疗，但 50% 的患者的神经系统仍然是致命的。有紧急情况开发新的治疗干预措施以降低复发率、增加总体发病率的需求尚未得到满足生存，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通过开发一种药物来改善高危神经母细胞瘤患者的预后针对个体化新抗原的个体化疫苗接种策略。中心假设是高风险神经母细胞瘤尽管肿瘤突变负荷（TMB）较低，但通过典型和非典型突变，用于识别、预测和验证最佳新抗原肽以进行工程设计有效的多价个性化神经母细胞瘤疫苗。拟议研究的动机是迫切需要提高高危患者的生存率并减少与治疗相关的发病率成神经细胞瘤。事实上，大多数高危神经母细胞瘤患者都达到了标准缓解疗法，在这里我们寻求利用适应性免疫系统来根除残留疾病并预防复发。我们将通过两个具体目标来检验我们的假设：1）定义高抗原的新抗原景观神经母细胞瘤患者和基因工程小鼠模型（GEMM）肿瘤的风险； 2）开发并测试易于转化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于每个高危患者都是可行的，并且认证我们的 GEMM 系统用于目标 2 中的临床前疫苗接种试验。我们将使用综合蛋白质组学方法为每种个性化疫苗鉴定多达八种免疫原性肽。在目标 2 中，我们将测试两者使用我们的自组装纳米颗粒多价肽疫苗的预防和治疗功效 CB57BL/6背景上的GEMM系统，然后将该疫苗平台与新的脂肽进行比较经过优化的聚合物疫苗系统可将肽递送至树突状细胞。该项目提出了一种创新的识别、优先考虑和验证高危神经母细胞瘤中新抗原的实验策略，以及临床相关神经母细胞瘤GEMM系统用于神经母细胞瘤疫苗的临床前评估。意义拟议的项目是创建和验证一种具有潜力的新型免疫治疗方法通过提供持久的治疗和减少治疗来彻底改变高风险神经母细胞瘤的护理标准- 相关发病率。该 MPI 合作项目的预期成果是建立临床前证明- 我们将寻求在这笔拨款的最后几年启动个性化神经母细胞瘤临床试验的概念考虑到我们现有的基础设施。该项目的成功完成也将实现个性化针对其他儿科恶性肿瘤的基于新抗原的疫苗开发。