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:
- 金额:$ 83.91万
- 依托单位:
- 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:
- 关键词:Activities of Daily LivingAdaptive Immune SystemAffinityAllograftingAntigen ReceptorsAntigensBiological ModelsCD8-Positive T-LymphocytesCD8B1 geneCancer BurdenCancer VaccinesCell membraneChildhoodChildhood Malignant Brain TumorChildhood Solid NeoplasmClinical TrialsCombined Modality TherapyCredentialingDataDendritic CellsDevelopmentDiseaseDisease remissionEngineeringEpigenetic ProcessEpitopesEvaluable DiseaseExhibitsFDA approvedGenerationsGenetic TranscriptionGenetically Engineered MouseGoalsGrantHLA AntigensHealthHumanImmune responseImmunizeImmunotherapeutic agentImmunotherapyIn VitroIncidenceIndividualInfiltrationInfrastructureLipidsMYCN geneMalignant Childhood NeoplasmMalignant NeoplasmsMethodsMissionMonoclonal AntibodiesMorbidity - disease rateMotivationMusMutationNeoplasm MetastasisNeuroblastomaOncogenicOncoproteinsOutcomePatient-Focused OutcomesPatientsPeptide VaccinesPeptidesPhenotypePolymersPreventionPrevention strategyPrincipal InvestigatorProliferatingProteinsPublic HealthPublishingRelapseResearchResidual NeoplasmResistanceSamplingSpecificitySpecimenSurvival RateSympathetic Nervous SystemSystemT cell responseT-Cell ReceptorTestingTherapeuticToxic effectTransgenic MiceTreatment EfficacyTumor Specific PeptideTumor-infiltrating immune cellsUnited States National Institutes of HealthVaccinesValidationadaptive immune responseadaptive immunitychimeric antigen receptorclinically relevantdensitydesigndisorder riskevidence baseexome sequencingexperiencehigh riskimmunogenicimmunogenicityimprovedimproved outcomeinnovationmouse modelnanoparticleneoantigensnovelnovel therapeutic interventionoverexpressionpre-clinicalpreclinical evaluationpredictive toolsproteogenomicsrelapse predictionrelapse preventionresponseself assemblysialogangliosidesstandard of caretranscriptome sequencingtumorvaccination strategyvaccine developmentvaccine evaluationvaccine formulationvaccine platformvaccine strategyvaccine 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.
项目摘要
这个多个主要研究者(MPI)的儿科免疫治疗网络项目提案的重点是
高风险神经母细胞瘤,一种多样的和神秘的恶性肿瘤,源于发展中的交感神经系统。
神经系统,尽管进行了密集的多模式治疗,但仍有50%的患者致命。目前迫切
开发新的治疗干预措施以降低复发率的需求未得到满足,
存活率,并减少与标准治疗相关的破坏性毒性。本项目的主要目标是
通过开发一种治疗神经母细胞瘤的药物,
针对个体化新抗原的个体化疫苗接种策略。核心假设是高风险
神经母细胞瘤,尽管肿瘤突变负荷(TMB)低,但具有足够数量的新表位,
典型和非典型突变,以鉴定、预测和验证要工程化的最佳新抗原肽
有效的多价个性化神经母细胞瘤疫苗。提出这项研究的动机是
迫切需要提高高风险患者的生存率并降低治疗相关的发病率
神经母细胞瘤事实上,大多数高危神经母细胞瘤患者在标准化疗后都能缓解。
治疗,在这里,我们寻求参与适应性免疫系统,以消除残留疾病,
复发我们将通过两个特定目的来测试我们的假设:1)定义高-
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,
认证我们的GEMM系统用于Aim 2的临床前疫苗接种试验。我们将使用一个整合的蛋白质基因组
该方法可以为每种个性化疫苗鉴定多达8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背景下的GEMM系统,然后将该疫苗平台与新的脂质肽进行比较
优化的聚合物疫苗系统将肽递送至树突细胞。该项目提出了一种创新的
实验策略,以确定,优先考虑,并验证新抗原在高风险神经母细胞瘤,和临床
用于神经母细胞瘤疫苗临床前评价的相关神经母细胞瘤GEMM系统。的意义
拟议的项目是创建和验证一种新的免疫方法,
通过提供持久的治疗和减少治疗,彻底改变高危神经母细胞瘤的护理标准-
相关疾病。该合作MPI项目的预期成果是建立临床前证明,
这是一个个性化的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
考虑到我们现有的基础设施该项目的成功完成还将使个性化
用于其他儿科恶性肿瘤的基于新抗原的疫苗开发。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JOHN M MARIS其他文献
JOHN M MARIS的其他文献
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{{ truncateString('JOHN M MARIS', 18)}}的其他基金
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10217467 - 财政年份:2018
- 资助金额:
$ 83.91万 - 项目类别:
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10578307 - 财政年份:2018
- 资助金额:
$ 83.91万 - 项目类别:
Discovery and Development of Optimal Immunotherapeutic Strategies for Childhood Cancers
儿童癌症最佳免疫治疗策略的发现和开发
- 批准号:
10578310 - 财政年份:2018
- 资助金额:
$ 83.91万 - 项目类别:
Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance
发现和利用神经母细胞瘤治疗耐药的机制
- 批准号:
9359221 - 财政年份:2017
- 资助金额:
$ 83.91万 - 项目类别:
Discovering and Exploiting Mechanisms of Neuroblastoma Therapy Resistance
发现和利用神经母细胞瘤治疗耐药的机制
- 批准号:
10265471 - 财政年份:2017
- 资助金额:
$ 83.91万 - 项目类别:
Discovering mechanisms of neuroblastoma tumorigenesis to improve patient outcomes
发现神经母细胞瘤肿瘤发生机制以改善患者预后
- 批准号:
9390172 - 财政年份:2017
- 资助金额:
$ 83.91万 - 项目类别:
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