Targeting Neoantigens in Glioblastoma
靶向胶质母细胞瘤中的新抗原
基本信息
- 批准号:10240743
- 负责人:
- 金额:$ 46.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-15 至 2021-10-19
- 项目状态:已结题
- 来源:
- 关键词:Adaptive Immune SystemAddressAnatomyAntigen-Presenting CellsAntigensAreaBrainBrain NeoplasmsCD8B1 geneCancer VaccinesCellsCervicalClinicalClinical TrialsClinical trial protocol documentComputational BiologyConduct Clinical TrialsDendritic CellsDevelopmentDiagnosisEnrollmentEpitopesGap JunctionsGenomeGenomicsGlioblastomaGoalsHistocompatibilityImmuneImmune TargetingImmune responseImmune systemImmunobiologyImmunogenomicsImmunologicsImmunologyImmunooncologyImmunotherapeutic agentImmunotherapyInvestigationLinkLocationLymphMHC Class II GenesMalignant NeoplasmsMalignant neoplasm of brainMethodologyModelingMusMutationNeuraxisNewly DiagnosedNivolumabNormal CellOutcomePatientsPeptide VaccinesPhysiologic pulsePolyvalent VaccinePopulationPre-Clinical ModelProcessRecurrent tumorReporterRoleSomatic MutationT cell responseT-LymphocyteTestingTherapeuticTherapeutic EffectTreatment EfficacyTumor AntigensTumor ImmunityTumor-Infiltrating LymphocytesVaccinationVaccinesWorkXCR1 geneanti-CTLA4anti-PD-1anti-tumor immune responsebrain cellcancer genomecancer genomicscancer typedesigneffective therapyeffectiveness evaluationexperimental studygenome sequencingimmune checkpoint blockadeimmune resistanceimmunogenicityimprovedin vivoinsightipilimumabmutantneoantigen vaccinationneoantigen vaccineneoantigensneoplastic cellnovelpre-clinicalprogramsresponsestandard of caresuccesstargeted treatmenttherapeutic vaccinetraffickingtumortumor microenvironmentvaccine efficacyvaccine responsevaccine trial
项目摘要
PROJECT SUMMARY
This proposal focuses on targeting neoantigens in malignant brain tumors in well defined orthotopic, syngeneic
preclinical models, understanding how type 1 conventional dendritic cells (cDC1) prime neoantigens, and how
immune responses to neoantigens develop in newly diagnosed glioblastoma (GBM) patients enrolled in a
novel clinical trial combining personalized vaccination with checkpoint blockade. GBM remains a lethal cancer
and carries a median survival of 15 months with standard-of-care treatments, highlighting a clear need for
more effective treatments. The application of genomics to immunotherapeutic approaches is an exciting area
of investigation in many cancer types, and this proposal employs this methodology. This nexus, termed “cancer
immunogenomics”, is used to identify tumor-specific somatic mutations that may be processed and presented
on major histocompatibility molecules. These “neoantigens” can be recognized by the immune system and
form the basis for anti-tumor immune responses. We have applied the cancer immunogenomics approach to
the study of GBM both in preclinical models as well as in a novel personalized immuno-oncology cancer
vaccine program for GBM patients. However, in order to fully exploit the potential of targeting neoantigens in
GBM, further work is needed to understand whether targeting multiple neoantigen targets using polyvalent
vaccines can improve tumor control and how neoantigens are presented to the immune system in brain
cancers. How antigen is presented in the central nervous system remains unclear, and understanding the
immunobiology of this process is inextricably linked to effective neoantigen targeting. In parallel, it is critical to
determine how anti-tumor immunity is amplified in patients treated with personalized cancer vaccines in
combination with immunopotentiating checkpoint blockade therapies. To this end, we are applying cancer
immunogenomics preclinically and translationally to address these key questions. In Aim 1, we will determine
the effectiveness of polyvlalent neoantigen vaccination targeting MHC class and and/or MHC class II
neoantigens on survival and the immunologic effects of these vaccines on the brain tumor microenvironment.
In Aim 2, we will test the hypothesis that cDC1 present neoantigen in vivo and can augment the efficacy of
neoantigen-targeting vaccines. We will also further characterize the anatomic location of this critical cell
population during the anti-tumor immune response. In Aim 3, we will perform correlative analysis of a novel
clinical trial we are conducting to determine whether checkpoint blockade agents augment the immune
responses generated with personalized vaccines and whether the genomes of recurrent tumors that progress
on this trial are remodeled and/or show evidence of neoantigen specific cancer immunoediting. Together,
these Aims will provide new insights into an immunogenomics-centered approach to treating GBM as well as
the immunobiology of neoantigen presenation and T cell specific immune priming that has clear and imperative
clinical implications.
项目摘要
该建议的重点是在明确的原位,同源基因靶向恶性脑肿瘤中的新抗原。
临床前模型,了解1型常规树突状细胞(cDC 1)如何引发新抗原,以及如何
新诊断的胶质母细胞瘤(GBM)患者对新抗原产生免疫应答,
结合个性化疫苗接种和检查点封锁的新型临床试验。GBM仍然是一种致命的癌症
标准治疗的中位生存期为15个月,突出了对以下方面的明确需求:
更有效的治疗。基因组学在免疫学方法中的应用是一个令人兴奋的领域
在许多癌症类型的研究中,这项建议采用了这种方法。这种关系被称为“癌症
免疫基因组学”用于鉴定可被加工和呈递的肿瘤特异性体细胞突变
主要组织相容性分子这些“新抗原”可以被免疫系统识别,
形成抗肿瘤免疫应答的基础。我们已经将癌症免疫基因组学方法应用于
在临床前模型以及新型个性化免疫肿瘤学癌症中研究GBM
GBM患者的疫苗计划。然而,为了充分利用靶向新生抗原的潜力,
GBM,需要进一步的工作来了解是否使用多价靶向多种新抗原靶点
疫苗可以改善肿瘤控制以及新抗原如何呈递给大脑中的免疫系统
癌的抗原如何在中枢神经系统中呈递尚不清楚,了解中枢神经系统中抗原的表达,
该过程的免疫生物学与有效的新抗原靶向密不可分。与此同时,
确定抗肿瘤免疫如何在接受个性化癌症疫苗治疗的患者中被放大,
联合免疫增强检查点阻断疗法。为此,我们将癌症
免疫基因组学的临床前和预防来解决这些关键问题。在目标1中,我们将确定
靶向MHC类和/或MHC II类的多价新抗原疫苗接种的有效性
新抗原对存活的影响以及这些疫苗对脑肿瘤微环境的免疫学作用。
在目的2中,我们将检验cDC 1在体内呈递新抗原并且可以增强免疫调节剂的功效的假设。
新抗原靶向疫苗。我们还将进一步描述这个关键细胞的解剖位置
在抗肿瘤免疫应答期间,在目标3中,我们将对一部小说进行相关分析
我们正在进行一项临床试验,以确定检查点阻断剂是否能增强免疫力。
个体化疫苗产生的反应,以及复发肿瘤的基因组是否进展
在该试验中被重塑和/或显示新抗原特异性癌症免疫编辑的证据。我们一起努力,
这些目标将为以免疫基因组学为中心的治疗GBM的方法提供新的见解,
新抗原呈递和T细胞特异性免疫引发的免疫生物学具有明确和必要的
临床意义
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Gavin Peter Dunn其他文献
Gavin Peter Dunn的其他文献
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