Lung Cancer Vaccine
肺癌疫苗
基本信息
- 批准号:10505679
- 负责人:
- 金额:$ 36.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdenocarcinomaAntigensAutologousBiopsyCancer ModelCancer VaccinesCarcinomaChestClinicalClinical TrialsCoculture TechniquesCollaborationsComputing MethodologiesCorrelative StudyCytotoxic T-LymphocytesDataDetectionDisease ProgressionExhibitsFemaleFrameshift MutationGenomicsGlassGoalsHumanImageImmuneImmune TargetingImmune checkpoint inhibitorImmunogeneticsImmunopreventionImmunosuppressionImpairmentInterceptInvestigationLesionLungLung AdenocarcinomaLung NeoplasmsLung noduleMHC Class I GenesMajor Histocompatibility ComplexMalignant neoplasm of lungMethodsModelingMolecularMusMutationMutation DetectionNatural HistoryNoduleNon-Small-Cell Lung CarcinomaOperative Surgical ProceduresOvaryPatientsPeptidesPhenotypePhysiologicalPlacentaPrevalencePreventionProcessProteinsRNARNA vaccineRegulatory T-LymphocyteResource SharingSolidSolid NeoplasmSourceT-LymphocyteTestingTestisTransgenic MiceTumor AntigensTumor ImmunityUncertaintyVaccinationVaccinesbasebiobankcancer immunotherapycheckpoint therapycohortcomputerizedcomputerized toolscytotoxiccytotoxic CD8 T cellsdensityefficacy testingexome sequencingexperienceimmune RNAimmunogenicimmunogenicityimprovedin vivoinsertion/deletion mutationinsightinterestlipid nanoparticlelung cancer screeninglung tumorigenesisminimally invasivemouse modelmulti-ethnicmutantnanoparticleneoantigen vaccinationneoantigensneoplasticnovelpre-clinicalpreclinical studypremalignantpreventprotein expressionscreening programsuccesstomographytranscriptomicstumortumor exometumor immunologytumor-immune system interactionsvaccine candidatevaccine developmentvaccine efficacyvaccine evaluation
项目摘要
PROJECT SUMMARY
Computerized chest tomography (CT) lung cancer screening programs have increased the detection of
premalignant non-solid (NS) nodules that harbor preinvasive or minimally invasive adenocarcinoma. Given that
NS nodules can progress to invasive adenocarcinoma (solid nodules), intercepting progression is considered an
urgent clinical priority. However, the cellular and molecular alterations that accompany disease progression are
poorly understood. NS nodules exhibit lower rates of HLA deletions than invasive/metastatic lung cancer, and
our integrated clinical and preclinical investigations have recently uncovered T cell-enriched immune
microenvironments, including elevated activated T regs in NS nodules. Global genomic analysis of NS nodules
identified high tumor-associated antigen (TAA) XAGE-1b and several HLA-restricted neoantigens. These
findings have led to the hypothesis that RNA-based vaccination against NS nodule-associated antigens and or
neoantigens can drive activation of T helper and cytotoxic CD8+ T cells while reducing tumor-infiltrating Tregs to
impair NS nodule progression to invasive adenocarcinoma.
We will test this hypothesis through two Specific Aims. Aim 1 will determine the potential of lipo-nanoparticle
RNA (LNP RNA) XAGE-1b vaccination in intercepting NS nodule progression in preclinical syngeneic models of
NSCLC. A state-of-the-art LNP-XAGE-1b RNA vaccine will be manufactured and optimized in collaboration with
the LNP-RNA shared resource facility. A novel physiologically relevant mouse model recapitulating the
progression of human NS nodules will be used to determine the efficacy of the XAGE-1b vaccine in intercepting
the progression of NSN to invasive carcinoma. Mechanisms associated with LNP RNA vaccine immune
interception will be elucidated with comprehensive immune profiling approaches. Aim 2 will delineate the most
immunogenic and cytotoxic patient lung NS nodule antigens and neoantigens identified in a multi-ethnic cohort
of clinically annotated NS nodules for vaccine payloads. Human class I MHC (HLA) transgenic mice will identify
the most immunogenic lung NSN vaccine cargo in vivo. Patient-specific tumoroid/autologous T-cell cocultures
and immunopeptidomics will be used to confirm immunogenicity and antigenic presentation on autologous
patient HLA. Finally, the cytotoxic potential of NS nodule patient neoantigen-specific T-cells against autologous
tumoroids will be used to rank neoantigens.
We expect to delineate the most immunogenic vaccine cargo together with informative correlative studies for
NCI PREVENT pre-IND vaccine development and NCI CP-NET LS immunoprevention clinical trials and provide
critical mechanistic insights into effective patient LNP RNA immune interception vaccines.
项目摘要
计算机化胸部断层扫描(CT)肺癌筛查计划增加了检测
具有前侵入性或微创腺癌的前固定性(NS)结节。鉴于
NS结节可以发展为浸润性腺癌(固体结节),截断的进展被认为是
紧急临床优先级。但是,伴随疾病进展的细胞和分子改变是
理解不佳。 NS结节比浸润性/转移性肺癌的HLA缺失率较低,并且
我们综合的临床和临床前研究最近发现了富含T细胞的免疫
微环境,包括NS结节中升高的激活的T regs。 NS结节的全球基因组分析
鉴定出高肿瘤相关的抗原(TAA)XAGE-1B和几种HLA限制的新抗原。这些
发现导致了以下假设:基于RNA的疫苗接种与NS结节相关的抗原和OR
新抗原可以驱动T助手和细胞毒性CD8+ T细胞的激活,同时将肿瘤浸润的Treg降低至
损害NS结节向浸润性腺癌的进展。
我们将通过两个具体目标检验这一假设。 AIM 1将确定Lipo-Nanoparpicle的潜力
RNA(LNP RNA)XAGE-1B疫苗接种在拦截NS结节进程中
NSCLC。最先进的LNP-XAGE-1B RNA疫苗将与
LNP-RNA共享资源设施。一种新型的生理相关小鼠模型,概括了
人NS结节的进展将用于确定Xage-1b疫苗拦截的功效
NSN向入侵癌的发展。与LNP RNA疫苗免疫相关的机制
截距将通过全面的免疫分析方法阐明。 AIM 2将最多描绘
免疫原性和细胞毒性患者肺NS结节抗原和新抗原在多族裔队列中鉴定
用于疫苗有效载荷的临床注释的NS结节。人类I类MHC(HLA)转基因小鼠将识别
体内最免疫原性的肺NSN疫苗货物。患者特异性瘤或自体T细胞共培养
免疫肽学将用于确认自体的免疫原性和抗原表现
患者HLA。最后,NS结节患者新抗原特异性T细胞对自体的细胞毒性潜力
瘤形成将用于对新抗原进行排名。
我们希望描述最免疫原性的疫苗货物以及信息丰富的相关研究
NCI预防疫苗前疫苗开发和NCI CP-NET LS免疫预防临床试验,并提供
对有效患者LNP RNA免疫截距疫苗的关键机理洞察力。
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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NASSER Khaled ALTORKI其他文献
NASSER Khaled ALTORKI的其他文献
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{{ truncateString('NASSER Khaled ALTORKI', 18)}}的其他基金
Immunoregulatory role of lung-resident club cell factors in lung cancer
肺驻留俱乐部细胞因子在肺癌中的免疫调节作用
- 批准号:
10587065 - 财政年份:2023
- 资助金额:
$ 36.26万 - 项目类别:
CAP-IT Center for LNP RNA Immunoprevention
CAP-IT LNP RNA 免疫预防中心
- 批准号:
10505675 - 财政年份:2022
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10251562 - 财政年份:2020
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10024065 - 财政年份:2019
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10465296 - 财政年份:2019
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10666525 - 财政年份:2019
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10117907 - 财政年份:2019
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10738024 - 财政年份:2019
- 资助金额:
$ 36.26万 - 项目类别:
Intercepting progression from pre-invasive to invasive lung adenocarcinoma
阻止从浸润前肺腺癌向浸润性肺腺癌的进展
- 批准号:
10532889 - 财政年份:2019
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$ 36.26万 - 项目类别:
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