Project 8 - TH17 Dendritic Cell Vaccine
项目8——TH17树突状细胞疫苗
基本信息
- 批准号:9149472
- 负责人:
- 金额:$ 28.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-09-01 至
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAnimal ModelAntigensBiological Response ModifiersBiostatistics CoreCD4 Positive T LymphocytesCD8B1 geneCancer EtiologyCancer PatientCancer RemissionCancer VaccinesCell MaturationCell physiologyCellsCessation of lifeCharacteristicsClinicClinicalClinical ResearchClinical TrialsCollaborationsCombined VaccinesCoupledCyclophosphamideCytotoxic T-LymphocytesDataDendritic Cell VaccineDendritic CellsDevelopmentDiseaseDisease remissionEmployee StrikesFOLR1 geneFailureFosteringGenerationsGenetic ModelsGoalsHelper-Inducer T-LymphocyteHumanIL2RA geneImmuneImmune responseImmune systemImmunityImmunosuppressionImmunosuppressive AgentsImmunotherapeutic agentImmunotherapyIndividualInfiltrationInterferon Type IIInterleukin-15Interleukin-17LeadLinkMAP Kinase GeneMAPK14 geneMalignant neoplasm of ovaryMemoryModelingMusMyelogenousMyeloid CellsNo Evidence of DiseaseOutcomeOvarianParalysedPathogenesisPathologicPatient-Focused OutcomesPatientsPeptidesPhasePhase I Clinical TrialsPhenotypePopulationPre-Clinical ModelProteinsRecurrenceRegulatory T-LymphocyteResistanceRoleSafetySignal TransductionStagingStem cellsSuppressor-Effector T-LymphocytesT cell responseT-LymphocyteTestingToxinTumor AntigensVaccinationVaccine DesignVaccinesWorkanergybasecancer immunotherapycell typechemotherapyconventional therapyimmunogenicityimprovedinhibitor/antagonistinnovationinsightinterestmeetingsmouse modelneoplastic cellnovelnovel strategiesovarian neoplasmoverexpressionpre-clinicalpreclinical efficacypreventprogramsresponsetherapeutic vaccinetraffickingtumortumor growthtumor microenvironmentvaccine developmentvaccine evaluationvaccine trial
项目摘要
PROJECT SUMMARY – Project 8
The host immune response to ovarian cancer (OvCa) has been repeatedly demonstrated and has a dramatic
association with survival; however, for the majority of patients, immune control of OvCa is temporary, and the
tumor cells persist, grow, and ultimately lead to patient death. We and others have shown that this ability of
OvCa to evade host immune responses is due in large part to the influence of regulatory T cells (Tregs) and
suppressive myeloid cells. Both Tregs and suppressive myeloid cells cause anergy of OvCa-reactive T helper
1 (Th1) and CD8 T cells. Tregs are induced not only during endogenous anti-OvCa immune responses, but
also in the context of anti-OvCa immunotherapies, thereby limiting efficacy. Multiple groups have made efforts
to target suppressor cells in OvCa using chemotherapy agents and toxins, but the effects of these agents are
transient and can also deplete beneficial cell types. In contrast, T helper 17 (Th17) cells have been
demonstrated to downregulate these suppressor cells while simultaneously promoting a proinflammatory
antigen-specific immune response. We have recently described a novel strategy of ex vivo DC maturation that
leads to a robust antigen-specific Th17 response. In a model of OvCa, mice treated with Th17-inducing DCs
demonstrated robust anti-OvCa Th17 immune responses, a dramatic reduction in Tregs, and durable OvCa
remissions. In addition to our studies demonstrating the promise of generating Th17 immune responses using
DCs matured ex vivo, we have also identified a novel OvCa antigen, the folate receptor alpha (FRα). This
protein is overexpressed on the vast majority of human (and mouse) OvCa tumors and is linked to worse
clinical outcomes. We have, therefore, identified antigenic peptides from FRα and completed a clinical study
testing these peptides in a therapeutic vaccine. Building on these results, we propose to 1) identify the
immune effectors underpinning the anti-tumor efficacy of Th17-inducing cancer vaccines, 2) determine whether
the induction of Th17 immune responses targeting ovarian cancer antigens will overcome local tumor immune
suppression by inhibiting Treg generation and modulating infiltrating myeloid cell function, and 3) perform a
phase 1 clinical trial to determine whether FRα-specific Th17 T cell responses can be safely generated in
OvCa patients following conventional therapy. Collectively, these aims will help elucidate the mechanisms by
which Th17-inducing DC vaccination suppresses tumor growth, and will provide an assessment of safety and
immunogenicity of this strategy for human OvCa patients, fostering the continuation of a Mayo SPORE
program of innovative immune-based approaches for preventing disease recurrence in OvCa.
项目摘要 - 项目8
宿主对卵巢癌(OVCA)的免疫反应已反复证明,并具有戏剧性
与生存相关;但是,对于大多数患者,OVCA的免疫控制是暂时的,并且
肿瘤细胞持续,生长并最终导致患者死亡。我们和其他人表明了这种能力
OVCA逃避宿主免疫反应在很大程度上归功于调节性T细胞(Tregs)和
抑制髓样细胞。 Tregs和抑制性髓样细胞都会引起OVCA反应T助手的反应
1(TH1)和CD8 T细胞。不仅在内源性抗抗反抗管免疫复杂期间诱导了Treg,而且还被诱导
同样在反抗抗乳液的免疫疗法的背景下,从而限制了效率。多个小组付出了努力
使用化学疗法剂和毒素靶向OVCA中的抑制细胞,但这些药物的作用是
瞬态,也可以有益细胞类型。相反,T辅助器17(Th17)细胞已经
证明可以下调这些抑制细胞,同时促进促炎性细胞
抗原特异性免疫反应。我们最近描述了一种新型的Ex Vivo DC成熟策略
导致强大的抗原特异性Th17响应。在OVCA模型中,用Th17诱导的DC处理的小鼠
表现出强大的抗抗抗菌Th17免疫反应,Treg的急剧减少和持久的OVCA
恢复。除我们的研究外,还证明了使用使用Th17免疫反应的希望
DCS成熟的离体,我们还确定了一种新型的OVCA抗原,叶酸受体α(FRα)。这
蛋白质在绝大多数人(和小鼠)OVCA肿瘤上过表达,并且与恶化有关
临床结果。因此,我们已经确定了来自FRα的抗原性胡椒剂并完成了临床研究
在治疗性疫苗中测试这些肽。在这些结果的基础上,我们建议1)确定
受Th17诱导癌症疫苗的抗肿瘤效率的免疫作用,2)确定是否是否确定是否是否
靶向卵巢癌抗原的Th17免疫反应的诱导将克服局部肿瘤免疫
通过抑制treg的产生并调节渗透髓样细胞功能,并执行抑制
第1阶段的临床试验,以确定是否可以在
常规治疗后的OVCA患者。总的来说,这些目标将有助于通过
Th17诱导的直流疫苗接种会抑制肿瘤的生长,并将评估安全性和
这种策略对人OVCA患者的免疫原性,促进了蛋黄酱的持续
创新的基于免疫的方法预防OVCA疾病复发的方法。
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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Keith L. Knutson其他文献
Keith L. Knutson的其他文献
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{{ truncateString('Keith L. Knutson', 18)}}的其他基金
Analysis of serum folate receptor and antibody level for ovarian cancer detection
卵巢癌检测血清叶酸受体及抗体水平分析
- 批准号:
7288266 - 财政年份:2006
- 资助金额:
$ 28.06万 - 项目类别:
Analysis of serum folate receptor and antibody level for ovarian cancer detection
卵巢癌检测血清叶酸受体及抗体水平分析
- 批准号:
7196223 - 财政年份:2006
- 资助金额:
$ 28.06万 - 项目类别:
HLA classl complex expression in breast cancer immunity
乳腺癌免疫中HLA classl复合物的表达
- 批准号:
7069061 - 财政年份:2005
- 资助金额:
$ 28.06万 - 项目类别:
HLA classl complex expression in breast cancer immunity
乳腺癌免疫中HLA classl复合物的表达
- 批准号:
7587413 - 财政年份:2005
- 资助金额:
$ 28.06万 - 项目类别:
HLA class l complex expression in breast cancer immunity
乳腺癌免疫中 HLA I 类复合物的表达
- 批准号:
7414086 - 财政年份:2005
- 资助金额:
$ 28.06万 - 项目类别:
HLA class l complex expression in breast cancer immunity
乳腺癌免疫中 HLA I 类复合物的表达
- 批准号:
7229604 - 财政年份:2005
- 资助金额:
$ 28.06万 - 项目类别:
HLA class l complex expression in breast cancer immunity
乳腺癌免疫中 HLA I 类复合物的表达
- 批准号:
6906817 - 财政年份:2005
- 资助金额:
$ 28.06万 - 项目类别:
Tumor rejection antigens induced via epitope spreading
通过表位扩散诱导肿瘤排斥抗原
- 批准号:
6725807 - 财政年份:2004
- 资助金额:
$ 28.06万 - 项目类别:
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