Tumor-Selective Oncolytic Vaccinia Virus and alphaDC1-Based Vaccine as a Combinat
肿瘤选择性溶瘤痘苗病毒和基于 alphaDC1 的疫苗作为组合
基本信息
- 批准号:8518923
- 负责人:
- 金额:$ 2.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-05 至
- 项目状态:未结题
- 来源:
- 关键词:AddressAdoptive Cell TransfersAdoptive TransferAnimal ModelAnimalsAnti-Inflammatory AgentsAnti-inflammatoryAntigensAutologousBindingBiodistributionBiological AssayBiopsy SpecimenC57BL/6 MouseCCL19 geneCCL22 geneCXCL11 geneCancer ModelCancer PatientCancer VaccinesCell MaturationCellsClinicalClinical ProtocolsClinical TrialsCoinCollaborationsColon CarcinomaColorectal CancerCombined Modality TherapyCytotoxic T-LymphocytesDataData AnalysesDendritic Cell VaccineDendritic CellsDevelopmentDoseEffector CellEngineeringEnvironmentEnzyme-Linked Immunosorbent AssayEragrostisGene ExpressionGenesGoalsHumanImageImmuneImmune responseImmunosuppressive AgentsImmunotherapyIndividualInfectionInfiltrationInflammatory InfiltrateInflammatory ResponseInjection of therapeutic agentInstructionInterferon-alphaLeadMalignant NeoplasmsMediatingMessenger RNAModelingMolecular ProfilingMusMutationNatural Killer CellsNatureNeoplasm MetastasisOncolyticOncolytic virusesPTGS2 genePaperPatientsPatternPhasePhase I Clinical TrialsPhysiologic pulsePositioning AttributePrincipal InvestigatorProcessProductionPropertyProteinsPublished CommentPublishingRANTESRandomizedRecombinantsRegimenRegulatory T-LymphocyteRelative (related person)Research PersonnelRoleRunningSerpinsSpecimenStaining methodStainsSuggestionT-LymphocyteTestingTh1 CellsTherapeuticTimeTime StudyToxic effectTransgenesTransgenic MiceTumor ImmunityTumor TissueVaccinationVaccinesVacciniaVaccinia virusVacciniumVertebral columnViralVirusWritinganticancer researchbasecancer cellcancer immunotherapycancer therapycelecoxibchemokineeffective therapyexperienceimprovedin vitro Assayin vivoinhibitor/antagonistinterestintravenous administrationmetastatic colorectalmolecular imagingneoplastic cellnovel strategiesoverexpressionpre-clinicalpreventprogramsresponsesafety testingtooltraffickingtumorvaccination strategyvector
项目摘要
Colorectal cancer is a relatively common malignancy with few curative options once metastases
develop. Among the new approaches under development for further treatment of colorectal cancer
patients are immunotherapy and oncolytic virotherapywhich show promising results in animal
models. A newly developed unique dendritic cell (DC) maturation process produces highly
activated DC's, coined aDC1. aDC1 vaccination has been particularly effective in animal models
and in human clinical trials at producing high levels of circulating Tc1/Th1 anti-tumor effector cells.
The next step in successful vaccination is to modify the tumor microenvironment to allow attraction
of these circulating effector cells into the tumor. We and others have found that the chemokine
milieu in the tumor microenvironment favors the attraction of Tc2/Th2 and Treg cells over Teff
(Th1/Tc1) cells. Circulating cytotoxic T cells fail to traffic to the tumor environment and mediate an
anti-tumor effect. Over the last 10 years, we have developed tumor-selective replicating
recombinant vaccinia viruses (W) that effectively target tumor after systemic delivery, spread
through the tumor, and express high levels of transgenes in the tumor environment. In this study,
we propose to investigate the effects W has on the chemokine milieu in the tumor
microenvironment, and investigate ways to improve the effects via mutation of immune relevant W
genes and expression of selective Th1/Tc1-attracting or Treg-attracting chemokines from the tumor-
targeted virus. The recombinant vaccinia serves two roles: as an oncolytic virus per se, and as a
vector to express the Teff-attracting chemokines in the tumor tissue. Our hypothesis is that the
combination of the two approaches would lead to a highly efficacious cancer therapy regimen for
colorectal cancer. Specifically, we have three aims. Aim 1 is to determine the profile of chemokine
expression and the composition of the inflammatory infiltrate in the tumor induced by recombinant,
tumor-selective W. Aim 2 is to study the ability of the most promising W from Aim1 to enhance
trafficking to the tumor of tumor-specific T cells derived from either adoptive cell transfer or aDC1
cancer vaccine, and to lead to improved anti-tumor response in combination therapy. And finally
aim 3 will be performing a phase I clinical trial testing the safety and efficacy of a combination of
aDC1 vaccination with systemic W administration in CRCpatients.
RELEVANCE (See instructions):
结直肠癌是一种相对常见的恶性肿瘤,一旦发生转移,
开发.在正在开发的进一步治疗结直肠癌的新方法中,
患者的免疫治疗和溶瘤病毒治疗在动物中显示出有希望的结果
模型一种新开发的独特的树突状细胞(DC)成熟过程产生高度的
激活了DC,称为DC 1 aDC 1疫苗接种在动物模型中特别有效
并在人体临床试验中产生高水平的循环Tc 1/Th 1抗肿瘤效应细胞。
成功接种疫苗的下一步是修改肿瘤微环境以允许吸引
这些循环效应细胞进入肿瘤。我们和其他人发现趋化因子
肿瘤微环境中的环境有利于Tc 2/Th 2和Treg细胞的吸引超过Teff
(Th1/Tc 1)细胞。循环的细胞毒性T细胞不能运输到肿瘤环境并介导肿瘤的发生。
抗肿瘤作用在过去的10年里,我们已经开发了肿瘤选择性复制
在全身递送后有效靶向肿瘤的重组牛痘病毒(W),
并在肿瘤环境中表达高水平的转基因。在本研究中,
我们建议研究W对肿瘤中趋化因子环境的影响,
微环境,并研究通过免疫相关W
来自肿瘤的选择性Th 1/Tc 1-吸引或Treg-吸引趋化因子的基因和表达-
目标病毒重组牛痘有两个作用:本身作为溶瘤病毒,和作为免疫抑制剂。
载体,以在肿瘤组织中表达吸引Tef的趋化因子。我们的假设是
这两种方法的组合将导致高度有效的癌症治疗方案,
结肠直肠癌具体来说,我们有三个目标。目的1:确定趋化因子的表达谱
表达和组成的炎性浸润在肿瘤中诱导的重组,
肿瘤选择性W.目的2是研究Aim 1中最有前途的W对增强
来源于过继细胞转移或aDC 1的肿瘤特异性T细胞向肿瘤的运输
癌症疫苗,并在联合治疗中导致改善的抗肿瘤反应。最后
目标3将进行一项I期临床试验,测试联合使用
CRC患者中aDC 1疫苗接种与全身W给药。
相关性(参见说明):
项目成果
期刊论文数量(0)
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DAVID L BARTLETT其他文献
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{{ truncateString('DAVID L BARTLETT', 18)}}的其他基金
Improving Vaccinia for Peritoneal Tumors: Enhanced Distribution & Immune Evasion
改善腹膜肿瘤痘苗:增强分布
- 批准号:
8469744 - 财政年份:2011
- 资助金额:
$ 2.29万 - 项目类别:
Improving Vaccinia for Peritoneal Tumors: Enhanced Distribution & Immune Evasion
改善腹膜肿瘤痘苗:增强分布
- 批准号:
8192269 - 财政年份:2011
- 资助金额:
$ 2.29万 - 项目类别:
Improving Vaccinia for Peritoneal Tumors: Enhanced Distribution & Immune Evasion
改善腹膜肿瘤痘苗:增强分布
- 批准号:
8876602 - 财政年份:2011
- 资助金额:
$ 2.29万 - 项目类别:
Improving Vaccinia for Peritoneal Tumors: Enhanced Distribution & Immune Evasion
改善腹膜肿瘤痘苗:增强分布
- 批准号:
8676470 - 财政年份:2011
- 资助金额:
$ 2.29万 - 项目类别:
Multimodality approach to hepatic colorectal metastases
肝结直肠转移的多学科治疗方法
- 批准号:
8457992 - 财政年份:2010
- 资助金额:
$ 2.29万 - 项目类别:
Multimodality approach to hepatic colorectal metastases
肝结直肠转移的多学科治疗方法
- 批准号:
7884722 - 财政年份:2010
- 资助金额:
$ 2.29万 - 项目类别:
Multimodality approach to hepatic colorectal metastases
肝结直肠转移的多学科治疗方法
- 批准号:
8653836 - 财政年份:2010
- 资助金额:
$ 2.29万 - 项目类别:
Multimodality approach to hepatic colorectal metastases
肝结直肠转移的多学科治疗方法
- 批准号:
8230780 - 财政年份:2010
- 资助金额:
$ 2.29万 - 项目类别:
Multimodality approach to hepatic colorectal metastases
肝结直肠转移的多学科治疗方法
- 批准号:
8076927 - 财政年份:2010
- 资助金额:
$ 2.29万 - 项目类别: