P5 - P-53-Based Vaccine for Small Cell Lung Cancer
P5 - P-53-Based Vaccine for Small Cell Lung Cancer
批准号:
8380101
负责人:
Dmitry I Gabrilovich
金额:
$40.0万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
已结题
起止时间:
至 2014-08-31
关键词:
AdenovirusesAntigensCancer PatientCancer VaccinesCarboplatinClinicalClinical TrialsClinical Trials DesignDataDendritic Cell VaccineDendritic CellsDendritic cell activationDependenceDisease ProgressionEnrollmentEpitopesEtoposideEvaluationExtensive StageFrequenciesImmuneImmune responseImmunityImmunizationImmunosuppressive AgentsImmunotherapyMaintenanceMalignant neoplasm of lungMutationMyeloid CellsNormal CellOutcomePaclitaxelPatientsPhasePhase II Clinical TrialsProcessProtein p53ProteinsRandomizedRegulatory T-LymphocyteReportingT cell responseTP53 geneTestingTimeTranslatingTretinoinTumor AntigensVaccinationVaccinesVariantarmbasecancer immunotherapycancer therapychemotherapycohortdesignimprovedlung small cell carcinomamutantneoplastic cellnovel vaccinesoverexpressionpre-clinicalresearch studyresponsesafety testingstandard of caretumor
中文摘要
广泛期小细胞肺癌(SCLC)是一种无法治愈的侵袭性肺癌。SCLC经常
与p53基因突变相关,通常导致肿瘤细胞中p53过表达。这种过表达
产生形成肿瘤特异性细胞免疫疗法的基础的多种抗原表位。依赖性
肿瘤细胞在异常p53上存活使这种蛋白质成为癌症免疫疗法的"理想"候选物。
由于其独特的功能,树突状细胞(DC)是肿瘤抗原(Ag)的最佳载体。我们
已经开发了一种基于使用腺病毒构建体用野生型p53转导DC的新疫苗。这
疫苗在临床前实验中证明了效力。基于这些观察结果,我们进行了I/II阶段
临床试验旨在测试Ad.p53-DC疫苗在广泛期患者中的安全性和有效性
SCLC。疫苗本身是安全的,并在两名患者中产生了主要的肿瘤反应。P53特异性T细胞应答
是由疫苗引起的。.我们的数据表明,对于那些没有
对疫苗接种产生免疫反应,缺乏免疫反应与
未成熟骨髓细胞(ImC)的积累,先前显示是免疫抑制性的。但主要
试验的结果是,在接受化疗的患者中,
疫苗接种后立即进行化疗。这些观察结果是完全出乎意料的,因为现有的范式
表明化疗对免疫反应的效力是有害的。在过去的8个月里,四组
包括我们的研究,几乎同时报告了在不同队列的患者中的类似观察结果,
疫苗和化疗药物。这表明了癌症治疗的一个可能的新方向,
直接顺序的免疫治疗和化疗可能会提供实质性的临床益处。所有以前的审判
包括我们的设计都不是为了评估这个范例。我们认为,这一问题对以下方面至关重要:
整个领域,值得进行明确的测试。因此,我们建议测试以下假设:(1)
Ad.p53-DC疫苗和随后的化疗的组合将导致在免疫应答方面的实质性改善。
p53-DC疫苗中加入全反式视黄酸(ATRA),
改善p53特异性免疫应答,从而改善SCLC患者的临床应答。拟议项目已
两个具体目标。
具体目标1。确定广泛期患者对Adv-p53 DC疫苗的临床应答
SCLC,疫苗接种后给予化疗是否更有效,全反式维甲酸是否增强了这一点
反应
具体目标2。确定免疫和化疗对p53特异性
免疫力
英文摘要
Extensive stage small cell lung cancer (SCLC) is an incurable, aggressive form of lung cancer. SCLC is frequently
associated with mutations in the p53 gene that often result in p53 overexpression in tumor cells. This overexpression
produces a variety of antigenic epitopes that form the basis for tumor specific cellular immunotherapy. Dependence of
tumor cells on abnormal p53 for their survival makes this protein an "ideal" candidate for cancer immunotherapy.
Because of their unique features, dendritic cells (DC) are the best vehicles for delivery of tumor antigens (Ags). We
have developed a new vaccine based on transduction of DC with wild-type p53 using an adenoviral construct. This
vaccine demonstrated potency in pre-clinical experiments. Based on those observations we performed a phase l/ll
clinical trial designed to test the safety and efficacy of the Ad.p53-DC vaccine in patients who have extensive stage
SCLC. The vaccine itself was safe, and produced major tumor responses in two patients. P53-specific T cell responses
were induced by the vaccine in half of the treated patients. . Our data demonstrated that for those patients who did not
develop an immunological response to vaccination, the lack of immune response was closely associated with
accumulation of immature myeloid cells (ImC), previously shown to be immunosuppressive. However, the main
findings from the trial were an unusually high frequency of major objective tumor regressions in patients treated with
chemotherapy immediately after the vaccine. These observations were quite unexpected since the existing paradigm
suggests that chemotherapy is detrimental to the efficacy of an immune response. During last 8 months, four groups
including ours nearly simultaneously reported similar observations in different cohorts of patients treated with different
vaccines and chemotherapeutics. This suggests a possible new direction in cancer treatment where the combination of
immunotherapy and chemotherapy in direct sequence may provide substantial clinical benefits. All previous trials
including ours were not designed to evaluate this paradigm. We believe that this issue is of paramount significance for
the entire field and deserves definitive testing. Therefore we propose to test the following hypotheses: (1) the
combination of the Ad.p53-DC vaccine and subsequent chemotherapy will result in a substantial improvement in the
clinical response, and (2) the addition of all-trans-retinoic acid (ATRA) to the Ad.p53-DC vaccine may substantially
improve the p53-specific immune response and hence clinical response in SCLC patients. The proposed project has
two specific aims.
Specific Aim 1. Determine the clinical response to the Adv-p53 DC vaccine in patients with extensive stage
SCLC, whether chemotherapy given after the vaccine is more effective, and whether all-ATRA enhances this
response.
Specific Aim 2. Determine the immune modifying effect of immunization and chemotherapy on p53-specific
immunity.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Potentiating the Effects of Targeted and Cytotoxic Agents on Cell-Based Immunoth
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批准号:8556438
-
项目类别:
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资助金额:$22.81万
-
财政年份:2013
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Lipids and Myeloid Cell Function in Cancer
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批准号:8927544
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财政年份:2012
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Lipids and Myeloid Cell Function in Cancer
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批准号:8388187
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资助金额:$35.32万
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财政年份:2012
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负责人:Dmitry I Gabrilovich
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依托单位:
Lipids and Myeloid Cell Function in Cancer
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批准号:8531197
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项目类别:
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资助金额:$35.63万
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财政年份:2012
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负责人:Dmitry I Gabrilovich
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依托单位:
Molecular network regulating dendritic cell differentiation in cancer
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批准号:8209108
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项目类别:
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资助金额:$30.25万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
P5 - P-53-Based Vaccine for Small Cell Lung Cancer
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批准号:8118132
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项目类别:
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资助金额:$36.3万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
Molecular network regulating dendritic cell differentiation in cancer
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批准号:7898348
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项目类别:
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资助金额:$31.19万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
Molecular network regulating dendritic cell differentiation in cancer
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批准号:8042692
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项目类别:
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资助金额:$30.25万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
Molecular network regulating dendritic cell differentiation in cancer
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批准号:8606429
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项目类别:
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资助金额:$32.51万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
Molecular network regulating dendritic cell differentiation in cancer
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批准号:8658930
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项目类别:
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资助金额:$31.5万
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财政年份:2010
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负责人:Dmitry I Gabrilovich
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依托单位:
Conference on Regulatory Myeloid Cells in Health and Diseases
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批准号:7668871
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项目类别:
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资助金额:$0.6万
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财政年份:2009
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负责人:Dmitry I Gabrilovich
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依托单位:
Correction of dendritic cells defects in cancer
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批准号:7808090
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项目类别:
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资助金额:$50.85万
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财政年份:2009
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依托单位:
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批准号:7449124
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资助金额:$18.69万
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财政年份:2008
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负责人:Dmitry I Gabrilovich
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依托单位:
Role of lipids in dendritic cell function
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批准号:7259297
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项目类别:
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资助金额:$24.9万
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财政年份:2007
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负责人:Dmitry I Gabrilovich
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依托单位:
Role of lipids in dendritic cell function
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批准号:7498992
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项目类别:
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资助金额:$20.38万
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财政年份:2007
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负责人:Dmitry I Gabrilovich
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依托单位:
Conference on immune suppression in cancer
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批准号:7223281
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项目类别:
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资助金额:$0.8万
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财政年份:2007
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依托单位:
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批准号:7313951
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资助金额:$30.36万
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财政年份:2007
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依托单位:
Mechanism of dendritic cell differentiation in cancer
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批准号:7741760
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资助金额:$25.69万
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财政年份:2004
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负责人:Dmitry I Gabrilovich
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依托单位:
Mechanism of dendritic cell differentiation in cancer
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批准号:7226272
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项目类别:
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资助金额:$24.34万
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财政年份:2004
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负责人:Dmitry I Gabrilovich
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依托单位:
Mechanism of dendritic cell differentiation in cancer
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批准号:8240073
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项目类别:
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资助金额:$24.92万
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财政年份:2004
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负责人:Dmitry I Gabrilovich
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依托单位:
国内基金
海外基金
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批准号:2022J011295
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项目类别:省市级项目
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资助金额:10.0万元
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批准年份:2022
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依托单位:
结核分枝杆菌持续感染期抗原(latency antigens)的重组BCG疫苗研究
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批准号:30801055
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依托单位: