Recombinant Immunotherapy for Renal Cell Carcinoma

肾细胞癌的重组免疫疗法

基本信息

  • 批准号:
    7066641
  • 负责人:
  • 金额:
    $ 26.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-06-15 至 2009-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Although many agents induce apoptosis, they are commonly associated with side effects that compromise health. TRAIL (TNF-related apoptosis-inducing ligand)/Apo-2L is generating excitement because it induces apoptosis in a wide range of tumor cells but not in normal cells and tissues. Preclinical studies using systemic TRAIL/Apo-2L doses are safe and can suppress tumor growth in vivo. Large amounts of TRAIL/Apo-2L are, however, needed to inhibit tumor formation, primarily because of the short in vivo half-life of the protein. Therefore, an alternative means of delivery may increase the relative activity of TRAIL/Apo-2L such that larger, more established tumors can be eradicated as efficiently as smaller tumors. This year in the U.S. approximately 30,000 new cases of renal cell carcinoma (RCC) will be diagnosed and nearly 12,000 deaths are expected from RCC. Metastatic RCC carries a median survival of 8 months and almost 30% of RCC patients are diagnosed with advanced metastatic disease. Furthermore, RCC is highly resistant to chemotherapy, a possible consequence of its association with the multidrug-resistance P-glycoprotein. RCC is regarded as an immunogenic tumor, with many reports of spontaneous regression and evidence of tumor-specific immune responses being a strong indicator of the immunogenicity of RCC. Thus, immunotherapy is being intensely studied as a treatment for RCC. Unfortunately, the response rates have been poor and significant toxicity reported, limiting the use of immunotherapy in the treatment of RCC. Gene transfer therapy offers new alternatives in the treatment of RCC. Employment of non-replicative viral gene delivery systems is making it possible to administer genes directly into tumors in situ. Previously, we described the cytotoxic activity of recombinant TRAIL/Apo-2L protein against human RCC cell lines, and the development and testing of a recombinant, replication-deficient adenoviral vector encoding the human TRAIL gene (Ad5-TRAIL). Transfer of the TRAIL gene into human tumor cells in vitro and in vivo, using immunodeficient mice, led to the rapid production and expression of TRAIL/Apo-2L protein, and apoptotic death of the tumor cells. However, it remains unknown whether Ad5-TRAIL will inhibit tumor growth in immunocompetent animals, and if the Ad5-TRAIL-induced tumor cell death will activate systemic antitumor immunity. With this in mind, the proposed project will employ a novel adenoviral vector encoding the mouse TRAIL gene (Ad5-mTRAIL) combined with agents to boost systemic immune responses through augmenting antigen presentation and stimulating T cell expansion to develop unique approaches for the treatment of RCC. Specific Aims: (1) Investigate the ability of DC to present antigens derived from apoptotic Renca cells to stimulate antitumor immunity and analyze the effector cells and mechanism of tumor rejection; and (2) Examine the ability of Gelfoam R and depsipeptide (FR901228) to augment Ad5-mTRAIL infectivity and transgene expression, making Ad5-mTRAIL gene transfer therapy more potent.
描述(由申请人提供):虽然许多药物诱导细胞凋亡,但它们通常伴有危害健康的副作用。TRAIL (tnf相关的凋亡诱导配体)/Apo-2L引起兴奋,因为它在广泛的肿瘤细胞中诱导凋亡,而不是在正常细胞和组织中。在临床前研究中,使用全身TRAIL/Apo-2L剂量是安全的,并且可以抑制体内肿瘤的生长。然而,抑制肿瘤形成需要大量的TRAIL/Apo-2L,这主要是因为该蛋白在体内的半衰期很短。因此,另一种递送方式可能会增加TRAIL/Apo-2L的相对活性,从而更大、更成熟的肿瘤可以像更小的肿瘤一样被有效地根除。今年,美国将诊断出大约3万例肾细胞癌(RCC)新病例,预计将有近1.2万人死于肾细胞癌。转移性肾细胞癌的中位生存期为8个月,几乎30%的肾细胞癌患者被诊断为晚期转移性疾病。此外,RCC对化疗具有高度耐药性,这可能是其与多重耐药p糖蛋白相关的结果。RCC被认为是一种免疫原性肿瘤,许多自发消退的报道和肿瘤特异性免疫反应的证据是RCC免疫原性的有力指标。因此,免疫疗法作为一种治疗肾细胞癌的方法正在被广泛研究。不幸的是,反应率很低,并且报道了显著的毒性,限制了免疫疗法在RCC治疗中的应用。基因转移治疗为肾细胞癌的治疗提供了新的选择。非复制性病毒基因传递系统的应用使得将基因直接注入原位肿瘤成为可能。先前,我们描述了重组TRAIL/Apo-2L蛋白对人RCC细胞系的细胞毒活性,以及编码人TRAIL基因的重组复制缺陷腺病毒载体(Ad5-TRAIL)的开发和测试。利用免疫缺陷小鼠,在体外和体内将TRAIL基因转移到人肿瘤细胞中,导致TRAIL/Apo-2L蛋白的快速产生和表达,肿瘤细胞凋亡。然而,目前尚不清楚Ad5-TRAIL是否会抑制免疫能力强的动物的肿瘤生长,以及Ad5-TRAIL诱导的肿瘤细胞死亡是否会激活全身抗肿瘤免疫。考虑到这一点,拟议的项目将采用一种新的腺病毒载体编码小鼠TRAIL基因(Ad5-mTRAIL),结合药物通过增加抗原呈递和刺激T细胞扩增来促进全身免疫反应,以开发治疗RCC的独特方法。具体目的:(1)研究DC呈递Renca细胞凋亡抗原刺激抗肿瘤免疫的能力,分析肿瘤排斥反应的作用细胞和机制;(2)检测Gelfoam R和沉积肽(FR901228)增强Ad5-mTRAIL感染和转基因表达的能力,使Ad5-mTRAIL基因转移治疗更有效。

项目成果

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Thomas S Griffith其他文献

Apoptosis-inducing Ligand Cell-mediated Delivery of Tumor Necrosis Factor-related Induction of Glioblastoma Apoptosis Using Neural Stem Updated Version Cited Articles Citing Articles E-mail Alerts Induction of Glioblastoma Apoptosis Using Neural Stem Cell-mediated Delivery of Tumor Necrosis Factor-r
细胞凋亡诱导配体 细胞介导的肿瘤坏死因子相关传递 使用神经干诱导胶质母细胞瘤细胞凋亡 更新版本 被引文章 引用文章 电子邮件提醒 使用神经干细胞介导的肿瘤坏死因子-r 诱导胶质母细胞瘤凋亡
  • DOI:
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Moneeb Ehtesham;P. Kabos;M. Gutierrez;N. Chung;Thomas S Griffith;Keith L. Black;John S. Yu
  • 通讯作者:
    John S. Yu
EARLY MICRORECANALIZATION OF VAS DEFERENS AFTER IMPLANTATION OF BIODEGRADABLE GRAFTS IN RATS THAT PREVIOUSLY UNDERWENT BILATERAL VASECTOMY
  • DOI:
    10.1016/s0022-5347(08)61866-2
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Christopher M Simons;Barry R De Young;Thomas S Griffith;Timothy L Ratliff;Surya K Mallapragada;Moshe Wald
  • 通讯作者:
    Moshe Wald
ACTIVATION OF TUMOR-SPECIFIC CD8+ T CELLS AFTER INTRATUMORAL Ad5-TRAIL/CpG ODN COMBINATION THERAPY
  • DOI:
    10.1016/s0022-5347(08)60117-2
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Rebecca L VanOosten;Thomas S Griffith
  • 通讯作者:
    Thomas S Griffith
PHASE I TRIAL OF Ad5-TRAIL-MEDIATED GENE TRANSFER IN MEN WITH LOCALLY-CONFINED PROSTATE CANCER PRIOR TO PLANNED RADICAL PROSTATECTOMY
  • DOI:
    10.1016/s0022-5347(08)61160-x
  • 发表时间:
    2008-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Thomas S Griffith;Badrinath R Konety;Fadi N Joudi;Tammy Madsen;Barbara Ziegler;Michael B Cohen;Timothy L Ratliff;Richard D Williams
  • 通讯作者:
    Richard D Williams

Thomas S Griffith的其他文献

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{{ truncateString('Thomas S Griffith', 18)}}的其他基金

BLRD Research Career Scientist Award Application
BLRD 研究职业科学家奖申请
  • 批准号:
    10582394
  • 财政年份:
    2023
  • 资助金额:
    $ 26.57万
  • 项目类别:
Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology
综合使用基因组学、代谢组学和细胞因子分析来验证使用“脏”小鼠研究脓毒症病理生理学
  • 批准号:
    10257687
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
CD4 T cell dysfunction and reprogramming during sepsis
脓毒症期间 CD4 T 细胞功能障碍和重编程
  • 批准号:
    10633073
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
Exploiting microbial exposure to study the immune response to uropathogenic E. coli
利用微生物暴露研究对尿路致病性大肠杆菌的免疫反应
  • 批准号:
    10413143
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
Integrated use of genomics, metabolomics, and cytokine profiling to validate the use of 'dirty' mice to study sepsis pathophysiology
综合使用基因组学、代谢组学和细胞因子分析来验证使用“脏”小鼠研究脓毒症病理生理学
  • 批准号:
    10512750
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
Exploiting microbial exposure to study the immune response to uropathogenic E. coli
利用微生物暴露研究对尿路致病性大肠杆菌的免疫反应
  • 批准号:
    10237569
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
CD4 T cell dysfunction and reprogramming during sepsis
脓毒症期间 CD4 T 细胞功能障碍和重编程
  • 批准号:
    10400169
  • 财政年份:
    2021
  • 资助金额:
    $ 26.57万
  • 项目类别:
Alterations in CD4 T cells during sepsis
脓毒症期间 CD4 T 细胞的变化
  • 批准号:
    9101373
  • 财政年份:
    2016
  • 资助金额:
    $ 26.57万
  • 项目类别:
Impairment and recovery of CD4 T cell-dependent B cell responses after sepsis
脓毒症后 CD4 T 细胞依赖性 B 细胞反应的受损和恢复
  • 批准号:
    10084212
  • 财政年份:
    2012
  • 资助金额:
    $ 26.57万
  • 项目类别:
Suppression of T cell immunity during sepsis
败血症期间 T 细胞免疫的抑制
  • 批准号:
    8601255
  • 财政年份:
    2012
  • 资助金额:
    $ 26.57万
  • 项目类别:

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TP-R:人类肥胖相关胰岛素抵抗的新型介质
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TP-R:人类肥胖相关胰岛素抵抗的新型介质
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HDAC 底物特异性和抑制的结构基础
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揭示吡嗪酰胺与其他抗结核药物协同作用的起源
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肿瘤微环境中治疗性蛋白质合成的细胞生物工厂
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NAAA 疼痛和炎症抑制剂
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POMC 神经元鞘脂介导的葡萄糖和能量稳态失调
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