Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses

了解和增强 T 细胞对高风险人乳头瘤病毒的反应

基本信息

  • 批准号:
    8458616
  • 负责人:
  • 金额:
    $ 46.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-07-01 至 2015-04-30
  • 项目状态:
    已结题

项目摘要

Cervical cancer is the second most common cancer among women worldwide, and the link between human papillomavirus (HPV) and the development of cervical cancer is well known. Despite the advent of early detection with Papanicolaou smears, cervical cancer is a major cause of morbidity and mortality in less developed nations. A prophylactic HPV vaccine is now available to prevent women from acquiring HPV infection, but it is not effective once HPV infection is established. Our long-term goal is to develop a therapeutic HPV vaccine that is effective in preventing cervical cancer caused by high-risk types of HPV in HPV-exposed individuals. We propose a novel combination of antigens and adjuvant. HPV-related transformation to a malignant phenotype is mediated by two gene products, E6 and E7, and their expression is required for maintenance of a transformed phenotype. Therefore, E6 and E7 proteins are candidate antigen sources for a therapeutic vaccine for women with HPV infection and/or squamous intraepithelial lesions (SILs). Our clinical study examining CD8 T-cell responses and spontaneous SIL regression showed that CD8 T-cell responses to HPV type 16 (HPV-16) E6 protein (particularly the central regions), but not the E7 protein, are significantly associated with regression of cervical lesions. Such protection appears to be crossreactive among all high-risk but not low-risk HPV types. Analogous studies are needed to assess whether CD4 T-cell responses to the E7 protein also have a role in SIL regression. We hypothesize that regions of HPV-16 E6 protein, and perhaps E7 protein, containing CD4 and CD8 T-cell epitopes associated with SIL regression are sources of effective antigens for a therapeutic HPV vaccine (antigens), and that Candida antigen, with anti-HPV effects inducing skin wart regression, is an effective adjuvant in enhancing vaccine immunogenicity (adjuvant). Our specific aims are to: (1a) identify regions within HPV-16 E6 and E7 proteins associated with cervical lesion regression and characterize the dominant CD4 T-cell epitopes; (1b) determine how Candida antigen may work to enhance immune response by examining interactions with pattern recognition receptors; (2) examine dosage and toxicity of the HPV peptide¿Candida vaccine; and (3) assure safety and examine immunogenicity and clinical responses to the candidate vaccine in a dose-escalation Phase I clinical trial. Successful completion of this project would lead to not only development of a novel therapeutic HPV vaccine for cervical cancer prevention, but also a novel adjuvant to enhance peptide vaccine immunogenicity, which can be applied to other cancers and infectious agents.
子宫颈癌是世界范围内妇女中第二大常见癌症, 乳头状瘤病毒(HPV)与宫颈癌的发展是众所周知的。尽管早期的 子宫颈癌是宫颈癌发病率和死亡率的主要原因, 发达国家。现在有一种预防性HPV疫苗可以预防女性感染HPV 感染,但一旦HPV感染建立,它就无效了。我们的长期目标是开发一种治疗 HPV疫苗可有效预防HPV暴露者中高危型HPV引起的宫颈癌 个体我们提出了一种新的抗原和佐剂的组合。HPV相关转化为 恶性表型由两种基因产物E6和E7介导,并且它们的表达是恶性表型所必需的。 转化表型的维持。因此,E6和E7蛋白是免疫应答的候选抗原来源。 HPV感染和/或鳞状上皮内病变(锡尔斯)女性的治疗性疫苗。我们的临床 检查CD 8 T细胞应答和自发性SIL消退的研究表明,CD 8 T细胞应答 HPV 16型(HPV-16)E6蛋白(特别是中心区域),而不是E7蛋白,与HPV-16的表达显著相关。 与宫颈病变的消退有关。这种保护似乎在所有高风险人群中产生交叉反应。 而不是低风险的HPV类型。需要类似的研究来评估CD 4 T细胞对E7的反应是否 蛋白质也在SIL消退中起作用。我们假设HPV-16 E6蛋白的区域,可能还有E7, 含有与SIL消退相关的CD 4和CD 8 T细胞表位的蛋白质是有效的来源 用于治疗性HPV疫苗的抗原(抗原),以及具有诱导抗HPV作用的念珠菌抗原 皮肤疣消退,是增强疫苗免疫原性的有效佐剂(佐剂)。我们的具体 目的是:(1a)鉴定HPV-16 E6和E7蛋白中与宫颈病变消退相关的区域 并表征占主导地位的CD 4 T细胞表位;(1b)确定念珠菌抗原如何增强 通过检查与模式识别受体的相互作用的免疫应答;(2)检查剂量和 HPV肽念珠菌疫苗的毒性;(3)确保安全性并检查免疫原性和临床 在剂量递增的I期临床试验中对候选疫苗的反应。成功完成本 该项目不仅将导致开发一种用于预防宫颈癌的新型治疗性HPV疫苗, 也是一种增强肽疫苗免疫原性的新型佐剂,可应用于其他癌症, 和传染性病原体。

项目成果

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Mayumi Nakagawa其他文献

Mayumi Nakagawa的其他文献

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{{ truncateString('Mayumi Nakagawa', 18)}}的其他基金

Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses-Renewal
了解和增强 T 细胞对高风险人乳头瘤病毒的反应 - 更新
  • 批准号:
    10306208
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses
了解和增强 T 细胞对高风险人乳头瘤病毒的反应
  • 批准号:
    8077943
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses
了解和增强 T 细胞对高风险人乳头瘤病毒的反应
  • 批准号:
    8657864
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses-Renewal
了解和增强 T 细胞对高风险人乳头瘤病毒的反应 - 更新
  • 批准号:
    10661537
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses
了解和增强 T 细胞对高风险人乳头瘤病毒的反应
  • 批准号:
    8249895
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to high Risk Human Papillomaviruses
了解和增强 T 细胞对高风险人乳头瘤病毒的反应
  • 批准号:
    7986855
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses-Renewal
了解和增强 T 细胞对高风险人乳头瘤病毒的反应 - 更新
  • 批准号:
    10415203
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
Understanding and Enhancing T-Cell Responses to High Risk Human Papillomaviruses
了解和增强 T 细胞对高风险人乳头瘤病毒的反应
  • 批准号:
    9036591
  • 财政年份:
    2010
  • 资助金额:
    $ 46.46万
  • 项目类别:
CYTOTOXIC T LYMPHOCYTE RESPONSE TO HPV 16
HPV 16 的细胞毒性 T 淋巴细胞反应
  • 批准号:
    6150274
  • 财政年份:
    1998
  • 资助金额:
    $ 46.46万
  • 项目类别:
CYTOTOXIC T LYMPHOCYTE RESPONSE TO HPV 16
HPV 16 的细胞毒性 T 淋巴细胞反应
  • 批准号:
    6497666
  • 财政年份:
    1998
  • 资助金额:
    $ 46.46万
  • 项目类别:

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