SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA

人类黑色素瘤的特异性主动免疫治疗

基本信息

项目摘要

The goal of this proposal is to optimize specific active immunotherapy for melanoma. Towards that end, several aspects of the immunology of human melanoma will be studied, to determine the mechanisms by which some patients achieve excellent clinical remissions with a therapeutic vaccine ("theraccine"). Theraccine has caused remissions of metastatic melanoma in 20% of patients, with a median response of 17 mo, associated with a rise in precursors of cytotoxic T lymphocytes (pCTL). Modifications of theraccine, such as lysates of 8-methoxypsoralen-sensitized UV light-irradiated cells, lyophilized lysates, and membrane vesicles, will be assessed by clinical trials, monitored closely by in vitro immunological assays. Low-dose cyclophosphamide and interleukin-2 will be combined with theraccine to try to increase CTL generation and thus, clinical response rates. A randomized Phase III trial in early stage melanoma (lb-lll) will be conducted in an attempt to eradicate microscopic residual diseases. To improve and simplify immunological correlations, additional assays will be compared with our estimate of the frequency of pCTL, including a proliferation assay and an assay for "lytic units" of cytotoxicity. Leukocytes and cytokines present in regressing lesions will be detected by immunohistochemistry. The antigens recognized by CTL and the interaction of CTL with melanomas will be studied in several ways. Specificity of tumor-infiltrating lymphocytes (TIL) and CTL from peripheral blood will be analyzed by cold target competition assays with melanoma lines and histologically different tumors. CTL clones will be established, phenotyped for surface markers and T cell receptor chains, and their specificity examined by direct cytotoxicity and cold target competition. CD8+ "classical" CTL and the broadly reactive (CD4+ only?) CTL found after theraccine treatment will be compared. The melanoma peptides recognized by CTL clones will be identified after Western immunoblotting by proliferation and competition assays. Immunogenic peptides will then be sequenced. The importance of accessory molecules and major histocompatibility complex alleles, especially HLA-A2, in the interaction of CTL and melanomas will be studied by statistical correlations with response, and by sorting or blocking of cytotoxicity by monoclonal antibodies in vitro. T cell receptor genes of cloned CTL from the blood or tumor and of uncloned TIL from regressing lesions will be examined with antibodies to gene products and by the polymerase chain reaction. Limited use of V region genes unique to melanoma will be identified by subtractive hybridization: of normal melanocytes and melanoma cells, and of squamous lung carcinoma and melanoma. Immunogenicity of fusion proteins will be tested by proliferation, competition assays, and cytotoxicity assays with protein- treated non-melanoma cells. A preselected combination of highly immunogenic MAA from cDNA clones will constitute the ultimate version of the melanoma theraccine.
这项提案的目标是优化特定的主动免疫疗法 黑色素瘤。为此,人类免疫学的几个方面 将对黑色素瘤进行研究,以确定一些 患者通过治疗性疫苗获得极好的临床缓解 (“theaccine”)。Theraccine疫苗导致转移性黑色素瘤缓解 20%的患者,中位反应时间为17个月,与 细胞毒性T淋巴细胞前体(PCTL)。疫苗的改进, 例如8-甲氧基补骨脂素敏化的紫外光照射细胞的裂解物, 冷冻干燥的裂解物和膜囊泡将由临床进行评估 试验,通过体外免疫学检测进行密切监测。低剂量 环磷酰胺和白介素2将与疫苗联合尝试 以增加CTL的产生,从而提高临床应答率。一个随机化的 早期黑色素瘤的第三阶段试验(Lb-Lll)将在 试图根除微小的残留病。为了改善和 简化免疫学相关性,将比较其他检测方法 与我们对PCTL频率的估计,包括增殖分析 以及细胞毒性的“裂解单位”测定。白细胞与细胞因子 消退性皮损中的存在将通过免疫组织化学进行检测。 CTL识别的抗原及其与黑色素瘤的相互作用 将从几个方面进行研究。肿瘤浸润性的特异性 外周血中的淋巴细胞(TIL)和CTL将用冷冻法进行分析 与黑色素瘤株和组织学不同的靶点竞争分析 肿瘤。将建立CTL克隆,对表面标记和 T细胞受体链及其特异性的直接检测 细胞毒性和冷靶竞争。CD8+“经典”CTL和 广泛的反应性(仅限CD4+?)疫苗治疗后发现CTL将 比较一下。CTL克隆识别的黑色素瘤多肽将是 免疫印迹后通过增殖和竞争鉴定 化验。然后将对免疫原肽进行测序。重要的是 辅助分子和主要组织相容性复合体等位基因, 尤其是人类白细胞抗原-A2在CTL与黑色素瘤相互作用中的作用将被研究 通过与响应的统计相关性以及通过对 单抗的体外细胞毒作用。T细胞受体基因 从血液或肿瘤中克隆的CTL和退行性变的未克隆的TIL 将用基因产品的抗体和由 聚合酶链式反应。限制使用独有的V区基因 黑色素瘤将通过消减杂交进行鉴定:正常 黑素细胞和黑色素瘤细胞,以及鳞状肺癌和 黑色素瘤。将通过以下方法测试融合蛋白的免疫原性 增殖、竞争试验和细胞毒性试验与蛋白质- 经过处理的非黑色素瘤细胞。预选的高度组合 来自cDNA克隆的免疫原性MAA将构成终极版本的 黑色素瘤疫苗。

项目成果

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Malcolm Stuart Mitchell其他文献

Malcolm Stuart Mitchell的其他文献

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{{ truncateString('Malcolm Stuart Mitchell', 18)}}的其他基金

MELANOMA-ASSOCIATED EPITOPES RECOGNIZED BY HUMAN T-CELLS
人类 T 细胞识别的黑色素瘤相关表位
  • 批准号:
    2098582
  • 财政年份:
    1993
  • 资助金额:
    $ 23.89万
  • 项目类别:
MELANOMA-ASSOCIATED EPITOPES RECOGNIZED BY HUMAN T-CELLS
人类 T 细胞识别的黑色素瘤相关表位
  • 批准号:
    2098583
  • 财政年份:
    1993
  • 资助金额:
    $ 23.89万
  • 项目类别:
MELANOMA-ASSOCIATED EPITOPES RECOGNIZED BY HUMAN T-CELLS
人类 T 细胞识别的黑色素瘤相关表位
  • 批准号:
    3202180
  • 财政年份:
    1993
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173747
  • 财政年份:
    1988
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173746
  • 财政年份:
    1988
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173749
  • 财政年份:
    1988
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173739
  • 财政年份:
    1988
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUNOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173738
  • 财政年份:
    1988
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUMOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173743
  • 财政年份:
    1984
  • 资助金额:
    $ 23.89万
  • 项目类别:
SPECIFIC ACTIVE IMMUMOTHERAPY OF HUMAN MELANOMA
人类黑色素瘤的特异性主动免疫治疗
  • 批准号:
    3173742
  • 财政年份:
    1984
  • 资助金额:
    $ 23.89万
  • 项目类别:

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ROLE OF CD4/CD8 MOLECULE IN T CELL SPECIFICITY
CD4/CD8 分子在 T 细胞特异性中的作用
  • 批准号:
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  • 财政年份:
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  • 批准号:
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  • 项目类别:
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  • 批准号:
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  • 财政年份:
    1990
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