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
- 批准号:3173739
- 负责人:
- 金额:$ 23.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1988
- 资助国家:美国
- 起止时间:1988-03-01 至 1993-11-30
- 项目状态:已结题
- 来源:
- 关键词:CD antigens T cell receptor cell adhesion molecules cell mediated lymphocytolysis test chimeric proteins clinical trials cyclophosphamide cytotoxic T lymphocyte human subject human therapy evaluation immunocytochemistry interleukin 2 leukocyte adhesion molecules lung neoplasms lymphocyte proliferation major histocompatibility complex melanoma molecular cloning monoclonal antibody neoplasm /cancer immunotherapy neoplasm /cancer vaccine nucleic acid hybridization polymerase chain reaction psoralens tissue /cell culture ultraviolet radiation western blottings
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.
该提案的目标是优化特异性主动免疫疗法,
黑素瘤 为此,人类免疫学的几个方面
黑色素瘤将被研究,以确定一些机制,
使用治疗性疫苗的患者获得了极好的临床缓解
(“theraccine”)。 Theraccine已导致转移性黑色素瘤的缓解,
20%的患者,中位缓解时间为17个月,
细胞毒性T淋巴细胞(pCTL)的前体。 疫苗的改良,
例如8-甲氧基吡喃烯敏化的UV光照射的细胞的裂解物,
冻干裂解物和膜囊泡,将通过临床评估
试验,通过体外免疫测定密切监测。 低剂量
环磷酰胺和白细胞介素-2将与疫苗联合使用,
以增加CTL产生,从而增加临床应答率。 一项随机
在早期黑色素瘤(lb-lll)中的III期试验将在
试图根除微观残留疾病。 改善和
为了简化免疫学相关性,将比较其他试验
与我们对pCTL频率的估计,包括增殖试验,
和细胞毒性的“裂解单位”的测定。 白细胞和细胞因子
将通过免疫组织化学检测退化病变中存在的蛋白质。
CTL识别的抗原及其与黑素瘤的相互作用
将从几个方面进行研究。 肿瘤浸润的特异性
来自外周血的淋巴细胞(TIL)和CTL将通过冷沉淀分析。
用黑色素瘤细胞系和组织学上不同的
肿瘤的 将建立CTL克隆,针对表面标志物进行表型分析,
T细胞受体链,并通过直接免疫荧光法检测其特异性
细胞毒性和冷靶竞争。 CD 8+“经典”CTL和
广泛反应性(仅CD 4+?)疫苗治疗后发现的CTL将被
比较了 CTL克隆识别的黑色素瘤肽将被
通过增殖和竞争在Western免疫印迹后鉴定
分析。 然后对免疫原性肽进行测序。 的重要性
辅助分子和主要组织相容性复合体等位基因,
特别是HLA-A2在CTL与黑色素瘤相互作用中的作用
通过与响应的统计相关性,以及通过对
通过体外单克隆抗体的细胞毒性。 T细胞受体基因
来自血液或肿瘤的克隆的CTL和来自消退的未克隆的TIL
病变将用基因产物的抗体进行检查,
聚合酶链反应 限制使用V区基因,
黑色素瘤将通过消减杂交鉴定:正常
黑色素细胞和黑色素瘤细胞,以及肺鳞状细胞癌,
黑素瘤 融合蛋白的免疫原性将通过
增殖、竞争测定和细胞毒性测定,
处理的非黑素瘤细胞。 一个预先选定的组合,
来自cDNA克隆的免疫原性MAA将构成
黑色素瘤疫苗
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 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:
3173748 - 财政年份:1988
- 资助金额:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 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:
$ 23.61万 - 项目类别:
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