CHEMOTHERAPY INDUCED IMMUNE-MEDIATED TUMOR ERADICATION

化疗诱导免疫介导的肿瘤根除

• 批准号: 3198968
• 负责人: MARGALIT B MOKYR
• 金额: $ 15.18万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-15 至 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3198968
• 关键词: T cell receptor; athymic mouse; cell mediated cytotoxicity; clone cells; combination cancer therapy; combination chemotherapy; cyclophosphamide; cytotoxic T lymphocyte; delayed hypersensitivity; disease /disorder model; immunosuppression; laboratory mouse; macrophage; melanoma; melphalan; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; plasma cell neoplasm; prednisone; procarbazine; suppressor T lymphocyte; vincristine

The long term objective of our program is to elucidate the mechanism(s) through which a widely used anticancer drug (melphalan) potentiates the tumor eradicating immunity in mice bearing a large tumor and extensive metastases. Although the tumor model that we will use, the MOPC-315 plasmacytoma, is not very immunogenic, following low-dose chemotherapy a CD8+ T-cell-dependent antitumor immunity develops in the hitherto immunosuppressed tumor bearers with sufficient potency to completely eradicate the large tumor burden not eradicated through the direct antitumor effects of the drug. To further characterize the CD8+ T-cells that are required for tumor eradication, we will analyze the T-cell receptor (TCR) repertoire of CD8+ T-cells derived from the regressing tumors. This will be done utilizing a panel of monoclonal antibodies directed against various V-beta gene segments of the TCR. In addition, with the aid of CD8+ T-cell clones, we will attempt to correlate the use of a particular V-beta segment(s) with a particular anti-MOPC-315 reactivity. Subsequently, we will determine the importance of T-cells expressing the particular V-beta gene product(s) to the therapeutic outcome of low-dose chemotherapy. Since a large number of macrophages is first evident in the s.c. tumor nodules of lowdose melphalan treated MOPC-315 tumor bearers two days after the appearance of a massive CD8+ lymphocytic infiltrate, experiments are proposed to determine if the CD8+ T-cells actually recruit macrophages into the tumor site as well as determine the importance of the macrophages for the therapeutic outcome. Experiments are also planned to determine if low-dose chemotherapy leads to the acquisition of potent tumor eradicating immunity in MOPC-315 tumor bearers as a result of elimination of the suppressive activity of CD4+ T-cells. We have worked out conditions under which the tumor eradicating immunity is reduced and, consequently, the effectiveness of the chemotherapeutic protocol is also decreased. Under these conditions, if the chemotherapy does not eliminate the suppressive activity of the CD4+ T-cells for tumor eradicating immunity, elimination of the CD4+ T-cells by the use of anti-L3T4 antibody can result in a more potent tumor eradicating immunity and a better cure rate. The potential importance of the proposed studies can be best summarized by a quotation from a recent review article on active immunotherapy of human melanoma exploiting the immunopotentiating effects of cyclophosphamide. In this article Berd and Mastrangelo (1) show that their results corroborate the findings in animal models and state that "application of ideas developed through basic investigation in immunoregulation will lead to more effective immunotherapy of human cancer."

我们计划的长期目标是阐明机制 广泛使用的抗癌药物（美法仑）通过其增强了 在携带大肿瘤和广泛肿瘤的小鼠中的肿瘤根除免疫 转移 虽然我们将使用的肿瘤模型，MOPC-315 浆细胞瘤，免疫原性不是很强，低剂量化疗后， CD 8 + T细胞依赖性抗肿瘤免疫在迄今为止的 免疫抑制的肿瘤携带者具有足够的效力， 根除通过直接化疗无法根除的巨大肿瘤负担 药物的抗肿瘤作用。 为了进一步表征CD 8 + T细胞 我们将分析T细胞， CD 8 + T细胞的TCR受体（TCR）库来源于消退的 肿瘤的 这将使用一组单克隆抗体完成 针对TCR的各种V-β基因区段。 此外，本发明还提供了一种方法， 在CD 8 + T细胞克隆的帮助下，我们将尝试将 具有特定抗MOPC-315反应性的特定V-β片段。 随后，我们将确定T细胞表达的重要性。 特别是V-β基因产物对低剂量化疗的治疗效果的影响 化疗 由于大量的巨噬细胞首先出现在 S.C.低剂量美法仑治疗的MOPC-315肿瘤携带者的肿瘤结节 在出现大量CD 8+淋巴细胞浸润后数天， 提出了实验来确定CD 8 + T细胞是否真的招募 巨噬细胞进入肿瘤部位，以及确定的重要性， 巨噬细胞的治疗效果。 实验还计划 确定低剂量化疗是否会导致获得有效的肿瘤 消除MOPC-315肿瘤携带者的免疫力， CD 4 + T细胞的抑制活性。 我们已经谈好了条件 在这种情况下，肿瘤根除免疫力降低，因此， 化疗方案的有效性也降低。 在这种情况下，如果化疗不能消除肿瘤， - CD 4 + T细胞对肿瘤根除免疫的抑制活性， 通过使用抗L3 T4抗体消除CD 4 + T细胞可导致 更有效的肿瘤消除免疫和更好的治愈率。 的 拟议研究的潜在重要性最好用以下几点来概括： 引自最近一篇关于人类主动免疫疗法的综述文章 利用环磷酰胺的免疫增强作用的黑色素瘤。 在 本文Berd和Mastrangelo（1）表明，他们的结果证实了 在动物模型中的发现，并指出，“应用的想法， 通过免疫调节的基础研究发展起来的， 人类癌症的有效免疫疗法。"