CHEMOTHERAPY INDUCED IMMUNE-MEDIATED TUMOR ERADICATION

化疗诱导免疫介导的肿瘤根除

• 批准号: 3198966
• 负责人: MARGALIT B MOKYR
• 金额: $ 12.17万
• 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/3198966
• 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."

我们项目的长期目标是阐明这一机制(S) 一种广泛使用的抗癌药物(马法兰)通过这种方式增强 荷瘤小鼠的肿瘤清除免疫研究 转移瘤。虽然我们将使用的肿瘤模型，MOPC-315 浆细胞瘤，免疫原性不强，在小剂量化疗后 到目前为止，CD8+T细胞依赖的抗肿瘤免疫在 免疫抑制的肿瘤载体，其效力足以完全 根除不能通过直接根除的大肿瘤负担 该药具有抗肿瘤作用。进一步鉴定CD8+T细胞 为了根除肿瘤，我们将分析T细胞 退化型CD8+T细胞的受体(TCR)谱 肿瘤。这将通过一组单抗来完成。 针对TCR的不同V-β基因片段。此外, 在CD8+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(S)。 随后，我们将确定T细胞表达 特定V-β基因产物(S)对小剂量治疗效果的影响 化疗。由于巨噬细胞的数量最早出现在 南加州大学。小剂量马法兰治疗MOPC-315肿瘤结节 在出现大量CD8+淋巴细胞渗透的几天后， 有人提议进行实验，以确定CD8+T细胞是否真的招募 巨噬细胞进入肿瘤部位以及确定 巨噬细胞对治疗结果的影响。实验也计划进行到 确定低剂量化疗是否会导致获得有效肿瘤 消除对MOPC-315肿瘤患者免疫功能的影响 抑制CD4+T细胞的活性。我们已经想好了条件 在这种情况下，肿瘤的根除免疫力会降低，因此， 化疗方案的有效性也降低了。 在这种情况下，如果化疗不能消除 CD4+T细胞对肿瘤清除免疫的抑制活性 通过使用抗L3T4抗体可以消除CD4+T细胞 在更强大的肿瘤根除免疫力和更好的治愈率。这个 建议研究的潜在重要性可以用一个 引用最近一篇关于人类主动免疫治疗的综述文章 利用环磷酰胺免疫增强作用的黑色素瘤。在……里面 本文Berd和Mastrelo(1)证明了他们的结果是确证的 在动物模型中的研究结果表明，“思想的应用 通过基础研究开发的免疫调节将导致更多 有效的免疫疗法治疗人类癌症。