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Anticancer therapy by hybrids of dendritic cells and interferon-α-overexpressing cells

树突状细胞和干扰素-α-过表达细胞的杂交抗癌治疗

基本信息

批准号：
14570509
负责人：
HIROISHI Kazumasa
金额：
$ 2.18万
依托单位：
Showa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Dendritic cell (DC)-based immunotherapy has been used clinically against cancer although most attempts showed insufficient responses. Fusion technique for DCs and tumor cells has been developed and widely used in experimental models as well as clinical trials. To overcome an immunosuppressed state in patients with tumors, tumor-based vaccination in combination with cytokine gene therapy has also been used in treatment of these tumors. We previously showed the efficacy of IFN-α-overexpressing tumor in a murine poorly immunogenic colorectal cancer model. Therefore, we thought that immunotherapy using hybrids of DCs and IFN-α-overexpressing tumor cells might have more antitumor effects compared with therapy with hybrids of DCs and wild-type cells. In this study, we evaluated antitumor effects of therapy with hybrids of DCs and IFN-α gene transduced colorectal cancer cells in a murine model. We established an IFN-α-overexpressing MC38 colorectal cancer cell line (MC38-IFNα, producing 157.0 … More +-4.2 ng of IFN-α/10^6cells/48h) using a retroviral vector. We made hybrids of DCs and MC38-IFNα cells with polyethyleneglycol. To evaluate the preventive effects, the hybrids were injected in immunocompetent mice 7 days before injection of wild-type MC38 (MC38-WT). As a therapy against established tumors, hybrids were inoculated contralaterally 7 days after MC38-WT cells had been injected. Hybrids were detected 17-25% of the fused DCs and MC38-IFNα cells, and these cells produced a large amount of IFN-α. Preinjection of hybrids prevented implantation of wild-type tumors effectively in all mice. In the therapeutic model against established tumors, hybrids of DCs and MC38-IFNα cells suppressed growth of the tumors more effectively than hybrids of DCs and MC38-WT cells. Immunohistochemical analysis showed marked infiltration of CD8^+ cells in the established tumors of mice treated with hybrids of DCs and MC38-IFNα cells. Immunotherapy using hybrids of DCs and IFN-α-transduced tumor cells induces cellular antitumor immune response effectively, and should be considered in clinical trials. Less

树突状细胞（DC）为基础的免疫疗法已用于临床上对癌症，但大多数尝试显示不足的反应。树突状细胞与肿瘤细胞的融合技术已经发展并广泛应用于实验模型和临床试验。为了克服肿瘤患者的免疫抑制状态，基于肿瘤的疫苗接种与细胞因子基因疗法的组合也已用于治疗这些肿瘤。我们先前在免疫原性差的小鼠结直肠癌模型中显示了IFN-α过表达肿瘤的疗效。因此，我们认为使用DC和IFN-α过表达肿瘤细胞的杂交瘤的免疫治疗可能比使用DC和野生型细胞的杂交瘤的治疗具有更好的抗肿瘤效果。在本研究中，我们评估了DC和IFN-α基因转导的结直肠癌细胞的杂交瘤在小鼠模型中的抗肿瘤作用。我们建立了IFN-α高表达的MC 38大肠癌细胞系（MC 38-IFNα，产生157.0 ...更多信息 +-4.2 ng IFN-α/10^6个细胞/48 h）。用聚乙二醇诱导DC与MC 38-IFNα细胞杂交。为了评估预防效果，在注射野生型MC 38（MC 38-WT）之前7天将杂交体注射到免疫活性小鼠中。作为针对已建立的肿瘤的疗法，在注射MC 38-WT细胞后7天对侧接种杂交体。DC与MC 38-IFNα融合细胞的杂交率为17-25%，这些细胞产生大量IFN-α。预注射杂交体有效地防止了所有小鼠中野生型肿瘤的植入。在针对已建立的肿瘤的治疗模型中，DC和MC 38-IFNα细胞的杂交体比DC和MC 38-WT细胞的杂交体更有效地抑制肿瘤的生长。免疫组织化学分析显示，在用DC和MC 38-IFNα细胞杂交瘤处理的小鼠肿瘤中，CD 8 ^+细胞明显浸润。DC与IFN-α转导的肿瘤细胞的杂交瘤免疫治疗可有效诱导细胞抗肿瘤免疫应答，临床试验中应予以考虑。少