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Basic and clinical studies on induction of killer lymphocytes against neck and kidney tumors

诱导杀伤淋巴细胞抗颈肾肿瘤的基础与临床研究

基本信息

批准号：
01480383
负责人：
TANABE Masao J
金额：
$ 4.16万
依托单位：
Faculty of Medicine, University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

This study was made to develop the effective immune therapy for the tumors basing on the results of both basic and clinical researches concerning the induction of killer lymphocytes against neck and kidney tumors. As the clinical trials, Hayakawa M.D. tried to treat the patients with advanced renal cancer with the adoptive transfer of Lymphokine-activated killer (LAK) cells. He developed the regional arterial infusion therapy which yielded the excellent clinical results.On the other hand, in the basic approach, Tanabe M.D. and Koja M.D. developed the new method for the induction of the cytotoxic T lymphocytes (CTL) against the tumor cells. They also showed in this new system that the CTL recognized only the absolute dominant antigen which had the important role on the immunological self-nonself discrimination.(Basic approach)1. The bone marrow (BM) cells had the helper activity which augmented to induce the CTL from their precursors.2. Using the BM cells which had the helper effect, th … More e CTL specific to the minor-H antigen were induced easily in primary cultures in vitro. By the genetic analysis, the CTL recognized only the X-chromosome linked gene product (Xir) antigen) which had the important role on the self-nonself discrimination.3. Using the BM cells, the CTL specific to the tumor cells were induced easily in primary cultures in vitro. By the analysis of the rumor antigen recognized by these CTL, the tumor cells had lost the intrinsic Xir antigen which were expressed on normal original cells as described above. On the contrary, the tumor cells gained the new intrinsic Xir-like antigen on their surfaces.(Clinical approach)LAK cells and tumor infiltrating lymphocytes (TIL) were obtained from patients with advanced renal cell carcinoma (RCC). Those killer cells-mediated cytotoxicities against autologous tumor cell were nonspecific. Therefore, when they were systemically infused, they rarely reached metastatic sites of RCC. In contrast, regional arterial administration yielded a remarkable accumulation of killer cells in the tumor tissue and they stayed there for a certain period of time. LAK cell and TIL produced IFN-alpha and/or TNF-gamma when they were cultured with autologous tumor cells. The positive rate of these cytokines in the serum of the patients treated with LAK/IL-2 therapy was higher than that in the patients without LAK/IL-2 therapy. Seven out of 12 metastatic lesions in 12 patients with RCC treated with LAK/IL-2 therapy showed regression, whereas no clinical response was obtained with systemic LAK/IL-2 therapy. Regional arterial administration of killer cells seems to be worthwhile and promising for treatment of the advanced RCC as far as the mass production of the specific CTL to RCC is not presently available. Less

本研究在基础研究和临床研究的基础上，针对颈部和肾脏肿瘤，探索有效的免疫治疗方法。作为临床试验，Hayakawa医学博士试图通过过继转移淋巴因子激活的杀伤细胞(LAK)来治疗晚期肾癌患者。他开发了区域动脉灌注疗法，取得了良好的临床效果。另一方面，在基础方法中，Tanabe M.D.和Koja M.D.开发了诱导细胞毒性T淋巴细胞(CTL)对抗肿瘤细胞的新方法。在这个新的系统中，他们还发现CTL只识别绝对优势抗原，而绝对优势抗原在免疫自非自我辨别中起着重要作用。(基础方法)1.骨髓(BM)细胞具有增强的辅助活性，可以从其前体诱导CTL。利用具有辅助作用的BM细胞，TH…体外原代培养更易诱导出针对Minor-H抗原的特异性细胞毒性T细胞。通过遗传分析，CTL只识别在自我非自我辨别中起重要作用的X染色体连锁基因产物(XIR)抗原。利用BM细胞，在体外原代培养条件下，很容易诱导出针对肿瘤细胞的CTL。通过对这些CTL识别的肿瘤抗原的分析，肿瘤细胞已经失去了如上所述在正常原始细胞上表达的固有XIR抗原。相反，肿瘤细胞表面获得了新的内在XIR样抗原。(临床方法)LAK细胞和肿瘤浸润性淋巴细胞(TIL)取自晚期肾细胞癌(RCC)。这些杀伤细胞介导的对自体肿瘤细胞的杀伤作用是非特异性的。因此，当它们被系统地注入时，它们很少到达肾癌的转移部位。相比之下，区域动脉注射在肿瘤组织中产生了显著的杀伤细胞积聚，并在那里停留了一段时间。LAK细胞和TIL与自体肿瘤细胞共同培养产生干扰素-α和/或肿瘤坏死因子-γ。经LAK/IL-2治疗的患者血清中这些细胞因子的阳性率高于未接受LAK/IL-2治疗的患者。经LAK/IL-2治疗的12例肾癌患者的12个转移灶中，有7个转移灶消退，而全身LAK/IL-2治疗无临床反应。由于目前还没有大规模生产针对肾癌的特异性CTL，区域动脉注射杀伤细胞似乎是治疗晚期肾癌的值得和有希望的方法。较少