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Study on Adoptive Immuno-therapy for Advanced Lung Cancer.

晚期肺癌过继免疫治疗的研究。

基本信息

批准号：
01570779
负责人：
WATANABE Yoh
金额：
$ 1.34万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-01570779/
关键词：
adoptive immunotherapy advanced lung cancer tumor infiltrating lymhocytes lymphokine activated killer cell recombinant inteleukin 2 cytotoxicity CD8 positive cells malignant pleural effusion 肺癌腫瘍浸潤リンパ球 CD8陽性細胞高密度細胞培養装置鶏卵法気管支動

项目摘要

It appears that lymph node metastases are more frequent in lung cancer than in other cancers due to impaired defensive mechanisms in the regional lymph nodes. However, little is known about the immunological function of Regional Lymph Node Lymphocytes (RLNL) in lung cancer patients. We have studied the immunological properties of RLNL in comparison with Peripheral Blood Lymphocytes (PBL). We measured the Natural Killer (NK) cell activity of RLNL and PBL in lung cancer patients and found that the NK activity was significantly more depressed in the RLNL than in the PBL. In contrast, Inter-Leukin-2 (IL-2) production was markedly higher in the RLNL than in the PBL. The cytotoxic effect of RLNL in non-metastatic lymph nodes on target cells, such as K562 cells, or PC-3 and PC-10 cells (NK-resistant, human lung cancer of adenocarcinoma and epidermoid carcinoma, respectively) was significantly enhanced by in vitro incubation with recombinant IL-2 (rIL-2). Furthermore, we clarified that both rI … More L-2 and OK-432, which is a biological response modifier and IL-2 inducer as well, augmented the cytotoxicity of RLNL and that these effector cells were lymphokine activated killer (LAK) celis. The depletion of lymphocyte subsets by pretreatment with specific monoclonal antibody showed that the LAK activity in RLNL was mediated by CD3^+ and CD8^+ cells, while the lymphocyte subsets contributing the LAK activity in PBL were CD3^+ and CD16^+ cells. It was concluded that a majority of the effector cells in RLNL were LAK cells of the cytotoxic T-cell population. Thus, therapeutic effects can be expected by LAK cells endogenously induced by regional infusion of OK-432 abd addition of exogenous LAK cells which can be produced in vitro by incubating the patient's lymphocytes with rIL-2. Local AIT through bronchial artery was performed on 7 patients with advanced lung cancer. Some therapeutic effects were noted in 5 (71%) out of 7 patients : partial response in 2, minor response in 3 and no change in 2.As the next step, possibility of adpotive immunotherapy using TIL (Tumor Infiltrating Lymphocyte) was studied Substantial augmentation of the cytotoxic activity against K562, Daudi and autologous tumor cell lines were induced by incubating the TILs with OK-432 or rIL-2, although these enhancement of the cytotoxicity was significantily low in comparison with that of the RLNLs and PBLs. By analysis of lymphocyte subsets, it was clarified that the majority of the TILs were T cells (most of them were CD8^+ cells), whereas B cells, macrophages and NK cells were minority. These tesults strongly indicates that, if not all, some part of cultured TIL contains cytotoxic T lymphocytes which have a specificity against autologous tumor cells. Accordingly, it was thought to be probable that some of the cytotoxic T cells (CTLs) in the TILs might have cytotoxicty against AT cells. Adoptive Immuno-Therapy (AIT) was tried on lung cancer patients with carcinomatous pleurosy. TILs were extracted from pleural effusion, and enhanced by rIL-2. The enhanced TILs with rIL-2 were infused into the thoracic cavity, and subsequently in two out of three cases the pleural effusion disappeared. Less

由于局部淋巴结防御机制受损，肺癌的淋巴结转移似乎比其他癌症更常见。然而，肺癌患者局部淋巴结淋巴细胞（RLNL）的免疫功能尚不清楚。我们研究了RLNL与外周血淋巴细胞（PBL）的免疫学特性。我们测定了肺癌患者RLNL和PBL的自然杀伤（NK）细胞活性，发现RLNL的NK活性明显低于PBL。相反，RLNL中白细胞介素-2（IL-2）的产生明显高于PBL。RLNL在非转移性淋巴结中对靶细胞的细胞毒性作用，如K562细胞或PC-3和PC-10细胞（分别为NK抗性的人肺癌腺癌和表皮样癌），通过与重组IL-2（rIL-2）体外孵育而显著增强。此外，我们还澄清， ...更多信息 L-2和OK-432（一种生物反应调节剂和IL-2诱导剂）增强RLNL的细胞毒作用，这些效应细胞是淋巴因子激活的杀伤（LAK）细胞。用特异性单克隆抗体预处理淋巴细胞亚群，结果表明RLNL中LAK活性由CD 3 ^+和CD 8 ^+细胞介导，而PBL中对LAK活性有贡献的淋巴细胞亚群为CD 3 ^+和CD 16 ^+细胞。结论：RLNL中的大多数效应细胞是细胞毒性T细胞群中的LAK细胞。因此，通过局部输注OK-432内源性诱导的LAK细胞和加入外源性LAK细胞可以预期治疗效果，所述外源性LAK细胞可以通过用rIL-2孵育患者的淋巴细胞而在体外产生。经支气管动脉行局部AIT治疗中晚期肺癌7例。在7例患者中的5例（71%）中观察到一些治疗效果：部分缓解2例，轻微缓解3例，无变化2例。下一步，探讨应用TIL进行适应性免疫治疗的可能性通过将TIL与OK-432或rIL-2一起温育，诱导对K562、Daudi和自体肿瘤细胞系的细胞毒活性的显著增强，尽管与RLNLs和PBL相比，这些细胞毒性的增强明显较低。通过淋巴细胞亚群分析，阐明了大多数TIL是T细胞（其中大多数是CD 8 ^+细胞），而B细胞、巨噬细胞和NK细胞是少数。这些结果有力地表明，即使不是全部，培养的TIL中也有一部分含有对自体肿瘤细胞具有特异性的细胞毒性T淋巴细胞。因此，认为TIL中的一些细胞毒性T细胞（CTL）可能对AT细胞具有细胞毒性。对肺癌伴癌性胸膜炎患者进行了连续性免疫治疗（AIT）。从胸腔积液中提取TILs，并用rIL-2增强。将rIL-2增强的TIL注入胸腔，随后3例中有2例胸腔积液消失。少