Study on Adoptive Immuno-therapy for Advanced Lung Cancer.

由于区域淋巴结的防御机制受损，淋巴结转移似乎在肺癌中比在其他癌症中更常见。然而，人们对肺癌患者区域淋巴结淋巴细胞（RLNL）的免疫功能知之甚少。我们研究了RLNL与外周血淋巴细胞（PBL）的免疫学特性。我们检测了肺癌患者RLNL和PBL的NK细胞活性，发现RLNL的NK细胞活性明显低于PBL。相反，白细胞介素-2 （IL-2）的产生在RLNL中明显高于PBL。重组IL-2 （rIL-2）体外培养可显著增强非转移性淋巴结RLNL对靶细胞(如K562细胞、PC-3细胞和PC-10细胞（分别为nk耐药的人肺癌腺癌和表皮样癌细胞）的细胞毒作用。此外，我们还明确了rI…More L-2和OK-432（一种生物反应调节剂和IL-2诱导剂）增强了RLNL的细胞毒性，并且这些效应细胞是淋巴因子激活的杀伤细胞（LAK）。特异性单克隆抗体预处理后的淋巴细胞亚群减少表明，LAK在RLNL中的活性是由CD3^+和CD8^+细胞介导的，而在PBL中贡献LAK活性的淋巴细胞亚群是CD3^+和CD16^+细胞。结果表明，RLNL中的大部分效应细胞为细胞毒性t细胞群中的LAK细胞。因此，通过局部输注OK-432内源性诱导LAK细胞，并添加外源性LAK细胞，可以通过体外培养患者淋巴细胞与il -2培养产生LAK细胞，从而达到治疗效果。对7例晚期肺癌经支气管动脉行局部AIT治疗。7例患者中有5例（71%）出现了一些治疗效果：2例部分缓解，3例轻微缓解，2例无变化。下一步，研究了使用TIL（肿瘤浸润淋巴细胞）进行适应性免疫治疗的可能性，通过将TIL与OK-432或rIL-2孵育，可以诱导对K562、Daudi和自体肿瘤细胞系的细胞毒活性显著增强，尽管与rlnl和pbl相比，这些细胞毒活性的增强明显较低。淋巴细胞亚群分析表明，TILs以T细胞为主（以CD8 +细胞为主），B细胞、巨噬细胞和NK细胞占少数。这些结果强烈表明，如果不是全部，部分培养的TIL含有细胞毒性T淋巴细胞，对自体肿瘤细胞具有特异性。因此，人们认为TILs中的一些细胞毒性T细胞（ctl）可能对AT细胞具有细胞毒性。采用过继免疫疗法（AIT）治疗肺癌伴癌性胸膜炎。从胸腔积液中提取til， il -2增强til。将含有il -2的增强TILs注入胸腔，随后3例中有2例胸腔积液消失。少

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