Study on Adoptive Immuno-therapy for Advanced Lung Cancer.

肺癌的淋巴结转移似乎比其他癌症更常见，这是由于区域淋巴结的防御机制受损所致。然而，对肺癌患者的区域淋巴结淋巴细胞(RLNL)的免疫功能却知之甚少。以外周血淋巴细胞(PBL)为对照，研究了RLNL的免疫学特性。我们测定了肺癌患者外周血和外周血中自然杀伤细胞(NK)的活性，发现RLNL的NK活性明显低于PBL。相反，白介素2(IL-2)在RLNL的产生明显高于PBL。重组IL-2(rIL-2)可显著增强非转移性淋巴结中RLNL对靶细胞如K562细胞、PC-3和PC-10细胞(NK耐药细胞、人肺癌和表皮样癌)的杀伤作用。此外，我们还澄清了ri…更多的L-2和作为生物反应调节剂和IL-2诱导剂的OK-432增强了RLNL的细胞毒作用，这些效应细胞是淋巴因子激活的杀伤细胞(LAK)。特异性单抗对淋巴细胞亚群的去除表明，RLNL的LAK活性是由CD3^+和CD8^+细胞介导的，而PBL中的LAK活性主要由CD3^+和CD16^+细胞介导。结论：RLNL中的效应细胞多为细胞毒性T细胞群中的LAK细胞。因此，通过区域输注OK-432内源性LAK细胞和外源性LAK细胞的加入可以预期治疗效果，外源性LAK细胞可以通过将患者的淋巴细胞与rIL-2孵育而在体外产生。对7例晚期肺癌患者行经支气管动脉局部AIT治疗。在7例患者中，5例(71%)有疗效：2例部分缓解，3例轻微缓解，2例无变化。下一步，我们研究了肿瘤浸润性淋巴细胞(TIL)用于适应性免疫治疗的可能性，TIL对K562、Daudi和自体肿瘤细胞的杀伤活性显著增强。淋巴细胞亚群分析表明，TIL以T细胞为主(以CD8~+细胞为主)，少数为B细胞、巨噬细胞和NK细胞。这些结果有力地表明，即使不是全部，也有一部分培养的TIL含有细胞毒性T淋巴细胞，这种T淋巴细胞对自体肿瘤细胞具有特异性。因此，我们认为TIL中的一些细胞毒性T细胞(CTL)可能对AT细胞具有细胞毒作用。采用过继免疫疗法(AIT)治疗肺癌癌性胸膜病患者。从胸腔积液中提取TIL，并用rIL-2增强。胸腔内注入rIL-2增强的TIL，3例中有2例胸腔积液消失。较少

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