Kroesen B J, ter Haar A, Spakman H, Willemse P, Sleijfer D T, de Vries E G, Mulder N H, Berendsen H H, Limburg P C, The T H
Department of Clinical Immunology, University Hospital Groningen, The Netherlands.
Cancer Immunol Immunother. 1993 Nov;37(6):400-7. doi: 10.1007/BF01526797.
In a pilot clinical study carcinoma patients with malignant ascites or pleural exudates have been treated locally with autologous lymphocytes activated ex vivo and redirected towards tumour cells with bispecific monoclonal antibodies. BIS-1, the bispecific monoclonal antibody used in this study, combines specificity against a tumour-associated antigen, AMOC-31, present on carcinomas, with a specificity against the CD3 complex on T lymphocytes. Patients selected for treatment had malignant pleural or peritoneal effusions. Treatment consisted of isolating autologous peripheral blood lymphocytes, ex vivo activation, incubation with bispecific monoclonal antibodies and injection at the effusion site of these BIS-1-redirected lymphocytes. To evaluate the effects of the bispecific monoclonal antibody, five patients received treatments with activated lymphocytes without bispecific antibodies. Effusion samples taken before and at various times after treatment were analysed by immunocytology and for the presence of the soluble factors carcinoembryonic antigen (CEA), interleukin-6 (IL-6), tumour necrosis factor (TNF), C-reactive protein and soluble CD8. In this way both immune activation and anti-tumour activity could be monitored. Conjugate formation between tumour cells and activated lymphocytes was seen as soon as 4 h after injection of BIS-1-redirected activated lymphocytes, followed by a disappearance or reduction of tumour cells after 24-48 h. In parallel with this, the soluble tumour marker CEA decreased in the effusion fluid following injection with the BIS-1-redirected lymphocytes. Furthermore, a steep increase in local granulocyte numbers was observed in the effusion fluid, which reached a maximum 24-48 h after the start of the treatment. Also levels of IL-6 and TNF were greatly elevated. The data suggest that the treatment induces both antitumour activity and a strong local inflammatory reaction. This is accompanied by no or only minor local and systemic toxicity, i.e. mild fever, which disappeared as the local inflammatory reaction diminished 48-72 h after treatment.
在一项初步临床研究中，对患有恶性腹水或胸腔积液的癌症患者进行了局部治疗，使用的是体外激活并用双特异性单克隆抗体重新导向肿瘤细胞的自体淋巴细胞。本研究中使用的双特异性单克隆抗体BIS-1，将针对癌组织上存在的肿瘤相关抗原AMOC-31的特异性与针对T淋巴细胞上CD3复合物的特异性结合起来。被选入治疗的患者有恶性胸腔或腹腔积液。治疗包括分离自体外周血淋巴细胞、体外激活、与双特异性单克隆抗体孵育以及将这些经BIS-1重新导向的淋巴细胞注射到积液部位。为了评估双特异性单克隆抗体的效果，5名患者接受了未使用双特异性抗体的激活淋巴细胞治疗。在治疗前及治疗后的不同时间采集的积液样本，通过免疫细胞学分析以及检测可溶性因子癌胚抗原（CEA）、白细胞介素-6（IL-6）、肿瘤坏死因子（TNF）、C反应蛋白和可溶性CD8的存在情况。通过这种方式可以监测免疫激活和抗肿瘤活性。在注射经BIS-1重新导向的激活淋巴细胞后4小时，就可见到肿瘤细胞与激活淋巴细胞之间形成共轭物，随后在24 - 小时后肿瘤细胞消失或减少。与此同时，注射经BIS-1重新导向的淋巴细胞后，积液中的可溶性肿瘤标志物CEA下降。此外，在积液中观察到局部粒细胞数量急剧增加，在治疗开始后24 - 48小时达到峰值。IL-6和TNF水平也大幅升高。数据表明该治疗诱导了抗肿瘤活性和强烈的局部炎症反应。同时伴有无或仅轻微的局部和全身毒性，即轻微发热，随着局部炎症反应在治疗后48 - 72小时消退而消失。
