de Jong W H, Steerenberg P A, Kreeftenberg J G, Tiesjema R H, Kruizinga W, van Noorle Jansen L M, Ruitenberg E J
Cancer Immunol Immunother. 1984;17(1):18-27. doi: 10.1007/BF00205492.
Four consecutively produced batches of Bacillus Calmette-Guérin (BCG) especially intended to be used for cancer immunotherapy were investigated for consistency of the vaccine. Each batch was investigated directly after production of the vaccine, so that the four batches were not tested simultaneously. The activity of the four batches was investigated in general safety assays, immunostimulation assays, and two different tumor models. General safety assays showed dose-dependent growth retardation and increased serum glutamic pyruvic transaminase activity in mice, and a long-lasting temperature rise in rabbits after IV administration of the BCG preparations. In a skin reactivity assay, reactions were found acceptable for all preparations when compared with a reference batch. The results of the immunostimulation and antitumor studies can be summarized as follows. All four batches induced a specific delayed-type hypersensitivity reaction to PPD, indicating the induction of cell-mediated immunity. A stimulating effect on lymphoreticular organs was concluded from increased spleen weight and enhanced cell proliferation in draining lymph nodes. Enhanced macrophage function (phagocytosis and killing of bacteria) was demonstrated by an increased resistance to Listeria monocytogenes. YAC lymphoma target cells were killed nonspecifically by BCG-activated peritoneal exudate cells (PEC), indicating the induction of natural killing activity by BCG. Intralesional injection of BCG induced tumor regression in the guinea pig line 10 hepatocellular carcinoma, followed by immunity to the line 10 tumor. In the murine 5D04 squamous cell carcinoma, BCG had no effect on the primary tumor. However, IV-injected BCG resulted in a decreased number of lung metastases. In general, the four consecutively produced batches showed similar safety and activity in the immunostimulation assays and antitumor activity. Since only minor differences between the batches were found, which can also be attributed to the variation in experimental conditions common to biological assays, it is concluded that the vaccine batches produced show an acceptable consistency.
对连续生产的四批特别用于癌症免疫治疗的卡介苗（BCG）进行了疫苗一致性研究。每批疫苗生产后立即进行研究，因此这四批疫苗并非同时进行测试。在一般安全性试验、免疫刺激试验和两种不同的肿瘤模型中研究了这四批疫苗的活性。一般安全性试验显示，给小鼠静脉注射卡介苗制剂后，出现剂量依赖性生长迟缓、血清谷丙转氨酶活性升高，给兔子静脉注射后出现持续时间较长的体温升高。在皮肤反应性试验中，与参考批次相比，所有制剂的反应均可接受。免疫刺激和抗肿瘤研究的结果总结如下。所有四批疫苗均诱导了对结核菌素纯蛋白衍生物（PPD）的特异性迟发型超敏反应，表明诱导了细胞介导的免疫。脾脏重量增加和引流淋巴结细胞增殖增强表明对淋巴网状器官有刺激作用。对单核细胞增生李斯特菌的抵抗力增强证明巨噬细胞功能（吞噬和杀灭细菌）增强。卡介苗激活的腹腔渗出细胞（PEC）可非特异性杀伤YAC淋巴瘤靶细胞，表明卡介苗可诱导自然杀伤活性。在豚鼠10号线肝细胞癌中，瘤内注射卡介苗可诱导肿瘤消退，随后对10号线肿瘤产生免疫。在小鼠5D04鳞状细胞癌中，卡介苗对原发性肿瘤无影响。然而，静脉注射卡介苗可减少肺转移灶数量。总体而言，连续生产的这四批疫苗在免疫刺激试验和抗肿瘤活性方面表现出相似的安全性和活性。由于各批次之间仅发现微小差异，这也可归因于生物试验常见的实验条件变化，因此得出结论，所生产的疫苗批次具有可接受的一致性。
