Zhang H, Zhang S, Cheung N K, Ragupathi G, Livingston P O
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Cancer Res. 1998 Jul 1;58(13):2844-9.
After 10 years of clinical trials in patients with advanced cancer, monoclonal antibodies (mAbs) against cell surface antigens have not lived up to their initial promise. One such cell surface antigen is the ganglioside GD2. GD2 is richly expressed at the cell surfaces of human neuroblastomas, sarcomas, and melanomas. We have described a murine lymphoma (EL4) that is syngeneic in C57BL/6 mice and expresses GD2, a mAb against GD2 (mAb 3F8), and we have prepared a conjugate vaccine (GD2-keyhole limpet hemocyanin plus immunological adjuvant QS-21) that consistently induces antibodies against GD2. We demonstrate here, for the first time in a syngeneic murine model, that passively administered and vaccine-induced antiganglioside antibodies prevent outgrowth of micrometastases, and we use this model to establish some of the parameters of this protection. The level of protection was proportional to antibody titer. Treatment regimens resulting in the highest titer antibodies induced the most protection, and protection was demonstrated even when immunization was initiated after tumor challenge. Treatment with 3F8 1, 2, or 4 days after i.v. tumor challenge was highly protective, but waiting until 7 or 10 days after challenge resulted in minimal protection. The results were similar whether number of liver metastases or survival was used as the end point. These results suggest that unmodified mAbs or antibody-inducing vaccines against GD2 (and possibly other cancer cell surface antigens) should be used exclusively in the adjuvant setting, where circulating tumor cells and micrometastases are the primary targets.
在对晚期癌症患者进行了10年的临床试验后，针对细胞表面抗原的单克隆抗体（mAb）并未达到其最初的预期。神经节苷脂GD2就是这样一种细胞表面抗原。GD2在人类神经母细胞瘤、肉瘤和黑色素瘤的细胞表面大量表达。我们描述了一种在C57BL/6小鼠中同基因的鼠淋巴瘤（EL4），它表达GD2以及一种针对GD2的单克隆抗体（单克隆抗体3F8），并且我们制备了一种结合疫苗（GD2-钥孔戚血蓝蛋白加免疫佐剂QS-21），该疫苗能持续诱导产生针对GD2的抗体。我们在此首次在同基因鼠模型中证明，被动给予和疫苗诱导产生的抗神经节苷脂抗体可阻止微转移灶的生长，并且我们利用该模型确定了这种保护作用的一些参数。保护水平与抗体滴度成正比。导致抗体滴度最高的治疗方案诱导的保护作用最强，并且即使在肿瘤攻击后开始免疫也能证明有保护作用。在静脉注射肿瘤攻击后1、2或4天用3F8治疗具有高度保护作用，但等到攻击后7或10天进行治疗则保护作用最小。无论以肝转移灶数量还是生存率作为终点，结果都是相似的。这些结果表明，未修饰的针对GD2（可能还有其他癌细胞表面抗原）的单克隆抗体或诱导抗体的疫苗应仅用于辅助治疗，此时循环肿瘤细胞和微转移灶是主要靶点。
