Musselli C, Livingston P O, Ragupathi G
Memorial Sloan Kettering Cancer Center, Department of Tumor Vaccinology, New York, NY 10021, USA.
J Cancer Res Clin Oncol. 2001 Oct;127 Suppl 2:R20-6. doi: 10.1007/BF01470995.
Passively administered and actively induced antibodies have been associated with the eradication of circulating tumor cells and micrometastases in mice and humans. We have identified a series of cell surface carbohydrate and peptide antigens on melanomas, sarcomas, and cancer of the breast, prostate. ovary, and lung tissues. We found that breaking tolerance toward these tumor antigens was best achieved using vaccines containing antigens chemically conjugated to keyhole limpet hemocyanin (KLH) plus a potent immunological adjuvant (QS-21). To date, by using this approach to vaccination. antibodies have been induced in patients against glycolipid antigens GM2, GD2, GD3, FucosylGM1, Globo H, and Lewis Y, and glycoprotein (mucin) antigens Tn, sialyl Tn. TF, and MUC1. More recently, in a comparative study we investigated the T cell response induced by MUCI-KLH conjugates. Although a MUC1-specific T cell response was not consistently detected in any patient, the role of KLH in orienting the cytokine environment was crucial. We were able to confirm that KLH in these conjugate vaccines induces a Th1 T cell response as demonstrated by the high anti-KLH INF-gamma secretion and the IgGI and IgG3 subclasses of this high titer IgG antibodies induced. Clinical trials using KLH conjugated glycolipid and glycoprotein vaccines, are currently ongoing. These range from phase I/II single antigens trials with glycosilated MUC1, polysialic acid, synthetic Fucosyl GMI and GD2, to phase II trials with a polyvalent vaccine containing six or seven antigens. Randomized phase II trials with polyvalent vaccines are planned for initiation in 2001-2002 in patients with ovarian, breast, and prostate cancer.
被动给予和主动诱导的抗体已与小鼠和人类循环肿瘤细胞及微转移灶的清除相关联。我们已在黑色素瘤、肉瘤以及乳腺癌、前列腺癌、卵巢癌和肺癌组织上鉴定出一系列细胞表面碳水化合物和肽抗原。我们发现，使用含有与钥孔血蓝蛋白（KLH）化学偶联的抗原以及强效免疫佐剂（QS-21）的疫苗，最能打破对这些肿瘤抗原的耐受性。迄今为止，通过这种疫苗接种方法，已在患者体内诱导出针对糖脂抗原GM2、GD2、GD3、岩藻糖基GM1、Glob H和Lewis Y以及糖蛋白（粘蛋白）抗原Tn、唾液酸Tn、TF和MUC1的抗体。最近，在一项比较研究中，我们调查了MUC1-KLH偶联物诱导的T细胞反应。尽管在任何患者中均未始终检测到MUC1特异性T细胞反应，但KLH在调节细胞因子环境中的作用至关重要。我们能够证实，这些偶联疫苗中的KLH诱导了Th1 T细胞反应，这表现为高抗KLH干扰素-γ分泌以及所诱导的这种高滴度IgG抗体的IgG1和IgG3亚类。目前正在进行使用KLH偶联糖脂和糖蛋白疫苗的临床试验。这些试验范围从针对糖基化MUC1、聚唾液酸、合成岩藻糖基GMI和GD2的I/II期单一抗原试验，到含有六种或七种抗原的多价疫苗的II期试验。计划于2001 - 2002年针对卵巢癌、乳腺癌和前列腺癌患者启动多价疫苗的随机II期试验。
