Riker A, Cormier J, Panelli M, Kammula U, Wang E, Abati A, Fetsch P, Lee K H, Steinberg S, Rosenberg S, Marincola F
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. 20892, USA.
Surgery. 1999 Aug;126(2):112-20.
Melanoma antigen (MA)-specific vaccination strongly enhances antitumor reactivity in vivo and is capable of producing strong cytotoxic T lymphocyte responses in vitro. Furthermore, specific human leukocyte antigen-restricted T cell activation is hypothesized to occur in response to peptide-based immunotherapy, which may lead to the preferential killing of tumor cells bearing the relevant MA. The development of melanoma antigen-loss variants may subsequently occur in vivo.
Analysis of 532 melanoma lesions from 204 patients was performed on fine-needle aspiration biopsy specimens. Lesions were graded for the expression of the MAs gp100 and MART-1 with use of immunocytochemistry. A total of 351 melanoma lesions were divided into cohorts on the basis of the treatment received. The pretreatment group (n = 175) consisted of lesions obtained before any form of gp100 immunotherapy, with the posttreatment group (n = 176) consisting of lesions obtained after vaccination with a modified gp100 epitope, gp209-2M +/- interleukin 2 (IL-2).
The percentage of lesions not expressing the gp100 antigen is greater than the percentage not expressing MART-1 (26% vs 14%). The frequency of lesions with high expression (> 75%) of gp100 significantly decreased with therapy (47% vs 34%) and conversely negative lesions increased (18% vs 29%). Treatment of lesions with peptide alone (no IL-2) revealed a significant decrease in gp100 expression (47% vs 32%), enhanced with the addition of IL-2 to therapy (47% vs 35%). The expression of MART-1 remained essentially unchanged unless IL-2 was added (54% vs 54%, MART-1 peptide alone, 54% vs 43%, MART-1 peptide + IL-2). Of 94 patients (181 lesions) assessed for gp100 expression before treatment, 10 patients responded to therapy. Pretreatment lesions in responding patients expressed some level of gp100 in all cases compared with 27% of nonresponding lesions, which were negative for gp100 expression. CONCLUSIONS. This study indirectly demonstrates that vaccination with an MA-derived peptide can result in immune selection in vivo. Furthermore, it provides strong immunologic evidence for the specificity of MA vaccines and to the relevance of MA expression in predicting the response to vaccination.
黑色素瘤抗原（MA）特异性疫苗接种可在体内显著增强抗肿瘤反应性，并能够在体外产生强烈的细胞毒性T淋巴细胞反应。此外，据推测，基于肽的免疫疗法会引发特定的人类白细胞抗原限制的T细胞活化，这可能导致优先杀伤携带相关MA的肿瘤细胞。黑色素瘤抗原缺失变体随后可能在体内出现。
对来自204例患者的532个黑色素瘤病灶进行细针穿刺活检标本分析。使用免疫细胞化学方法对病灶的MA gp100和MART-1表达进行分级。根据接受的治疗，将总共351个黑色素瘤病灶分为不同队列。预处理组（n = 175）由在任何形式的gp100免疫疗法之前获取的病灶组成，后处理组（n = 176）由用修饰的gp100表位gp209-2M ± 白细胞介素2（IL-2）接种疫苗后获取的病灶组成(1)。
不表达gp100抗原的病灶百分比高于不表达MART-1的病灶百分比（26% 对14%）。gp100高表达（> 75%）的病灶频率随治疗显著降低（47% 对34%），相反，阴性病灶增加（18% 对29%）。单独用肽（无IL-2）治疗病灶显示gp100表达显著降低（47% 对32%），在治疗中添加IL-2后增强（47% 对35%）。除非添加IL-2，MART-1的表达基本保持不变（单独MART-1肽为54% 对54%，MART-1肽 + IL-2为54% 对43%）。在治疗前评估gp100表达的94例患者（181个病灶）中，10例患者对治疗有反应。有反应患者的预处理病灶在所有病例中均表达一定水平的gp100，相比之下，27% 的无反应病灶gp100表达为阴性。结论。本研究间接表明，用MA衍生肽接种疫苗可在体内导致免疫选择。此外，它为MA疫苗的特异性以及MA表达在预测疫苗接种反应中的相关性提供了有力的免疫学证据。
