Shrayer D P, Bogaars H, Wolf S F, Hearing V J, Wanebo H J
Surgical Oncology Research Laboratory, Roger Williams Medical Center, Providence, RI 02908, USA.
Int J Oncol. 1998 Aug;13(2):361-74.
The annual incidence of malignant melanoma is estimated at 10-12 per 100,000 inhabitants in countries of central Europe and the United States, and alarmingly there has been a dramatic upward trend in that estimate. The B16 murine melanoma is a rapidly growing metastatic tumor of spontaneous origin, as are human malignant melanomas. Melanoma cells produce specific antigens which are uniquely different from normal cellular antigens, and the expression of such antigens is the cornerstone for preparation of anti-melanoma vaccines. One major problem in evaluating the effectiveness of vaccination and other biologic therapies is the variability of experimental tumor models. A new metastatic model of experimental melanoma which was developed in our laboratory imitates the major clinical stages of malignant metastatic melanoma: stage I, primary (local) tumor growth and bone marrow invasion; stage II, regional lymph node involvement; and stage III, metastasis to distant organs, such as the lungs. This model has been used successfully for screening vaccines constructed in our laboratory. Immunization with formalinized vaccines (of extracellular antigens, intact melanoma cells, or B700 antigen) or irradiated vaccines (of intact melanoma cells) partially inhibit primary melanoma tumor growth, reduce metastasis to regional lymph nodes and lungs, and significantly increase mean survival time. These anti-tumor effects were improved when polyvalent and monovalent vaccines were combined with IL-2 therapy. We also compared the immunogenic activity of vaccines made from B16 melanoma cells transfected with genes encoding murine IL-2 or GM-CSF, and effects on tumor bearing mice were compared with or without therapy using the corresponding lymphokines. In sum, comparison of antibody production, growth of primary melanoma tumors, number of surviving mice, mean survival time, and percent of mice with lung metastases, showed that the best course of immunotherapy involves vaccination of mice with irradiated B16 melanoma cells transfected to secrete GM-CSF, coupled with GM-CSF therapy.
在中欧国家和美国，恶性黑色素瘤的年发病率估计为每10万居民中有10 - 12例，且令人担忧的是，这一估计数呈急剧上升趋势。B16小鼠黑色素瘤是一种自发产生的快速生长的转移性肿瘤，人类恶性黑色素瘤也是如此。黑色素瘤细胞产生的特异性抗原与正常细胞抗原截然不同，此类抗原的表达是制备抗黑色素瘤疫苗的基石。评估疫苗接种及其他生物疗法有效性的一个主要问题是实验肿瘤模型的变异性。我们实验室开发的一种新的实验性黑色素瘤转移模型模拟了恶性转移性黑色素瘤的主要临床阶段：I期，原发性（局部）肿瘤生长及骨髓浸润；II期，区域淋巴结受累；III期，转移至远处器官，如肺部。该模型已成功用于筛选我们实验室构建的疫苗。用福尔马林固定疫苗（细胞外抗原、完整黑色素瘤细胞或B700抗原）或辐照疫苗（完整黑色素瘤细胞）进行免疫接种可部分抑制原发性黑色素瘤肿瘤生长，减少向区域淋巴结和肺部的转移，并显著延长平均存活时间。当多价和单价疫苗与白细胞介素 - 2疗法联合使用时，这些抗肿瘤作用得到了改善。我们还比较了用编码小鼠白细胞介素 - 2或粒细胞 - 巨噬细胞集落刺激因子（GM - CSF）的基因转染的B16黑色素瘤细胞制成的疫苗的免疫原活性，并比较了使用相应淋巴因子治疗或不治疗对荷瘤小鼠的影响。总之，通过比较抗体产生、原发性黑色素瘤肿瘤生长、存活小鼠数量、平均存活时间以及发生肺转移的小鼠百分比，结果表明免疫治疗的最佳方案是用转染以分泌GM - CSF的辐照B16黑色素瘤细胞对小鼠进行疫苗接种，并结合GM - CSF疗法。
