Division of Immunotherapy, Shizuoka Cancer Center Research Institute, Shizuoka 411-8777, Japan.
Oncol Rep. 2012 Oct;28(4):1131-8. doi: 10.3892/or.2012.1956. Epub 2012 Aug 7.
Metastatic and chemoresistant melanoma can be a good target of immunotherapy because it is an intractable cancer with a very poor prognosis. Previously, we tested a dendritic cell (DC)-based phase I vaccine, and confirmed that it was safe. In the present study, we performed a phase II trial of a DC vaccine for metastatic melanoma patients with mainly the HLA-A24 genotype, and investigated the efficacy of the vaccine. Twenty-four patients with metastatic melanoma were enrolled into a phase II study of DC-based immunotherapy. The group included 19 HLA-A24-positive (A2402) patients and 3 HLA-A2-positive (A0201) patients. The protocol for DC production was similar to that in the phase I trial. Briefly, a cocktail of 5 melanoma-associated synthetic peptides (gp100, tyrosinase, MAGE-A2, MAGE-A3 and MART-1 or MAGE‑A1) restricted to HLA-A2 or A24 and KLH were used for DC pulsing. Finally, DCs were injected subcutaneously (s.c.) into the inguinal region in the dose range of 1-5x107 per shot. The DC ratio (lin-HLA-DR+) of the vaccine was 38.1±13.3% and the frequency of CD83+ DCs was 25.7±20.8%. Other parameters regarding DC processing were not different from phase I. Immune response-related parameters including the ELISPOT assay, DTH reaction to peptide or KLH, DC injection numbers were shown to be related to a good prognosis. The ELISPOT reaction was positive in 75% of the patients vaccinated. The increase of anti-melanoma antigen antibody titer before vaccination was also shown to be a prognosis factor, but that post-vaccination was not. Based on immunohistochemical analysis, CD8 and IL-17 were not involved in the prognosis. Adverse effects of more than grade III were not seen. Overall survival analysis revealed a significant survival prolongation effect in DC-given melanoma patients. These results suggest that peptide cocktail-treated DC vaccines may be a safe and effective therapy against metastatic melanoma in terms of prolongation of overall survival time.
转移性和化疗耐药性黑色素瘤可以成为免疫治疗的一个良好靶点，因为它是一种预后极差的难治性癌症。此前，我们测试了一种基于树突状细胞（DC）的 I 期疫苗，并证实其安全性。在本研究中，我们对主要 HLA-A24 基因型的转移性黑色素瘤患者进行了 DC 疫苗的 II 期试验，以研究疫苗的疗效。24 名转移性黑色素瘤患者被纳入基于 DC 的免疫治疗 II 期研究。该组包括 19 名 HLA-A24 阳性（A2402）患者和 3 名 HLA-A2 阳性（A0201）患者。DC 产生的方案与 I 期试验相似。简而言之，使用黑色素瘤相关的 5 种合成肽（gp100、酪氨酸酶、MAGE-A2、MAGE-A3 和 MART-1 或 MAGE-A1）的鸡尾酒与 HLA-A2 或 A24 和 KLH 结合，用于 DC 冲击。最后，将 DC 以 1-5x107 个/次的剂量皮下（s.c.）注射到腹股沟区域。疫苗的 DC 比（lin-HLA-DR+）为 38.1±13.3%，CD83+DC 频率为 25.7±20.8%。DC 处理的其他参数与 I 期没有区别。免疫反应相关参数，包括 ELISPOT 测定、肽或 KLH 的 DTH 反应、DC 注射次数，均与预后良好相关。接种疫苗的患者中有 75%的 ELISPOT 反应阳性。接种前抗黑色素瘤抗原抗体滴度的增加也被证明是一个预后因素，但接种后则不是。基于免疫组织化学分析，CD8 和 IL-17 与预后无关。未观察到 III 级以上的不良事件。总生存分析显示，给予 DC 的黑色素瘤患者的总生存时间有显著延长。这些结果表明，基于肽鸡尾酒处理的 DC 疫苗可能是一种安全有效的转移性黑色素瘤治疗方法，可以延长总生存时间。
