Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402.
Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402.
复制标题
DOI：
10.1186/1479-5876-8-84
复制
发表时间：
2010-09-16
影响因子：
7.4
通讯作者：
Tahara H
中科院分区：
文献类型：
--
作者：
Baba T;Sato-Matsushita M;Kanamoto A;Itoh A;Oyaizu N;Inoue Y;Kawakami Y;Tahara H
肿瘤相关抗原（TAA）gp 100是最早发现的抗原之一，并已用于治疗黑色素瘤患者的临床试验。然而，由于种族差异，限制于HLA-A*2402的gp 100表位肽尚未进行广泛的临床研究。由于它是日本人群中最常见的HLA I类等位基因，我们使用HLA-A*2402 gp 100肽进行了癌症疫苗接种的I期临床试验，以治疗转移性黑素瘤患者。测试基于HLA-A*2402 gp 100肽的癌症疫苗的I期临床方案旨在评估安全性作为主要终点，并获得东京大学机构审查委员会的批准。还收集了与免疫学和抗肿瘤应答相关的信息作为次要终点。根据方案设定的标准招募HLA-A*2402阳性的IV期黑素瘤患者，并用由用不完全弗氏佐剂（IFA）乳化的表位肽（VYFFLPDHL，gp 100-in 4）组成的疫苗进行免疫，总共4次，间隔两周。在每次疫苗接种之前，从血液中分离外周血单核细胞（PBMC）并储存在-80 ° C下。将储存的PBMC解冻，并通过IFN-γ- ELISPOT和MHC-Dextramer测定来检查肽特异性T淋巴细胞的频率。在本研究入组的6例患者中未观察到大于I级的相关不良事件。在入选患者中未观察到临床反应，尽管在两名患者中接种疫苗后观察到白癜风。用ELISPOT试验在4例患者中观察到肽特异性免疫应答的促进。此外，使用MHC-Dextramer测定在所有患者中观察到CD 8 + gp 100-in 4 + CTL的显著增加。从一些患者的PBMC中成功地建立了特异于gp 100-in 4的细胞毒性T淋巴细胞（CTL）克隆，这些CTL克隆能够裂解内源性表达HLA限制性gp 100-in 4的黑色素瘤细胞系888 mel。我们的研究结果表明，这种HLA限制性gp 100-in 4肽疫苗接种方案耐受性良好，可以在多个患者中诱导抗原特异性T细胞应答。虽然没有观察到客观的抗肿瘤作用，但这种方法的有效性可以通过适当的修改来增强。
The tumor associated antigen (TAA) gp100 was one of the first identified and has been used in clinical trials to treat melanoma patients. However, the gp100 epitope peptide restricted to HLA-A*2402 has not been extensively examined clinically due to the ethnic variations. Since it is the most common HLA Class I allele in the Japanese population, we performed a phase I clinical trial of cancer vaccination using the HLA-A*2402 gp100 peptide to treat patients with metastatic melanoma. The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays. No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+ gp100-in4+ CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4. Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.