Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer.
Phase I clinical study of anti-apoptosis protein, survivin-derived peptide vaccine therapy for patients with advanced or recurrent colorectal cancer.
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DOI：
10.1186/1479-5876-2-19
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发表时间：
2004-06-13
影响因子：
7.4
通讯作者：
Hirata K
中科院分区：
文献类型：
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作者：
Tsuruma T;Hata F;Torigoe T;Furuhata T;Idenoue S;Kurotaki T;Yamamoto M;Yagihashi A;Ohmura T;Yamaguchi K;Katsuramaki T;Yasoshima T;Sasaki K;Mizushima Y;Minamida H;Kimura H;Akiyama M;Hirohashi Y;Asanuma H;Tamura Y;Shimozawa K;Sato N;Hirata K
Survivin是含有单一杆状病毒IAP重复结构域的IAP家族成员。它在胎儿发育过程中表达，但在终末分化的正常成人组织中检测不到。我们曾报道Survivin及其剪接变异体Survivin-2B在多种肿瘤组织和肿瘤细胞系中大量表达，适合作为活性特异性抗癌免疫的靶抗原。随后，我们鉴定了一种可被CD8+细胞毒性T淋巴细胞(CTL)识别的人类白细胞抗原-A24限制性抗原肽Survivin-2B80-88(AYACNTSTL)。因此，我们开始了一项I期临床研究，评估Survivin-2B多肽疫苗对表达Survivin的晚期或复发结直肠癌患者的疗效。Survivin-2B多肽皮下接种6次，间隔14天。在完成接种计划的15名患者中，3名患者出现轻微毒性，包括贫血(2级)、全身不适(1级)和发烧(1级)。所有患者均未观察到严重不良反应。在6例患者中，肿瘤标志物(CEA和CA19-9)水平在接种期间一过性下降。1例患者肿瘤体积轻微缩小，被认为是轻微反应。3名患者没有发现任何变化，而其余11名患者经历了肿瘤进展。用HLAA24/多肽四聚体对1例患者外周血淋巴细胞进行分析，发现4次免疫后多肽特异性CTL频率从CD8+T细胞的0.09%增加到0.35%。这项I期临床研究表明，基于Survivin-2B多肽的疫苗接种是安全的，应进一步考虑对表达HLA-A24的结直肠癌患者的潜在免疫和临床疗效。
Survivin is a member of the inhibitor of apoptosis protein (IAP) family containing a single baculovirus IAP repeat domain. It is expressed during fetal development but becomes undetectable in terminally differentiated normal adult tissues. We previously reported that survivin and its splicing variant survivin-2B was expressed abundantly in various types of tumor tissues as well as tumor cell lines and was suitable as a target antigen for active-specific anti-cancer immunization. Subsequently, we identified an HLA-A24-restricted antigenic peptide, survivin-2B80-88 (AYACNTSTL) recognized by CD8+ cytotoxic T lymphocytes (CTLs). We, therefore, started a phase I clinical study assessing the efficacy of survivin-2B peptide vaccination in patients with advanced or recurrent colorectal cancer expressing survivin. Vaccinations with survivin-2B peptide were given subcutaneously six times at 14-day intervals. Of 15 patients who finished receiving the vaccination schedule, three suffered slight toxicities, including anemia (grade 2), general malaise (grade 1), and fever (grade 1). No severe adverse events were observed in any patient. In 6 patients, tumor marker levels (CEA and CA19-9) decreased transiently during the period of vaccination. Slight reduction of the tumor volume was observed in one patient, which was considered a minor responder. No changes were noted in three patients while the remaining eleven patients experienced tumor progression. Analysis of peripheral blood lymphocytes of one patient using HLA-A24/peptide tetramers revealed an increase in peptide-specific CTL frequency from 0.09% to 0.35% of CD8+ T cells after 4 vaccinations. This phase I clinical study indicates that survivin-2B peptide-based vaccination is safe and should be further considered for potential immune and clinical efficacy in HLA-A24-expression patients with colorectal cancer.