A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors
A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors
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DOI：
10.1097/00002371-199903000-00007
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发表时间：
1999-03-01
影响因子：
3.9
通讯作者：
Schlom, J
中科院分区：
文献类型：
--
作者：
Khleif, SN;Abrams, SI;Schlom, J
ras基因突变发生在20%的人类癌症中。这些基因反过来又产生癌细胞特有的突变蛋白质，使它们与免疫系统的正常细胞区别开来。因此，突变的Ras蛋白可能成为免疫治疗的潜在靶点。我们在晚期癌症患者中进行了一项I期/试点临床试验，以测试毒性和通过接种反映密码子12突变的13-mer突变Ras肽诱导免疫反应的能力。这些肽对应于每个患者自身的肿瘤Ras突变。患者每月x 3次皮下接种特异性Ras肽和Deter佐剂（RiBi ImmunoChem Research, Inc., Hamilton， MT, usa），在五种不同的肽剂量水平（100,500,1,000,1,500和5,000 μ g）之一。10名可评估患者中有3名产生突变的Ras特异性CD4+和/或CD8+ t细胞免疫反应。在密码子12处特异性Gly to Val突变的CD8+细胞毒细胞能够裂解携带相应突变而非野生型ras基因的hla - a2匹配的肿瘤细胞系。该治疗具有良好的耐受性，没有证据表明五种剂量水平中的任何一种都有严重的急性或延迟的全身副作用。我们证明，我们可以在癌症患者中产生特异性t淋巴细胞反应，检测Ras癌蛋白中单个氨基酸的差异。没有发现免疫反应和轻微副作用是剂量依赖的。这种方法可能为产生肿瘤定向治疗提供一个独特的机会。此外，在体外用相应的肽刺激这些细胞产生特异性t细胞系，可用于过继免疫治疗。
Mutations in the ras genes occur in 20% of all human cancers. These genes, in turn, produce mutated proteins that are unique to cancer cells, rendering them distinguishable from normal cells by the immune system. Thus, mutated Ras proteins may form potential targets for immune therapy. We conducted a phase I/pilot clinical trial in patients with advanced cancers to test the toxicity and the ability to induce an immune response by vaccination with 13-mer mutated Ras peptides reflecting codon 12 mutations. These peptides corresponded to each of the patient's own tumor Ras mutation. Patients were vaccinated monthly x 3 subcutaneously with the specific Ras peptide along with Deter adjuvant (RiBi ImmunoChem Research, Inc., Hamilton, MT, U.S.A.) at one of five different peptide dose levels (100, 500, 1,000, 1,500, and 5,000 mu g). Three out of 10 evaluable patients generated a mutant Ras specific CD4+ and/or CD8+ T-cell immune response. The CD8+ cytotoxic cells specific for Gly to Val mutation at codon 12 were capable of lysing an HLA-A2-matched tumor cell line carrying the corresponding mutant but not the wild-type ras gene. The treatment has been well tolerated with no evidence of serious acute or delayed systemic side effects on any of the five dose levels. We demonstrated that we can generate in cancer patients specific T-lymphocyte responses that detect single amino acid differences in Ras oncoproteins. Neither the immune responses nor the minor side effects seen were found to be dose dependent. This approach may provide a unique opportunity for generating a tumor-directed therapy. Also, in vitro stimulation of these cells with the corresponding peptide generated specific T-cell lines that could be used for adoptive immune therapy.