HER2-specificT-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan
HER2-specificT-cell immune responses in patients vaccinated with truncated HER2 protein complexed with nanogels of cholesteryl pullulan
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DOI：
10.1158/1078-0432.ccr-06-1546
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发表时间：
2006-12-15
影响因子：
11.5
通讯作者：
Shiku, Hiroshi
中科院分区：
文献类型：
--
作者：
Kitano, Shigehisa;Kageyama, Shinichi;Shiku, Hiroshi
目的：研制一种新型的肿瘤抗原蛋白复合物-胆固醇普鲁兰多糖（CHP）纳米粒抗原递送系统。为了靶向HER 2抗原，我们制备了截短的HER 2蛋白1-146（146 HER 2）与CHP（CHP-HER 2疫苗）复合。我们设计了一项临床研究，以评估疫苗的安全性和HER 2特异性T细胞免疫应答，通过新开发的酶联免疫斑点试验，用mRNA转导的植物血凝素刺激的CD 4（+）T细胞在HLA-A2402阳性的治疗难治性HER 2表达cancer.Experimental Design患者中进行测量。每例患者均接受s.c.每两周接种一次300 μ g CHP-HER 2疫苗，共接种三次，然后加强接种。通过酶联免疫斑点试验（ELISA）检测CHP-HER 2疫苗免疫应答，检测CHP-HER 2疫苗免疫耐受性。唯一的副作用是在接种部位出现1级短暂性皮肤反应。在接受4 - 8次疫苗接种的5名患者中检测到HER 2特异性CD 8（+）和/或CD 4（+）T细胞免疫应答，其中在这些患者中检测到两种T细胞应答。结论：CHP-HER 2疫苗是安全的，可诱导HER 2特异性的CD 8（+）和/或CD 4（+）T细胞免疫应答。
Purpose: We developed a complex of tumor antigen protein, with a novel nanoparticle antigen delivery system of cholesteryl pullulan (CHP). To target HER2 antigen, we prepared truncated HER2 protein 1-146 (146HER2) complexed with, CHP, the CHP-HER2 vaccine. We designed a clinical study to assess the safety of the vaccine and HER2-specific T-cell immune responses measured by the newly developed enzyme-linked immunospot assay with mRNA-transduced phytohemagglutinin-stimulated CD4(+) T cells in HLA-A2402-positive patients with therapy-refractory HER2-expressing cancers.Experimental Design: Nine patients with various types of solid tumors were enrolled. Each patient was s.c. vaccinated biweekly with 300 mu g of CHP-HER2 vaccine for three times followed by booster doses. HER2-specific T-cell responses were evaluated by enzyme-linked immunospot assay by targeting autologous phytohemagglutinin-stimulated CD4(+) T cells transduced with 146HER2-encoding mRNA to cover both identified peptides and unknown epitopes for MHC class I and class II that might exist in the sequence of the Vaccine protein.Results: CHP-HER2 vaccine was well tolerated; the only adverse effect was grade 1 transient skin reaction at the sites of vaccination. HER2-specific CD8(+) and/or CD4(+) T-cell immune responses were detected in five patients who received four to eight vaccinations, among whom both T-cell responses were detected in these patients. In four patients with CD8(+) T-cell responses, two patients reacted to previously identified HER2(63-71) peptide and the other two reacted only to 146HER2 mRNA-transduced cells.Conclusions: CHP-HER2 vaccine was safe and induced HER2-specific CD8(+) and/or CD4(+) T-cell immune responses.