Kyte Jon Amund, Kvalheim Gunnar, Lislerud Kari, thor Straten Per, Dueland Svein, Aamdal Steinar, Gaudernack Gustav
Section for Immunotherapy, Department of Immunology, Cancer Research Institute, The Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
Cancer Immunol Immunother. 2007 May;56(5):659-75. doi: 10.1007/s00262-006-0222-y. Epub 2006 Sep 1.
We have developed an individualized melanoma vaccine based on autologous dendritic cells (DCs) transfected with autologous tumor-mRNA. The vaccine targets the unique spectrum of tumor antigens in each patient and may recruit multiple T cell clones. In a recent phase I/II trial, we demonstrated T cell responses against vaccine antigens in 9/19 patients evaluable by T cell assays. Here, we report a follow-up study that was conducted to characterize interesting T cell responses and to investigate the effects of long-term booster vaccination. Two patients were selected for continued vaccine therapy. The clinical follow-up suggested a favorable clinical development in both patients. The immunological data (T cell proliferation/IFNgamma ELISPOT/Bioplex cytokine assays) indicated sustained T cell responses and suggested an enhancing effect of booster vaccinations. Both CD4(+) and CD8(+) T cell responses were demonstrated. From post-vaccination samples, we generated 39 T cell clones that responded specifically to stimulation by mRNA-transfected DCs and 12 clones that responded to mock-transfected DCs. These data clearly indicate a two-component vaccine response, against transfected and non-transfected antigens. T cell receptor (TCR) clonotype mapping, performed on 11 tDC-specific clones, demonstrated that 10/11 clones had different TCRs. The results thus indicate a broad spectrum T cell response against antigens encoded by the transfected tumor-mRNA. We generally observed mixed Th1/Th2 cytokine profiles, even in T cell clones that were confirmed to be derived from a single cell. This finding suggests that cytokine patterns after cancer vaccination may be more complex than indicated by the classic Th1/Th2 dichotomy.
我们研发了一种基于自体树突状细胞（DCs）的个体化黑色素瘤疫苗，该DCs用自体肿瘤mRNA进行转染。这种疫苗针对每位患者独特的肿瘤抗原谱，可能募集多个T细胞克隆。在最近的一项I/II期试验中，我们通过T细胞检测在9/19例可评估患者中证实了针对疫苗抗原的T细胞反应。在此，我们报告一项后续研究，旨在表征有趣的T细胞反应并研究长期加强疫苗接种的效果。选择两名患者继续进行疫苗治疗。临床随访表明两名患者的临床进展良好。免疫数据（T细胞增殖/IFNγ ELISPOT/生物芯片细胞因子检测）显示T细胞反应持续存在，并提示加强疫苗接种具有增强作用。CD4(+)和CD8(+) T细胞反应均得到证实。从接种疫苗后的样本中，我们获得了39个对mRNA转染的DCs刺激有特异性反应的T细胞克隆和12个对模拟转染的DCs有反应的克隆。这些数据清楚地表明了针对转染和未转染抗原的双组分疫苗反应。对11个tDC特异性克隆进行的T细胞受体（TCR）克隆型图谱分析表明，10/11个克隆具有不同的TCR。因此，结果表明针对转染的肿瘤mRNA编码抗原存在广泛的T细胞反应。我们通常观察到混合的Th1/Th2细胞因子谱，即使在被证实源自单个细胞的T细胞克隆中也是如此。这一发现表明癌症疫苗接种后的细胞因子模式可能比经典的Th1/Th2二分法所表明的更为复杂。
