Taylor Graham S, Jia Hui, Harrington Kevin, Lee Lip Wai, Turner James, Ladell Kristin, Price David A, Tanday Manjit, Matthews Jen, Roberts Claudia, Edwards Ceri, McGuigan Lesley, Hartley Andrew, Wilson Steve, Hui Edwin P, Chan Anthony T C, Rickinson Alan B, Steven Neil M
Cancer Research UK Centre, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
Division of Cancer Biology, The Institute of Cancer Research/The Royal Marsden Hospital, London, United Kingdom.
Clin Cancer Res. 2014 Oct 1;20(19):5009-22. doi: 10.1158/1078-0432.CCR-14-1122-T. Epub 2014 Aug 14.
Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials.
爱泼斯坦-巴尔病毒（EBV）与多种癌症相关，其中肿瘤细胞表达EBV抗原EBNA1和LMP2。设计了一种包含重组痘苗病毒MVA-EL的治疗性疫苗，以增强对这些肿瘤抗原的免疫力。进行了一项I期试验，以证明MVA-EL在一系列剂量下的安全性和免疫原性。
英国的16例EBV阳性鼻咽癌（NPC）患者接受了三次皮内注射MVA-EL，每隔3周注射一次，剂量水平在5×10⁷至5×10⁸蚀斑形成单位（pfu）之间。在筛选时、每个疫苗周期后以及疫苗接种后期间采集血样。使用IFNγ ELISpot试验，用重叠的EBNA1/LMP2肽混合物或HLA匹配的表位肽测量T细胞反应。使用多色流式细胞术对功能性反应性T细胞群体进行表征。
疫苗接种总体耐受性良好。14例患者中有8例（7/14，EBNA1；6/14，LMP2）接种疫苗后对至少一种抗原的免疫力增强，包括识别与不同种族相关的EBV毒株之间不同的表位。免疫表型分析显示，疫苗接种分别诱导了CD4和CD8区内针对EBNA1和LMP2的反应性T细胞群体的分化和功能多样化。
MVA-EL在不同种族中是安全且具有免疫原性的，因此适用于全球针对不同EBV阳性癌症的试验，以及在NPC最常见的东南亚地区。建议在当前的I期B和II期试验中使用最高剂量（5×10⁸ pfu）进行研究。
