Nagorsen Dirk, Thiel Eckhard
Medical Department of Hematology and Oncology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Cancer Immunol Immunother. 2008 Dec;57(12):1903-10. doi: 10.1007/s00262-008-0493-6. Epub 2008 Mar 4.
Immunological treatment of cancer has made some very promising advances during the last years. Anti-cancer vaccination using peptides or peptide-pulsed dendritic cells and adoptive transfer of in vitro generated, epitope-specific T cells depend on a well-fitting interaction of HLA molecule and epitope. Accurate HLA-typing is a key factor for successful anti-cancer vaccination. No comprehensive data and no suggestion exist on the HLA-typing in this setting. We performed a systematic review of PubMed analyzing HLA-typing data in cancer vaccination trials over the last 4 years (2004-2007). Then, using the SYFPEITHI database, we calculated the peptide binding prediction of the eight most often used HLA-A0201 binding epitopes. Finally, high-resolution typing [by sequence-specific primers (SSP)] data of a HLA-A02 or HLA-A24 positive population in Berlin, Germany, were analyzed. Forty-five cancer vaccination trials with 764 patients were included. Eighteen studies were performed in the USA, 13 in Europe, 12 in Asia (mainly Japan), and two in Australia. Most common diseases targeted were melanoma, prostate cancer, colorectal cancer, renal cell cancer, and breast cancer. The trials tested protocols using peptide plus adjuvants without DC or protocols using peptide-pulsed DC. In 38 trials (84%) HLA-A2 positive patients were vaccinated, in 11 studies (24%) HLA-A24 positive patients were vaccinated. Nineteen studies with 291 patients (38%) presented the HLA type as four-digit code (high-resolution), 26 studies with 473 patients (62%) presented the HLA-type in a low-resolution code. The method of HLA determination was given in six out of 45 trials (13%). Using the SYFPEITHI database we calculated the peptide binding prediction of the eight most often used HLA-A0201 binding tumor antigen-derived epitopes for binding to HLA-A0203. While the epitopes had a binding score of 17-28 for HLA-A0201, the score for binding to HLA-A0203 was zero in seven out of eight tested peptides. Only for one peptide the score was eight. Finally, we analyzed high-resolution data of HLA-A02 and HLA-A24 positive patients in Berlin, Germany. We found the HLA-A0201 allele and HLA-A2402 allele in 95%, respectively. HLA-A0201 and HLA-A*2402 are most commonly used for peptide based vaccine in cancer. Data on HLA-typing given in the included cancer vaccine manuscripts are fractional. Only 13% report the method of HLA typing and most HLA types are given as low-resolution code. Looking at the binding of specific peptides to both the alleles, it is important to perform high-resolution typing. Further suggestions for immunogenetic laboratories and clinical tumor immunologists regarding HLA-typing for cancer vaccine trials and adoptive T cell transfer approaches are discussed.
在过去几年中，癌症的免疫治疗取得了一些非常有前景的进展。使用肽或肽脉冲树突状细胞的抗癌疫苗接种以及体外产生的表位特异性T细胞的过继转移依赖于HLA分子和表位的良好适配相互作用。准确的HLA分型是成功进行抗癌疫苗接种的关键因素。在这种情况下，不存在关于HLA分型的全面数据和建议。我们对PubMed进行了系统综述，分析了过去4年（2004 - 2007年）癌症疫苗试验中的HLA分型数据。然后，使用SYFPEITHI数据库，我们计算了8种最常用的HLA - A0201结合表位与HLA - A0203的肽结合预测。最后，分析了德国柏林HLA - A02或HLA - A24阳性人群的高分辨率分型[通过序列特异性引物（SSP）]数据。纳入了45项有764例患者的癌症疫苗试验。18项研究在美国进行，13项在欧洲，12项在亚洲（主要是日本），2项在澳大利亚。最常见的目标疾病是黑色素瘤、前列腺癌、结直肠癌、肾细胞癌和乳腺癌。这些试验测试了使用肽加佐剂但无树突状细胞的方案或使用肽脉冲树突状细胞的方案。在38项试验（84%）中对HLA - A2阳性患者进行了疫苗接种，在11项研究（24%）中对HLA - A24阳性患者进行了疫苗接种。19项有291例患者（38%）的研究将HLA类型表示为四位数代码（高分辨率），26项有473例患者（62%）将HLA类型表示为低分辨率代码。45项试验中有6项（13%）给出了HLA测定方法。使用SYFPEITHI数据库，我们计算了8种最常用的HLA - A0201结合肿瘤抗原衍生表位与HLA - A0203结合的肽结合预测。虽然这些表位与HLA - A0201的结合分数为17 - 28，但在8个测试肽中有7个与HLA - A0203结合的分数为零。只有一个肽的分数为8。最后，我们分析了德国柏林HLA - A02和HLA - A24阳性患者的高分辨率数据。我们分别在95%的患者中发现了HLA - A0201等位基因和HLA - A2402等位基因。HLA - A0201和HLA - A2402最常用于癌症的基于肽的疫苗。纳入的癌症疫苗手稿中给出的HLA分型数据不完整。只有13%报告了HLA分型方法，大多数HLA类型以低分辨率代码给出。考虑到特定肽与这两个等位基因的结合情况，进行高分辨率分型很重要。讨论了针对免疫遗传学实验室和临床肿瘤免疫学家在癌症疫苗试验和过继性T细胞转移方法的HLA分型方面的进一步建议。
