Development new generation peptides derived from CA9 as tailar-made vaccines for renal cell carcinoma

我们之前已经开发了3种CA9衍生肽疫苗（CA9p219, p288, p323），它们能够诱导HLA-A2402限制性CA9特异性CTL。最近，在23例细胞因子难治性RCC患者中进行了一项i期肽疫苗接种试验，结果显示效果良好，未发生任何重大不良事件。然而，特异性CTL的诱导需要3个月以上，临床反应需要6个月以上。这可能是由于免疫原性肽相对较低。本研究的目的是开发更多具有免疫原性的新型肽疫苗，使其具有更高的诱导ca9特异性CTL反应的能力。制备CA9p219和CA9p288修饰肽等25种ca99mer多肽，通过MHC稳定实验检测其与HLA-A24分子的亲和力。令人惊讶的是，CA9p219虽然被计算机软件估计有很高的亲和力，但其亲和力却很低，在临床试验中实际上具有最高的CTL诱导能力，这表明真正的亲和力与亲和力估计无关。基于这些数据，我们筛选了本研究中制备的所有肽是否能诱导CA9特异性CTL反应。我们发现几种多肽具有更高的诱导CA9特异性CTL反应的能力。我们目前正在研究这些肽对CA9阳性癌细胞（SW620）的直接杀伤能力。

We have previously developed 3 CA9-derived peptide vaccines (CA9p219, p288, p323) having the ability to induce HLA-A2402 restricted CA9 specific CTL. Recently a phase-I peptide vaccination trial was carried out in 23 patients with cytokine refractory RCC patients, and resulted in promising efficacy without any major adverse events. However, more than 3 months were needed for induction of specific CTL and more than 6 months were needed for clinical responses. This may be due to relatively low immunogenic peptides. The aim of our study is to develop more immunogenic new peptide vaccines having the higher ability to induce CA9-specific CTL response. We made 25 kinds of CA9 9mer peptides including modified peptides of CA9p219 and CA9p288, and checked their affinity to HLA-A24 molecule by MHC stabilization assay. Surprisingly, CA9p219 had a low affinity although it has high affinity estimation by the computer software and actually had the highest ability of CTL induction in the clinical trial, indicating that real affinity is not associated with the affinity estimation. Based on these data, we screened all peptide made in this study whether these peptides could induce CA9 specific CTL responses. We found several peptides have the higher ability to induce CA9 specific CTL responses. We are currently investigating direct killing capability to CA9 positive cancer cells (SW620) of these peptides.