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

我们已经开发了3种CA9多肽疫苗(CA9p219、p288、p323)，它们能够诱导人类白细胞抗原A2402限制性CA9特异性CTL。最近在23例细胞因子难治性肾癌患者中进行了一期多肽疫苗接种试验，取得了良好的疗效，没有发生任何重大不良事件。但诱导特异性CTL需要3个月以上，临床应答需要6个月以上。这可能是由于免疫原肽相对较低所致。本研究的目的是开发更具免疫原性、诱导CA9特异性CTL反应能力更强的新型多肽疫苗。我们制备了包括CA9p219和CA9p288修饰多肽在内的25种CA99多肽，并用MHC稳定化实验检测了它们与人类白细胞抗原A24分子的亲和力。令人惊讶的是，尽管计算机软件对CA9p219的亲和力估计很高，但它的亲和力很低，而且在临床试验中实际上具有最高的CTL诱导能力，表明真正的亲和力与亲和力估计无关。在这些数据的基础上，我们筛选了本研究制备的所有多肽是否能够诱导CA9特异性CTL反应。我们发现有几个多肽具有较高的诱导CA9特异性CTL反应的能力。我们目前正在研究这些多肽对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.