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

我们先前已经开发了3种具有诱导HLA-A2402限制性CA 9特异性CTL的能力的CA 9衍生肽疫苗（CA 9 p219、p288、p323）。最近，在23名细胞因子难治性RCC患者中进行了I期肽疫苗接种试验，并产生了有希望的疗效，没有任何重大不良事件。然而，诱导特异性CTL需要3个月以上，临床应答需要6个月以上。这可能是由于相对低的免疫原性肽。本研究的目的是开发免疫原性更强、诱导CA 9特异性CTL应答能力更强的新型肽疫苗。我们制备了25种CA 9 9肽，其中包括CA 9 p219和CA 9 p288的修饰肽，并通过MHC稳定化试验检测了它们与HLA-A24分子的亲和力。令人惊讶的是，CA 9 p219具有低亲和力，尽管其通过计算机软件具有高亲和力估计，并且实际上在临床试验中具有最高的CTL诱导能力，这表明真实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可以诱导CA 9特异性CTL应答。我们发现有几种多肽具有较高的诱导CA 9特异性CTL应答的能力。我们目前正在研究这些肽对CA 9阳性癌细胞（SW 620）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.