Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients
Safety and antibody immune response of CHP-NY-ESO-1 vaccine combined with poly-ICLC in advanced or recurrent esophageal cancer patients
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DOI：
10.1007/s00262-021-02892-w
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发表时间：
2021-03-22
影响因子：
5.8
通讯作者：
Shiku, Hiroshi
中科院分区：
文献类型：
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作者：
Ishikawa, Takeshi;Kageyama, Shinichi;Shiku, Hiroshi
胆固醇支链淀粉 (CHP) 和 NY-ESO-1 抗原蛋白 (CHP-NY-ESO-1) 的纳米颗粒复合物向 MHC I 类和 II 类途径呈递多个表位肽，导致 CD8(+) 和 CD4(+) T 细胞应答。 Poly-ICLC 是一种合成的双链 RNA，是 Toll 样受体 (TLR)-3 的激动剂，也是黑色素瘤分化相关基因 (MDA)-5 的细胞质受体。它应该是一种合适的癌症疫苗的免疫佐剂，以克服抑制性肿瘤微环境。我们对晚期或复发性食管癌患者进行了 CHP-NY-ESO-1 联合多聚 ICLC 的 1 期临床试验。每两周以 200/0.5 或 200/1.0（分别为队列 1 和 2）的剂量施用 CHP-NY-ESO-1/poly-ICLC (μ g/mg)，总共六剂。主要终点是安全性和免疫反应。次要终点是肿瘤反应。总共招募了 16 名患者，每个队列中有 6 名患者完成了试验。最常见的不良事件 (AE) 是注射部位皮肤反应 (86.7%)。未观察到 3 级或以上的药物相关 AE。没有观察到肿瘤反应，三名患者 (30%) 病情稳定。两个队列之间的免疫反应相当，所有患者 (100%) 均在接种 2.5 次疫苗后达到抗体反应。将单独的 CHP-NY-ESO-1 与聚 ICLC 组合进行比较，两组中的所有患者均表现出抗体反应，但组合组中的滴度更高。在小鼠模型中，将抗 PD-1 抗体添加到 CHP-NY-ESO-1/poly-ICLC 组合中可抑制表达 NY-ESO-1 的肿瘤的生长。将疫苗与 PD-1 阻断剂相结合有望在人体试验中发挥作用。
The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8(+) and CD4(+) T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (mu g/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.