1区 · 医学
Article
作者: Han, Yanyan ; Tang, Longqing ; Tan, Jiehui ; Zhou, Qian ; Xu, Lixia ; Xie, Yubin ; Li, Dongming ; Li, Xiaoshuang ; Zeng, Xuezhen ; Chen, Shuling ; Dai, Zihao ; Liu, Zelong ; Lai, Jiaming ; Mei, Jie ; He, Minghui ; Xiao, Han ; Li, Shaoqiang ; Su, Tianhong ; Ma, Yifan ; Chen, Zebin ; Peng, Baogang ; Peng, Zhenwei ; Wang, Wei ; Hu, Wei ; Peng, Sui ; Hu, Huanjing ; Li, Bin ; Kuang, Ming ; Shen, Shunli ; Zhou, Xiangjun
Abstract:A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.