Introduction Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) signaling blockade is the most effective strategy for the treatment of immune evading hepatocellular carcinoma (HCC). While immune checkpoint inhibitor has revolutionized the concept of cancer treatment, it has also led to unexpected tumor growth. Regulatory T cells express PD-1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) receptors, which are proliferated and activated by antibody binding, and their ratio to CD8+ T cells is altered, which is one of the causes for hyper progressive disease (HPD). We examined the frequency of HPD in anti-PD-1/PD-L1 monotherapy and combination therapy with vascular endothelial growth factor (VEGF) antibody and anti-CTLA-4 antibodies. Methods This was a prospective and retrospective cohort study which enrolled 198 patients with unresectable HCC from January 2015 to December 2021 at the Kindai University Hospital. Fifty-eight patients received anti-PD-1/PD-L1 monotherapy, 119 patients combination with VEGF antibody, and 21 patients combination with anti-CTLA-4 antibody. We defined HPD as tumor growth rate (TGR) ratio ≥4, ΔTGR ≥40%, and tumor growth kinetics ratio ≥4. Results The HPD rate was 10.3% (6/58) in anti-PD-1/PD-L1 monotherapy, 1.7% (2/119) in combination with VEGF antibody, and 4.8% (1/21) in combination with anti-CTLA-4 antibody (p = 0.034). The odds ratio for HPD in the combined anti-CTLA-4 antibody group was 0.433 (95% confidence interval [CI]: 0.05-3.83) when compared to the anti-PD-1/PD-L1 monotherapy group and 2.93 (95% CI: 0.25-33.79) when compared to the combined VEGF antibody group. Conclusion The frequency of HPD in unresectable HCC compared to anti-PD-1/PD-L1 monotherapy was decreased with the combination with anti-VEGF antibody and not increased with anti-CTLA-4 antibody. Anti-PD-1/PD-L1 combined with anti-CTLA-4 antibody is now available in real-world and needs to be further validated with accumulated clinical practice.

中文翻译：

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联合免疫疗法和抗程序性细胞死亡蛋白 1/程序性死亡配体 1 单一疗法治疗不可切除的肝细胞癌的超进展性疾病发生率。


简介 程序性细胞死亡蛋白 1 (PD-1)/程序性死亡配体 1 (PD-L1) 信号传导阻断是治疗免疫逃避性肝细胞癌 (HCC) 的最有效策略。虽然免疫检查点抑制剂彻底改变了癌症治疗的概念，但它也导致了意想不到的肿瘤生长。调节性T细胞表达PD-1和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）受体，这些受体通过抗体结合而增殖和激活，并且它们与CD8+T细胞的比例发生改变，这是过度治疗的原因之一。进行性疾病（HPD）。我们检查了抗 PD-1/PD-L1 单一疗法以及血管内皮生长因子 (VEGF) 抗体和抗 CTLA-4 抗体联合疗法中 HPD 的频率。方法 这是一项前瞻性和回顾性队列研究，入组了 2015 年 1 月至 2021 年 12 月在近代大学医院的 198 名不可切除的 HCC 患者。 58 名患者接受了抗 PD-1/PD-L1 单一疗法，119 名患者接受了 VEGF 抗体联合治疗，21 名患者接受了抗 CTLA-4 抗体联合治疗。我们将 HPD 定义为肿瘤生长率 (TGR) 比率≥4、ΔTGR ≥40%、肿瘤生长动力学比率≥4。结果 抗PD-1/PD-L1单药治疗的HPD率为10.3%（6/58），与VEGF抗体联合治疗的HPD率为1.7%（2/119），与抗PD-1/PD-L1抗体联合治疗的HPD率为4.8%（1/21）。 CTLA-4 抗体 (p = 0.034)。与抗 PD-1/PD-L1 单一疗法组相比，联合抗 CTLA-4 抗体组中 HPD 的优势比为 0.433（95% 置信区间 [CI]：0.05-3.83）和 2.93（95% 置信区间 [CI]：0.05-3.83）。 CI：0.25-33.79）与联合 VEGF 抗体组相比。 结论 与抗 PD-1/PD-L1 单药治疗相比，不可切除的 HCC 中与抗 VEGF 抗体联合治疗的 HPD 频率降低，而与抗 CTLA-4 抗体联合治疗的 HPD 频率不增加。抗PD-1/PD-L1联合抗CTLA-4抗体现已在现实世界中使用，需要通过积累的临床实践进一步验证。