Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma.
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DOI：
10.1016/j.jhep.2016.10.029
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发表时间：
2017-03
影响因子：
25.7
通讯作者：
Greten TF
中科院分区：
文献类型：
--
作者：
Duffy AG;Ulahannan SV;Makorova-Rusher O;Rahma O;Wedemeyer H;Pratt D;Davis JL;Hughes MS;Heller T;ElGindi M;Uppala A;Korangy F;Kleiner DE;Figg WD;Venzon D;Steinberg SM;Venkatesan AM;Krishnasamy V;Abi-Jaoudeh N;Levy E;Wood BJ;Greten TF
Tremelimumab 是一种全人源单克隆抗体，可与活化 T 淋巴细胞表面的细胞毒性 T 淋巴细胞相关蛋白 4 (CTLA-4) 结合。消融疗法诱导外周免疫反应，这可能会增强晚期肝细胞癌 (HCC) 患者的抗 CTLA4 治疗效果。本研究旨在证明曲美木单抗是否可以安全可行地与消融联合使用。纳入32名HCC患者：男：女：28：4；中位年龄：62 岁（范围 36-76 岁）。患者每 4 周接受两种剂量水平的 tremelimumab（静脉注射 3.5 和 10 mg/kg），共 6 剂，然后每月输注 3 次，直至达到停止治疗标准。第36天，患者接受次全射频消融或化疗。每 8 周通过对比增强 CT 或 MRI 扫描进行一次分期。没有遇到剂量限制性毒性。最常见的毒性是瘙痒。在 19 名可评估的患者中，有 5 名（26.3%；95% CI：9.1–51.2%）获得了确认的部分缓解。 14 名可量化 HCV 患者中，有 12 名患者的病毒载量显着降低。六周的肿瘤活检显示患者的 CD8+ T 细胞明显增加，仅显示出临床益处。该难治性 HCC 人群的 6 个月和 12 个月肿瘤无进展生存概率分别为 57.1% 和 33.1%，肿瘤进展中位时间为 7.4 个月（95% CI 4.7 至 19.4 个月）。中位总生存期为 12.3 个月（95% CI 9.3 至 15.4 个月）。 Tremelimumab 与肿瘤消融相结合是晚期 HCC 患者的潜在新疗法，并导致肿瘤内 CD8+ T 细胞的积累。观察到积极的临床活性，HCV 病毒载量可能替代减少。研究表明，通过直接方法（称为消融）杀死肿瘤可以导致免疫系统被激活或开启。免疫系统也有可能识别并杀死残留的癌症。有一些称为免疫检查点抑制剂的新药物可以增强这种效果。在这里，我们测试其中一种药物（tremelimumab）和消融。
Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10 mg/kg i.v.) every 4 weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8 weeks. No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1–51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4 months (95% CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95% CI 9.3 to 15.4 months). Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation.