Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study
Cryoablation combined with transarterial infusion of pembrolizumab (CATAP) for liver metastases of melanoma: an ambispective, proof-of-concept cohort study
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冷冻消融联合经动脉输注派姆单抗 (CATAP) 治疗黑色素瘤肝转移：一项矛盾的概念验证队列研究
DOI：
10.1007/s00262-020-02566-z
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发表时间：
2020-04-24
影响因子：
5.8
通讯作者：
Fan, Weijun
中科院分区：
文献类型：
--
作者：
Shen, Lujun;Qi, Han;Fan, Weijun
背景
在黑色素瘤中，肝转移的存在与PD - 1阻断疗法的治疗反应不佳相关。提出了一种将冷冻消融与帕博利珠单抗经动脉灌注相结合的新型治疗方案（CATAP），并在这类患者中评估了其可行性和安全性。
方法
这项注册的双向队列研究纳入了15名患有多发性肝转移的黑色素瘤患者，他们接受了计划的两阶段CATAP治疗：在联合阶段，第1天进行次全冷冻消融，其中1 - 2个肝内病灶被完全消融，其他病灶不做处理，随后在第3天进行帕博利珠单抗经动脉灌注，每3周一次，至少一个周期；在灌注阶段，建议每3周进行一次帕博利珠单抗动脉灌注，直至疾病进展。主要终点是根据RECIST（1.1版）评估的客观缓解率；次要终点包括无进展生存期（PFS）和安全性；探索性终点是外周血样本中细胞因子和免疫细胞组成的变化。
结果
在纳入的15名患者中，未观察到3 - 4级不良事件或重大并发症。1名患者（6.7%）达到完全缓解，3名患者（20.0%）达到部分缓解。整个队列以及皮肤黑色素瘤患者的CATAP总体缓解率分别为26.7%（95%置信区间（CI）4.3 - 49.0%）和33.3%（95%CI 2.5 - 64.1%）。在一线静脉注射帕博利珠单抗治疗失败的部分患者（2/6；33.3%）中观察到临床反应。总体中位无进展生存期和肝无进展生存期分别为4.0个月（95%CI 2.5 - 5.5）和5.73个月（95%CI 1.1 - 10.4）。在联合阶段第一个治疗周期后3周，观察到CD3 - CD16 + CD56 +细胞（自然杀伤细胞；P = 0.0124）显著增加，CD4 + CD25 +细胞（调节性T细胞；P = 0.0546）略有显著减少。
结论
CATAP疗法对伴有肝转移的黑色素瘤患者显示出积极的临床活性和良好的安全性。
BackgroundThe presence of liver metastasis correlates with poor therapeutic response of PD-1 blockade therapy in melanoma. A novel treatment protocol by combining cryoablation with transarterial infusion of pembrolizumab (CATAP) was proposed, and its feasibility and safety was assessed among this group of patients.MethodsThis registered ambispective cohort study enrolled fifteen melanoma patients with multiple hepatic metastases who received planned two-stage CATAP therapy: in the combined stage, subtotal cryoablation on day 1, in which one to two intrahepatic lesions were ablated completely with other lesions left untreated, sequentially combined transarterial infusion of pembrolizumab on day 3, every three weeks, for at least one cycle; in the infusion stage, arterial infusion of pembrolizumab was recommended at three-week interval until disease progression. The primary endpoint was objective response rate by RECIST (version 1.1); secondary end points included progression-free survival (PFS) and safety; exploratory endpoints were changes of cytokines and immune cell compositions in peripheral blood samples.ResultsOf the 15 patients enrolled, no grade 3–4 adverse events or major complications were observed. One patient (6.7%) achieved complete response, and 3 (20.0%) achieved partial response. The overall response rates of CATAP for the entire cohort and patients with cutaneous melanoma were 26.7% (95% confidence interval (CI) 4.3–49.0%) and 33.3% (95% CI 2.5–64.1%), respectively. Clinical response was observed in a proportion of patients (2/6; 33.3%) who failed first-line intravenous pembrolizumab treatment. The median overall PFS time and hepatic PFS time were 4.0 (95% CI 2.5–5.5) and 5.73 (95% CI 1.1–10.4) months, respectively. A significant increase in CD3-CD16 + CD56 + cells (natural killer cells;P= 0.0124) and a marginally significant decrease in CD4 + CD25 + cells (regulatory T cells;P= 0.0546) were observed three weeks after the first cycle of treatment in the combined stage.ConclusionsThe CATAP therapy demonstrated positive clinical activity and a favorable safety profile for melanoma patients with liver metastasis.