Hiram Polk, Jr. MD Department of Surgery, University of Louisville, KY.
Hiram Polk, Jr. MD Department of Surgery, University of Louisville, KY.
Surgery. 2020 Oct;168(4):610-616. doi: 10.1016/j.surg.2020.04.057. Epub 2020 Jul 4.
Combining immune checkpoint blockade therapy with operative disruptive immunomodulation using irreversible electroporation may overcome the resistance to systemic therapy found in patients with locally advanced, unresectable pancreatic cancer. We describe the safety profile and efficacy of IRE with nivolumab.
In the preclinical phase of study, human pancreatic cell lines were cultured with interferon-γ (10 ng/mL) and murine models of pancreatic cancer were treated with irreversible electroporation and programmed death ligand-1 (PD-L1) expression was measured. In this phase 1b clinical trial (NCT03080974), surgical ablative irreversible electroporation was performed followed by nivolumab. The primary end point was dose-limiting toxicity.
Human pancreatic cells express PD-L1 when cultured with interferon-γ: quantitative polymerase chain reaction MiaPaca (15.2 rel. fold ± 0.5; P < .01) and S20-13 (31.0 rel. fold ± 4.4; P < .01). Murine orthotopic tumors treated by irreversible electroporation had an increase in signal intensity score for the expression of PD-L1 in residual tumor (P < .01). Ten patients were included in the safety analysis with a 12-month median follow-up (interquartile range 6.0, 15.8). No dose-limiting toxicities occurred. Seven patients developed grade 3/4 treatment-related adverse events; none required a dose modification of nivolumab; nivolumab-related adverse events occurred in 1 patient. Mean time to progression was 6.3 months (confidence interval 3.5-10.0) with current median overall survival of 18.0 months (confidence interval 9.2-26.8).
Irreversible electroporation induces expression of PD-L1 in vitro. Combination therapy with concurrent nivolumab is well tolerated. A multicenter, phase 2 adjuvant trial is underway using irreversible electroporation and nivolumab in patients with locally advanced pancreatic cancer.
联合免疫检查点阻断疗法和不可逆电穿孔的手术破坏免疫调节可能会克服局部晚期、不可切除的胰腺癌患者对系统治疗的抵抗。我们描述了使用不可逆电穿孔联合纳武利尤单抗的安全性概况和疗效。
在研究的临床前阶段，用干扰素-γ（10ng/ml）培养人胰腺细胞系，并在鼠模型的胰腺癌中进行不可逆电穿孔治疗，测量程序性死亡配体-1（PD-L1）的表达。在这项 I 期 b 期临床试验（NCT03080974）中，进行手术消融性不可逆电穿孔，然后给予纳武利尤单抗。主要终点是剂量限制毒性。
用干扰素-γ培养时，人胰腺细胞表达 PD-L1：定量聚合酶链反应 MiaPaca（15.2rel. fold±0.5；P<0.01）和 S20-13（31.0rel. fold±4.4；P<0.01）。用不可逆电穿孔治疗的鼠原位肿瘤，残留肿瘤中 PD-L1 的信号强度评分增加（P<0.01）。10 例患者纳入安全性分析，中位随访 12 个月（四分位距 6.0，15.8）。未发生剂量限制毒性。7 例患者发生 3/4 级治疗相关不良事件；无需调整纳武利尤单抗剂量；1 例发生纳武利尤单抗相关不良事件。中位无进展时间为 6.3 个月（置信区间 3.5-10.0），目前的中位总生存期为 18.0 个月（置信区间 9.2-26.8）。
不可逆电穿孔在体外诱导 PD-L1 的表达。联合使用纳武利尤单抗的联合治疗耐受性良好。一项多中心、2 期辅助试验正在进行中，在局部晚期胰腺癌患者中使用不可逆电穿孔和纳武利尤单抗。
