ABSTRACT

Purpose: Local tumor ablation through irreversible electroporation (IRE) may offer a novel therapeutic option for locally advanced pancreatic cancer (LAPC). It may also serve as a means of in vivo vaccination. To obtain evidence of the induction of systemic antitumor immunity following local IRE-mediated ablation, we performed an explorative immune monitoring study. Methods: In ten patients enrolled in a clinical trial exploring the safety, feasibility, and efficacy of percutaneous image-guided IRE in LAPC, we determined the frequency and activation state of lymphocytic and myeloid subsets in pre- and post-treatment peripheral blood samples using flow cytometry. Tumor-specific systemic T cell responses to the pancreatic cancer associated antigen Wilms Tumor (WT)1 were determined after in vitro stimulation in an interferon-y enzyme-linked immunospot assay (Elispot), at baseline and at 2 weeks and 3 months after IRE. Results: Our data showed a transient decrease in systemic regulatory T cells (Treg) and a simultaneous transient increase in activated PD-1⁺ T cells, consistent with the temporary reduction of tumor-related immune suppression after the IRE procedure. Accordingly, we found post-IRE boosting of a pre-existing WT1 specific T cell response in two out of three patients as well as the de novo induction of these responses in another two patients. There was a trend for these WT1 T cell responses to be related to longer overall survival (p = .055). Conclusions: These findings are consistent with a systemic and tumor-specific immune stimulatory effect of IRE and support the combination of percutaneous IRE with therapeutic immune modulation.

抽象的

目的：通过不可逆电穿孔（IRE）进行局部肿瘤消融可能为局部晚期胰腺癌（LAPC）提供新的治疗选择。它也可以用作体内疫苗接种的手段。为了获得局部IRE介导的消融后诱导全身抗肿瘤免疫的证据，我们进行了探索性免疫监测研究。方法：在10名参加临床试验的患者中，他们探索了LAPC中经皮图像引导的IRE的安全性，可行性和有效性，我们使用流法确定了治疗前后外周血样本中淋巴细胞和髓样亚群的频率和激活状态细胞计数。在干扰素-酶联免疫斑点测定法（Elispot）体外刺激后，基线，IRE后2周和3个月，确定对胰腺癌相关抗原Wilms肿瘤（WT）1的肿瘤特异性全身T细胞反应。结果：我们的数据显示系统性调节性T细胞（Treg）暂时减少，而激活的PD-1 ^+却同时出现瞬时增加T细胞，与IRE手术后肿瘤相关免疫抑制的暂时减少相一致。因此，我们发现三位患者中有两位在IRE后加强了已有的WT1特异性T细胞应答，另外两名患者则从头诱导了这些应答。这些WT1 T细胞应答与总生存期较长有关（p = .055）。结论：这些发现与IRE的全身性和肿瘤特异性免疫刺激作用一致，并支持经皮IRE与治疗性免疫调节的组合。