Geboers Bart, Timmer Florentine, Vos Danielle, Scheffer Hester, Bakker Joyce, Ruarus Alette, Vroomen Laurien, Stam Anita, Lougheed Sinéad, Schouten Evelien, Puijk Robbert, van den Tol Petrousjka, Lagerwaard Frank, de Vries Jan, Bruynzeel Anna, Meijerink Martijn, de Gruijl Tanja
Department of Radiology and Nuclear Medicine, Amsterdam UMC (location VUmc), Amsterdam, The Netherlands
Cancer Centre Amsterdam, Amsterdam, The Netherlands.
J Immunother Cancer. 2025 Mar 26;13(3):e010222. doi: 10.1136/jitc-2024-010222.
Irreversible electroporation (IRE) and stereotactic ablative body radiotherapy (SABR) are cytoreductive therapies for locally advanced pancreatic cancer (LAPC). Both may signify immunogenic cell death. We aimed to compare systemic immune responses between the treatments.
As part of the randomized phase II CROSSFIRE trial (NCT02791503), comparing the oncological efficacy of IRE to SABR in patients with LAPC, pre- and post-treatment (2 weeks and 3 months) peripheral blood samples were collected. Frequency and activation status of lymphocytic and myeloid subsets were determined using flow cytometry. T cell responses to pancreatic cancer associated with Wilms tumor-1 (WT-1) and survivin tumor antigens were determined by interferon-γ enzyme-linked immunospot assay.
In total, 20 IRE and 20 SABR-treated participants were analyzed (20 men; median age 65 (IQR 55-70)). IRE induced immediate decreases in systemic regulatory T cell (Treg) and conventional type-1 dendritic cell rates, coinciding with CD4/CD8 T cell activation by upregulation of PD-1, which was associated with improved overall survival (OS). SABR similarly induced immediate CD4/CD8 T cell activation by upregulation of Ki67 and CD25 but resulted in asynchronously delayed Treg downregulation. SABR also induced a durable increase in CD4 EM T cells, associated with improved OS. Ablation-induced WT-1 or survivin-specific T cell responses were observed in 9/16 (56%) immune competent participants (IRE n=5, SABR n=4) and were associated with longer OS.
Distinct immune stimulatory responses associated with improved OS, suggest that SABR might benefit from combined Treg depletion strategies while IRE could benefit from PD-1 checkpoint inhibition.
The trial was registered on clinical trials.gov (NCT02791503).
不可逆电穿孔（IRE）和立体定向消融体部放疗（SABR）是局部晚期胰腺癌（LAPC）的细胞减灭疗法。两者都可能意味着免疫原性细胞死亡。我们旨在比较这两种治疗方法之间的全身免疫反应。
作为随机II期CROSSFIRE试验（NCT02791503）的一部分，该试验比较了IRE与SABR对LAPC患者的肿瘤学疗效，收集了治疗前和治疗后（2周和3个月）的外周血样本。使用流式细胞术确定淋巴细胞和髓细胞亚群的频率和激活状态。通过干扰素-γ酶联免疫斑点试验确定T细胞对与威尔姆斯瘤-1（WT-1）和生存素肿瘤抗原相关的胰腺癌的反应。
总共分析了20名接受IRE治疗和20名接受SABR治疗的参与者（20名男性；中位年龄65岁（四分位间距55 - 70岁））。IRE导致全身调节性T细胞（Treg）和传统1型树突状细胞比率立即下降，同时通过PD-1上调使CD4/CD8 T细胞激活，这与总生存期（OS）改善相关。SABR同样通过上调Ki67和CD25诱导立即的CD4/CD8 T细胞激活，但导致Treg下调异步延迟。SABR还导致CD4 EM T细胞持续增加，与OS改善相关。在9/16（56%）免疫功能正常的参与者中观察到消融诱导的WT-1或生存素特异性T细胞反应（IRE组n = 5，SABR组n = 4），并且与更长的OS相关。
与OS改善相关的不同免疫刺激反应表明，SABR可能受益于联合Treg耗竭策略，而IRE可能受益于PD-1检查点抑制。
该试验在临床试验.gov上注册（NCT02791503）。
