Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA.
Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA.
J Immunother Cancer. 2023 Jan;11(1). doi: 10.1136/jitc-2022-005425.
In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC.
Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality.
In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator(ICOS) CD4 T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10 B-cell frequency. Monotherapy also led to a trend in increased mature CD208dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1) eomesodermin (EOMES)) CD8 T-cell frequency, with a concomitantly decreased dysfunctional (PD-1 EOMES) CD8 T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation.
Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors.
NCT02562898.
在胰腺导管腺癌（PDAC）的临床前研究中，伊布替尼改善了标准护理化疗的抗肿瘤疗效。这导致了一项 1b 期临床试验，以确定在晚期 PDAC 患者中使用伊布替尼治疗的安全性、耐受性和免疫效应。
以前未经治疗的 PDAC 患者参加了一项 1b 期临床试验（ClinicalTrials.gov），以确定伊布替尼与吉西他滨和 nab-紫杉醇标准方案联合使用时的安全性、毒性和最大耐受剂量。为了研究伊布替尼单独的免疫反应，该试验包括一个免疫反应臂，其中患者接受伊布替尼单药治疗一周，然后伊布替尼联合吉西他滨和 nab-紫杉醇。在伊布替尼单药治疗前后，通过内镜超声引导原发性 PDAC 肿瘤活检和血液采集。通过飞行时间质谱细胞术和统计支架分析评估血液中免疫细胞的丰度和功能状态的变化，通过多重免疫组化评估局部肿瘤微环境（TME）中的变化。通过测序和克隆性分析评估 B 细胞受体和 T 细胞受体库的变化。
在血液中，伊布替尼单药治疗显著增加了激活诱导的共刺激因子（ICOS）CD4 T 细胞和单核细胞的频率。在 TME 中，伊布替尼单药治疗导致 B 细胞丰度呈下降趋势，但白细胞介素 10 B 细胞频率增加。单药治疗还导致成熟 CD208+树突状细胞密度增加，晚期效应（程序性死亡蛋白 1（PD-1）Eomesodermin（EOMES））CD8 T 细胞频率增加，同时功能失调（PD-1 EOMES）CD8 T 细胞频率降低。当伊布替尼与化疗联合使用时，这些免疫变化中的大多数都没有观察到。有部分临床反应的患者在开始治疗前具有更多样化的 T 和 B 细胞受体库。
伊布替尼单药治疗使循环和 TME 中的免疫景观向激活的 T 细胞、单核细胞和 DC 倾斜。当与标准护理化疗联合使用时，没有观察到这些影响。未来的研究可能集中在其他治疗组合上，以增强伊布替尼在实体肿瘤中的免疫调节作用。
NCT02562898。
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