Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.
Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma.
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DOI：
10.1136/jitc-2022-005425
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发表时间：
2023-01
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
在胰腺导管腺癌(PDAC)的临床前研究中，伊布鲁替尼提高了标准护理化疗的抗肿瘤效果。这导致了一项1b期临床试验，以确定伊布鲁替尼治疗晚期PDAC患者的安全性、耐受性和免疫学效果。之前未接受治疗的PDAC患者参加了1b期临床试验(ClinicalTrials.gov)，以确定在使用吉西他滨和NAB-紫杉醇的标准方案时，伊布鲁替尼的安全性、毒性和最大耐受量。为了研究单独对ibrutinib的免疫反应，该试验包括一种免疫反应臂，患者在免疫反应臂中每天服用ibrutinib，持续一周，然后ibrutinib联合吉西他滨和NaB-紫杉醇。在内窥镜超声引导下采集伊布鲁替尼单药治疗前后的PDAC肿瘤活检标本和血样。采用飞行时间法和统计支架分析法检测血液免疫细胞丰度和功能状态的变化，采用多重免疫组织化学方法检测局部肿瘤微环境(TME)中免疫细胞数量和功能状态的变化。通过测序和克隆性分析，评估B细胞受体和T细胞受体谱系的变化。在血液中，伊布鲁替尼单一治疗显著增加了活化的可诱导T细胞共刺激分子+(ICOS+)CD4+T细胞和单核细胞的频率。在TME中，伊布鲁替尼单一治疗导致B细胞丰度下降，但IL-10+B细胞频率增加。单一治疗还导致成熟CD208+树突状细胞密度增加，迟效应者(程序性细胞死亡蛋白1(PD-1-)Eomesodermin(EOMS+))CD8+T细胞频率增加，功能障碍(PD-1+EOMES+)CD8+T细胞频率降低。当伊布鲁替尼联合化疗时，这些免疫变化中的大多数都没有观察到。部分临床反应的患者在治疗开始前T和B细胞受体谱系更加多样化。伊布鲁替尼单一治疗使循环和TME中的免疫格局向激活的T细胞、单核细胞和DC倾斜。当伊布鲁替尼与标准护理化疗相结合时，没有观察到这些效果。未来的研究可能集中在其他治疗组合上，以增强伊布鲁替尼对实体瘤的免疫调节作用。NCT02562898。
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 CD208+dendritic 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.
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影响因子：
8.8
作者：
Ino Y;Yamazaki-Itoh R;Shimada K;Iwasaki M;Kosuge T;Kanai Y;Hiraoka N
通讯作者：
Hiraoka N
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
2.3
作者：
Poch, Bertram;Lotspeich, Errki;Gansauge, Frank
通讯作者：
Gansauge, Frank
影响因子：
11.2
作者：
Masso-Valles, Daniel;Jauset, Toni;Soucek, Laura
通讯作者：
Soucek, Laura
影响因子：
10.9
作者：
Overman, Michael;Javle, Milind;Maitra, Anirban
通讯作者：
Maitra, Anirban