Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, VA, USA.
Oncology, IMED Biotech Unit, AstraZeneca Pharmaceuticals, Waltham, MA, USA.
J Immunother Cancer. 2018 Nov 16;6(1):119. doi: 10.1186/s40425-018-0436-5.
The Janus kinase (JAK) and signal transduction and activation of transcription (STAT) signaling pathway is an attractive target in multiple cancers. Activation of the JAK-STAT pathway is important in both tumorigenesis and activation of immune responses. In diffuse large B-cell lymphoma (DLBCL), the transcription factor STAT3 has been associated with aggressive disease phenotype and worse overall survival. While multiple therapies inhibit upstream signaling, there has been limited success in selectively targeting STAT3 in patients. Antisense oligonucleotides (ASOs) represent a compelling therapeutic approach to target difficult to drug proteins such as STAT3 through of mRNA targeting. We report the evaluation of a next generation STAT3 ASO (AZD9150) in a non-Hodgkin's lymphoma population, primarily consisting of patients with DLBCL.
Patients with relapsed or treatment refractory lymphoma were enrolled in this expansion cohort. AZD9150 was administered at 2 mg/kg and the 3 mg/kg (MTD determined by escalation cohort) dose levels with initial loading doses in the first week on days 1, 3, and 5 followed by weekly dosing. Patients were eligible to remain on therapy until unacceptable toxicity or progression. Blood was collected pre- and post-treatment for analysis of peripheral immune cells.
Thirty patients were enrolled, 10 at 2 mg/kg and 20 at 3 mg/kg dose levels. Twenty-seven patients had DLBCL. AZD9150 was safe and well tolerated at both doses. Common drug-related adverse events included transaminitis, fatigue, and thrombocytopenia. The 3 mg/kg dose level is the recommended phase 2 dose. All responses were seen among DLBCL patients, including 2 complete responses with median duration of response 10.7 months and 2 partial responses. Peripheral blood cell analysis of three patients without a clinical response to therapy revealed a relative increase in proportion of macrophages, CD4+, and CD8+ T cells; this trend did not reach statistical significance.
AZD9150 was well tolerated and demonstrated efficacy in a subset of heavily pretreated patients with DLBCL. Studies in combination with checkpoint immunotherapies are ongoing.
Registered at ClinicalTrials.gov: NCT01563302 . First submitted 2/13/2012.
Janus 激酶（JAK）和信号转导及转录激活因子（STAT）信号通路是多种癌症的一个有吸引力的靶点。JAK-STAT 通路的激活在肿瘤发生和免疫反应激活中都很重要。在弥漫性大 B 细胞淋巴瘤（DLBCL）中，转录因子 STAT3 与侵袭性疾病表型和总体生存率较差相关。虽然多种疗法抑制上游信号，但在患者中选择性靶向 STAT3 的成功有限。反义寡核苷酸（ASO）通过靶向 mRNA 提供了一种有吸引力的治疗方法来靶向难以用药的蛋白质，如 STAT3。我们报告了一种下一代 STAT3 ASO（AZD9150）在非霍奇金淋巴瘤患者中的评估，主要由 DLBCL 患者组成。
复发或治疗耐药的淋巴瘤患者入组本扩展队列。AZD9150 以 2mg/kg 和 3mg/kg（通过递增队列确定的 MTD）剂量水平给药，初始负荷剂量在第 1、3 和 5 天，随后每周给药。患者有资格继续接受治疗，直到出现不可接受的毒性或进展。在治疗前和治疗后采集血液用于分析外周免疫细胞。
30 例患者入组，10 例接受 2mg/kg 剂量，20 例接受 3mg/kg 剂量。27 例患者患有 DLBCL。AZD9150 在两个剂量水平均安全且耐受良好。常见的药物相关不良事件包括转氨基酶升高、疲劳和血小板减少症。3mg/kg 剂量水平是推荐的 2 期剂量。所有反应均见于 DLBCL 患者，包括 2 例完全缓解，中位缓解持续时间为 10.7 个月，2 例部分缓解。对 3 例无临床反应的患者进行外周血细胞分析显示，巨噬细胞、CD4+和 CD8+T 细胞的比例相对增加；但这一趋势没有达到统计学意义。
AZD9150 耐受良好，在一组接受过多重治疗的 DLBCL 患者中显示出疗效。正在进行与检查点免疫疗法联合的研究。
ClinicalTrials.gov 注册：NCT01563302。首次提交日期 2012 年 2 月 13 日。
