Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue-DA2010, Boston, MA, 02215, USA.
Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, USA.
Cancer Immunol Immunother. 2021 Oct;70(10):2991-3000. doi: 10.1007/s00262-021-02910-x. Epub 2021 Mar 20.
Checkpoint kinase 1 (CHK1) has dual roles in both the DNA damage response and in the innate immune response to genotoxic stress. The combination of CHK1 inhibition and immune checkpoint blockade has the potential to enhance anti-tumoral T-cell activation.
This was an open-label phase 1 study evaluating the CHK1 inhibitor prexasertib and the anti-PD-L1 antibody LY3300054. After a lead-in of LY3300054 (Arm A), prexasertib (Arm B) or the combination (Arm C), both agents were administered intravenously at their respective recommended phase 2 doses (RP2Ds) on days 1 and 15 of a 28-day cycle. Flow cytometry of peripheral blood was performed before and during treatment to analyze effects on immune cell populations, with a focus on T cell subsets and activation. Plasma cytokines and chemokines were analyzed using the Luminex platform.
Among seventeen patients enrolled, the combination was tolerable at the monotherapy RP2Ds, 105 mg/m prexasertib and 700 mg LY3300054. Dose-limiting toxicities included one episode each of febrile neutropenia (Arm C) and grade 4 neutropenia lasting > 5 days (Arm B). One patient had immune-related AST/ALT elevation after 12 cycles. Three patients with CCNE1-amplified, high-grade serous ovarian cancer (HGSOC) achieved partial response (PR), 2 lasting > 12 months; a fourth such patient maintained stable disease > 12 months. Analysis of peripheral blood demonstrated evidence of CD8 + T-cell activation in response to treatment.
Prexasertib in combination with PD-L1 blockade was tolerable and demonstrated preliminary activity in CCNE1-amplified HGSOC with evidence of cytotoxic T-cell activation in patient blood samples.
ClinicalTrials.gov identifier: NCT03495323. Registered April 12, 2018.
细胞周期检查点激酶 1（CHK1）在 DNA 损伤反应和对遗传毒性应激的固有免疫反应中具有双重作用。CHK1 抑制剂与免疫检查点阻断的联合应用有可能增强抗肿瘤 T 细胞的激活。
这是一项评估 CHK1 抑制剂 prexasertib 和抗 PD-L1 抗体 LY3300054 的开放标签 I 期研究。在 LY3300054 的导入期（A 组）后，给予 prexasertib（B 组）或联合治疗（C 组），在 28 天周期的第 1 天和第 15 天以各自的推荐的 2 期剂量（RP2D）静脉内给药。在治疗前和治疗期间通过外周血流式细胞术分析对免疫细胞群的影响，重点分析 T 细胞亚群和激活。使用 Luminex 平台分析血浆细胞因子和趋化因子。
在 17 名入组患者中，在单药治疗的 RP2D 下，105mg/m prexasertib 和 700mg LY3300054 的联合治疗是可耐受的。剂量限制毒性包括 C 组各 1 例发热性中性粒细胞减少症和 B 组 1 例持续>5 天的 4 级中性粒细胞减少症。1 例 CCNE1 扩增、高级别浆液性卵巢癌（HGSOC）患者在 12 个周期后出现免疫相关 AST/ALT 升高。3 例 CCNE1 扩增、HGSOC 患者获得部分缓解（PR），其中 2 例缓解持续时间>12 个月；第 4 例此类患者疾病稳定>12 个月。外周血分析显示治疗后存在 CD8+T 细胞激活的证据。
prexasertib 联合 PD-L1 阻断是可耐受的，并在 CCNE1 扩增的 HGSOC 中显示出初步活性，患者血液样本中存在细胞毒性 T 细胞激活的证据。
ClinicalTrials.gov 标识符：NCT03495323。于 2018 年 4 月 12 日注册。
