Division of Oncology, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Drive, HCI-RS-2703, Salt Lake City, UT, 84112, USA.
Comprehensive Cancer Centers of Nevada, University of Nevada Las Vegas School of Medicine, Las Vegas, NV, USA.
Target Oncol. 2021 Nov;16(6):773-787. doi: 10.1007/s11523-021-00833-2. Epub 2021 Oct 25.
Sasanlimab is a monoclonal antibody that binds to the programmed cell death receptor 1 (PD-1). Anti-PD-1 monoclonal antibodies have improved patient clinical outcomes; however, not all treated patients derive clinical benefit. Further insights on potential biomarkers beyond PD-L1 expression levels would help to identify the patients most likely to respond to treatment.
This study evaluated tumor biopsies from patients treated with intravenous or subcutaneous sasanlimab to identify biomarkers of response and characterize pharmacodynamic activity.
Anti-PD-1/PD-ligand 1 (PD-L1)-naive patients with advanced solid tumors received sasanlimab intravenously at 1, 3, or 10 mg/kg every 3 weeks (n = 23) or subcutaneously at 300 mg every 4 weeks (n = 15). Best tumor percentage change from baseline was determined by RECIST. Whole-exome DNA and RNA sequencing were performed in tumor samples collected from treated patients at protocol-defined timepoints. PD-L1 and CD8 protein expression were evaluated in tumor biopsies by immunohistochemistry. Associations with response were assessed by linear regression analysis.
Baseline tumor mutational burden (TMB), as well as PD-L1 and CD8 expression, were significantly associated with response to sasanlimab across the multiple dose levels, routes of administration, and range of tumor types evaluated. TMB is an independent biomarker from the various tumor inflammatory genes and signatures evaluated. Gene set enrichment analysis showed that higher baseline expression levels of genes related to the interferon-γ and PD-1 signaling pathways and the cell cycle were significantly associated with response to sasanlimab across tumor types. No differences were observed between routes of administration with regard to response to sasanlimab for the biomarkers of interest (TMB, PD-L1, CD8, and interferon-γ signature). Evaluation of pharmacodynamic changes showed increased tumor expression of genes enriched in adaptive immune response pathways.
Our findings indicate an active, immunomodulatory mechanism for the anti-PD-1 antibody sasanlimab across different tumor types and routes of administration.
ClinicalTrials.gov identifier NCT02573259; registered October 2015.
Sasanlimab 是一种单克隆抗体，可与程序性细胞死亡受体 1（PD-1）结合。抗 PD-1 单克隆抗体改善了患者的临床结局；然而，并非所有接受治疗的患者都能从中获益。进一步了解 PD-L1 表达水平以外的潜在生物标志物将有助于确定最有可能对治疗产生反应的患者。
本研究评估了接受静脉或皮下注射 sasanlimab 治疗的患者的肿瘤活检，以确定反应的生物标志物并描述药效动力学活性。
接受过治疗的抗 PD-1/PD-Ligand 1（PD-L1）的晚期实体瘤患者接受静脉内或皮下注射 sasanlimab，剂量分别为 1、3 或 10mg/kg，每 3 周一次（n=23）或皮下注射 300mg，每 4 周一次（n=15）。根据 RECIST 确定最佳肿瘤基线百分比变化。在方案规定的时间点从接受治疗的患者的肿瘤样本中进行全外显子 DNA 和 RNA 测序。通过免疫组织化学评估肿瘤活检中的 PD-L1 和 CD8 蛋白表达。通过线性回归分析评估与反应的相关性。
在评估的多种剂量水平、给药途径和肿瘤类型范围内，基线肿瘤突变负担（TMB）以及 PD-L1 和 CD8 表达与 sasanlimab 的反应显著相关。TMB 是各种肿瘤炎症基因和特征评估中独立的生物标志物。基因集富集分析显示，基线时与干扰素-γ和 PD-1 信号通路以及细胞周期相关的基因表达水平较高，与各种肿瘤类型对 sasanlimab 的反应显著相关。对于感兴趣的生物标志物（TMB、PD-L1、CD8 和干扰素-γ 特征），给药途径之间观察到的 sasanlimab 反应无差异。药效学变化的评估显示肿瘤中与适应性免疫反应途径相关的基因表达增加。
我们的研究结果表明，抗 PD-1 抗体 sasanlimab 在不同的肿瘤类型和给药途径中具有积极的免疫调节作用。
ClinicalTrials.gov 标识符 NCT02573259；注册于 2015 年 10 月。
