Howard A. Burris and Jeffrey R. Infante, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; Stephen M. Ansell, Mayo Clinic, Rochester, MN; John J. Nemunaitis, Mary Crowley Cancer Research Center, Dallas, TX; Geoffrey R. Weiss and Timothy Bullock, University of Virginia, Charlottesville, VA; Victor M. Villalobos and Branimir I. Sikic, Stanford Cancer Institute, Stanford, CA; Matthew H. Taylor, Oregon Health & Science University, Portland, OR; Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ; William E. Carson III, The Ohio State University, Columbus, OH; Thomas R. Hawthorne, Thomas A. Davis, Michael J. Yellin, and Tibor Keler, Celldex Therapeutics, Hampton, NJ.
J Clin Oncol. 2017 Jun 20;35(18):2028-2036. doi: 10.1200/JCO.2016.70.1508. Epub 2017 May 2.
Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.
目的 CD27 是 T 细胞上的一种共刺激分子，与配体 CD70 结合后，诱导细胞内信号转导，介导细胞激活、增殖、效应功能和存活。Varlilumab 是一种新型的、首创的、激动型 CD27 抗体，可刺激 CD27 通路，从而在肿瘤模型中激活 T 细胞并发挥抗肿瘤活性。这项首次在人体中进行的剂量递增和扩展研究评估了 varlilumab 在晚期实体瘤患者中的安全性、药理学和活性。
方法 在 3+3 剂量递增设计中（n=25），患者接受单次静脉注射 varlilumab（0.1、0.3、1.0、3.0 或 10mg/kg），观察 28 天，然后根据肿瘤反应进行多达五个多剂量周期（每周一次，持续 4 周）。在黑色素瘤（n=16）和肾细胞癌（RCC；n=15）患者中，以 3.0mg/kg 开始入组扩展队列。主要目的是评估 varlilumab 的安全性、最大耐受剂量和最佳生物学剂量。次要目的是评估 varlilumab 的药代动力学、药效学和临床抗肿瘤活性。
结果 varlilumab 的暴露量在剂量组之间呈线性和剂量比例关系。只有一名患者在 1.0mg/kg 剂量水平时出现剂量限制性毒性-3 级短暂无症状低钠血症。治疗相关不良事件的严重程度通常为 1 级或 2 级。在所有剂量水平均观察到与 CD27 刺激一致的生物学活性-趋化因子诱导、T 细胞刺激、调节性 T 细胞耗竭。一名转移性 RCC 患者出现部分缓解（78%缩小，无进展生存期>2.3 年）。8 名患者的疾病稳定时间>3 个月，包括一名转移性 RCC 患者，无进展生存期>3.9 年。
结论 varlilumab 剂量递增至 10mg/kg 耐受性良好，未确定最大耐受剂量。Varlilumab 具有生物学和临床活性。
