Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies
Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, for hematologic malignancies
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DOI：
10.1182/bloodadvances.2019001079
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发表时间：
2020-05-12
期刊：
影响因子：
7.5
通讯作者：
Yellin, Michael J.
中科院分区：
文献类型：
--
作者：
Ansell, Stephen M.;Flinn, Ian;Yellin, Michael J.
CD27 是 T 细胞上的一种共刺激分子，通过与其配体 CD70 结合，诱导介导细胞活化、增殖、效应功能和细胞存活的细胞内信号。 Varlilumab 是一种新型、一流的激动剂免疫球蛋白 G1 抗 CD27 抗体，在动物模型中介导抗肿瘤免疫并直接杀死 CD27+ 肿瘤细胞。这项首次人体剂量递增和扩展研究评估了 varlilumab 在血液系统恶性肿瘤患者中的作用。主要目标是评估 Varlilumab 的安全性以及最大耐受剂量和最佳生物剂量。次要目标是评估药代动力学、药效学、免疫原性和抗肿瘤活性。在 3 + 3 剂量递增设计中，30 名 B 细胞 (n = 25) 或 T 细胞 (n = 5) 恶性肿瘤患者接受 varlilumab（0.1、0.3、1、3 或 10 mg/kg IV）单剂量治疗，观察期为 28 天，随后每周给药（每个周期 4 剂，最多 5 个周期，具体取决于肿瘤反应）。在扩展队列中，另外 4 名霍奇金淋巴瘤患者每 3 周接受 0.3 mg/kg varlilumab（每个周期 4 剂，最多 5 个周期）。没有观察到剂量限制性毒性。与治疗相关的不良事件，通常为 1 至 2 级，包括疲劳、食欲下降、贫血、腹泻和头痛。各剂量组的暴露呈线性且与剂量成比例，并导致促炎细胞因子和可溶性 CD27 增加。一名 IV 期霍奇金淋巴瘤患者出现完全缓解，并在超过 33 个月时保持缓解状态，无需进一步抗癌治疗。这些数据支持对varlilumab治疗血液恶性肿瘤的进一步研究，特别是针对非冗余免疫调节途径的联合方法。
CD27, a costimulatory molecule on T cells, induces intracellular signals mediating cellular activation, proliferation, effector function, and cell survival on binding to its ligand, CD70. Varlilumab, a novel, first-in-class, agonist immunoglobulin G1 anti-CD27 antibody, mediates antitumor immunity and direct killing of CD27+ tumor cells in animal models. This first-in-human, dose-escalation, and expansion study evaluated varlilumab in patients with hematologic malignancies. Primary objectives were to assess safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate pharmacokinetics, pharmacodynamics, immunogenicity, and antitumor activity. In a 3 + 3 dose-escalation design, 30 patients with B-cell (n = 25) or T-cell (n = 5) malignancies received varlilumab (0.1, 0.3, 1, 3, or 10 mg/kg IV) as a single dose with a 28-day observation period, followed by weekly dosing (4 doses per cycle, up to 5 cycles, depending on tumor response). In an expansion cohort, 4 additional patients with Hodgkin lymphoma received varlilumab at 0.3 mg/kg every 3 weeks (4 doses per cycle, up to 5 cycles). No dose-limiting toxicities were observed. Treatment-related adverse events, generally grade 1 to 2, included fatigue, decreased appetite, anemia, diarrhea, and headache. Exposure was linear and dose-proportional across dose groups and resulted in increases in proinflammatory cytokines and soluble CD27. One patient with stage IV Hodgkin lymphoma experienced a complete response and remained in remission at >33 months with no further anticancer therapy. These data support further investigation of varlilumab for hematologic malignancies, particularly in combination approaches targeting nonredundant immune regulating pathways.