Vey Norbert, Karlin Lionel, Sadot-Lebouvier Sophie, Broussais Florence, Berton-Rigaud Dominique, Rey Jérôme, Charbonnier Aude, Marie Delphine, André Pascale, Paturel Carine, Zerbib Robert, Bennouna Jaafar, Salles Gilles, Gonçalves Anthony
Institut Paoli-Calmettes, Marseille, France.
Aix-Marseille Université, Marseille, France.
Oncotarget. 2018 Apr 3;9(25):17675-17688. doi: 10.18632/oncotarget.24832.
Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers.
Thirty-seven patients with hematological malignancies ( = 22) or solid tumors ( = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 ( = 9) or 3 mg/kg ( = 8).
No dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D-positive NK cells.
This phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR.
抗KIR单克隆抗体（mAb）可增强自然杀伤（NK）细胞的抗肿瘤反应。我们评估了抗KIR2D单克隆抗体lirilumab在各类癌症患者中的安全性。
本研究纳入了37例血液系统恶性肿瘤患者（n = 22）或实体瘤患者（n = 15）。按照3 + 3设计进行剂量递增（0.015至10 mg/kg）。患者计划接受四个周期的治疗。在第二个（扩展）阶段，17例患者分别接受0.015 mg/kg（n = 9）或3 mg/kg（n = 8）的治疗。
未记录到剂量限制性毒性。与lirilumab相关的最常见不良事件为瘙痒（19%）、乏力（16%）、疲劳（14%）、输液相关反应（14%）和头痛（11%），大多为轻度或中度。药代动力学呈剂量依赖性且为线性，每4周重复给药导致的蓄积最小。所有剂量均实现了完全KIR占据（>95%），且占据持续时间与剂量相关。淋巴细胞亚群的数量或分布未观察到显著变化，KIR2D阳性NK细胞的分布也未减少。
该1期试验表明，lirilumab在达到能够完全且持续阻断KIR的剂量时，具有令人满意的安全性。
