临床前，白介素 15 (IL-15) 单一疗法可促进抗肿瘤免疫反应，当 IL-15 与免疫检查点抑制剂 (ICIs) 联合使用时，抗肿瘤免疫反应会增强。这项首次人体研究研究了 NIZ985（一种包含生理活性 IL-15 和 IL-15 受体 α 的重组异二聚体）作为单一疗法以及与斯帕他珠单抗（一种抗程序性细胞死亡蛋白 1（抗 PD-1））联合使用的情况单克隆抗体，用于晚期实体瘤患者。这项 I/Ib 期研究有两个剂量递增组：单药 NIZ985 皮下注射，每周三次（TIW，用药 2 周/停药 2 周）或每周一次（QW，3 周）开/关 1 周），以及皮下注射 NIZ985 TIW 或 QW 联合斯帕他珠单抗（每 4 周静脉注射 400mg (Q4W)）。剂量扩展阶段研究了 NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W 在根据批准的适应症分层的抗 PD-1 敏感或抗 PD-1 耐药肿瘤类型患者中的情况。主要目标是剂量扩展阶段NIZ985的安全性、耐受性以及最大耐受剂量（MTD）和/或扩展推荐剂量（RDE）。 截至2020年2月17日，83名患者（中位年龄：63岁）年；范围：28-85）接受剂量递增（N=47；单药 NIZ985：n=27；NIZ985/spartalizumab n=20）和剂量扩展（N=36）治疗。没有发生剂量限制性毒性，也没有确定 MTD。最常见的治疗相关不良事件 (TRAE) 是注射部位反应（主要为 1-2 级；单药 NIZ985：85% (23/27)）； NIZ985/斯帕他珠单抗：89% [50/56]）。最常见的 3-4 级 TRAE 是淋巴细胞计数减少（单药 NIZ985：7% [2/27]；NIZ985/spartalizumab：5% [3/56]）。最佳总体缓解是单药组疾病稳定（30% (8/27)），NIZ985/spartalizumab 组部分缓解（5% [3/56]；黑色素瘤、胰腺癌、胃癌）。在剂量扩展中，抗PD-1敏感肿瘤类型队列的疾病控制率为45%（5/11），抗PD-1耐药肿瘤类型队列的疾病控制率为20%（5/25）。各臂的药代动力学参数相似。单药和联合治疗产生了 CD8 T 细胞和自然杀伤细胞增殖的短暂增加以及多种细胞因子的诱导。NIZ985 在单药和 NIZ985/spartalizumab 方案中具有良好的耐受性。 RDE 设定为 1μg/kg TIW。观察到该组合针对已知对 ICI 反应较差的肿瘤类型的抗肿瘤活性。NCT02452268.© 作者（或其雇主）2023。根据 CC BY-NC 允许重复使用。不得商业再利用。请参阅权利和权限。英国医学杂志出版。

Preclinically, interleukin-15 (IL-15) monotherapy promotes antitumor immune responses, which are enhanced when IL-15 is used in combination with immune checkpoint inhibitors (ICIs). This first-in-human study investigated NIZ985, a recombinant heterodimer comprising physiologically active IL-15 and IL-15 receptor α, as monotherapy and in combination with spartalizumab, an anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibody, in patients with advanced solid tumors.This phase I/Ib study had two dose-escalation arms: single-agent NIZ985 administered subcutaneously thrice weekly (TIW, 2 weeks on/2 weeks off) or once weekly (QW, 3 weeks on/1 week off), and NIZ985 TIW or QW administered subcutaneously plus spartalizumab (400 mg intravenously every 4 weeks (Q4W)). The dose-expansion phase investigated NIZ985 1 µg/kg TIW/spartalizumab 400 mg Q4W in patients with anti-PD-1-sensitive or anti-PD-1-resistant tumor types stratified according to approved indications. The primary objectives were the safety, tolerability, and the maximum tolerated doses (MTDs) and/or recommended dose for expansion (RDE) of NIZ985 for the dose-expansion phase.As of February 17, 2020, 83 patients (median age: 63 years; range: 28-85) were treated in dose escalation (N=47; single-agent NIZ985: n=27; NIZ985/spartalizumab n=20) and dose expansion (N=36). No dose-limiting toxicities occurred nor was the MTD identified. The most common treatment-related adverse event (TRAE) was injection site reaction (primarily grades 1-2; single-agent NIZ985: 85% (23/27)); NIZ985/spartalizumab: 89% [50/56]). The most common grade 3-4 TRAE was decreased lymphocyte count (single-agent NIZ985: 7% [2/27]; NIZ985/spartalizumab: 5% [3/56]). The best overall response was stable disease in the single-agent arm (30% (8/27)) and partial response in the NIZ985/spartalizumab arm (5% [3/56]; melanoma, pancreatic cancer, gastric cancer). In dose expansion, the disease control rate was 45% (5/11) in the anti-PD-1-sensitive and 20% (5/25) in the anti-PD-1-resistant tumor type cohorts. Pharmacokinetic parameters were similar across arms. The transient increase in CD8+ T cell and natural killer cell proliferation and induction of several cytokines occurred in response to the single-agent and combination treatments.NIZ985 was well tolerated in the single-agent and NIZ985/spartalizumab regimens. The RDE was established at 1 µg/kg TIW. Antitumor activity of the combination was observed against tumor types known to have a poor response to ICIs.NCT02452268.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.