Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors.
Phase I study of single agent NIZ985, a recombinant heterodimeric IL-15 agonist, in adult patients with metastatic or unresectable solid tumors.
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DOI：
10.1136/jitc-2021-003388
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发表时间：
2021-11
影响因子：
10.9
通讯作者：
Pavlakis GN
中科院分区：
文献类型：
--
作者：
Conlon K;Watson DC;Waldmann TA;Valentin A;Bergamaschi C;Felber BK;Peer CJ;Figg WD;Potter EL;Roederer M;McNeel DG;Thompson JA;Gupta S;Leidner R;Wang-Gillam A;Parikh NS;Long D;Kurtulus S;Ho Lee L;Chowdhury NR;Bender F;Pavlakis GN
NIZ 985是生理活性白细胞介素（IL-）15和IL-15受体α的重组异源二聚体。在临床前模型中，NIZ 985促进细胞毒性淋巴细胞增殖、杀伤功能和器官/肿瘤浸润，从而产生抗癌作用。在这项首次人体研究中，我们评估了NIZ 985在转移性或不可切除的实体瘤患者中的安全性、药代动力学和免疫作用。单一药剂NIZ 985剂量递增数据来自NIZ 985作为单一疗法的I期剂量递增/扩展研究。在加速的3+3剂量递增试验设计中，成人患者（N=14）在每个28天周期的前2周接受0.25、0.5、1、2或4 μg/kg皮下NIZ 985每周三次（TIW）。通过ELISA和多重电致发光测定监测IL-15和内源性细胞因子。多参数流式细胞术评估外周血单个核细胞的频率、表型和增殖。通过总体缓解率（实体瘤缓解评价标准V.1.1）评估初步抗肿瘤活性。截至2020年3月2日，中位治疗持续时间为7.5周（范围1.1-77.1）。13例患者已停止治疗，1例（葡萄膜黑色素瘤）仍在接受治疗，病情稳定。最佳临床缓解为疾病稳定（3/14例患者; 21%）。最常见的不良事件（AE）为环状出血性注射部位反应（100%）、寒战（71%）、疲乏（57%）和发热（50%）。6名受试者（43%）发生治疗相关3/4级AE; 3名受试者（21%）发生治疗相关严重AE（SAE）。未达到符合方案的最大耐受剂量。血清IL-15在第一周的药代动力学积累，随后在第2周水平显着降低，这可能是由于扩大的淋巴细胞库更快地消耗细胞因子。NIZ 985治疗与几种细胞因子的增加相关，包括干扰素（IFN）-γ、IL-18、C-X-C基序趋化因子配体10和肿瘤坏死因子-β，以及注射部位细胞毒性淋巴细胞增殖（包括自然杀伤细胞和CD 8 + T细胞）的显著诱导、CD 16+单核细胞增加和CD 163+巨噬细胞增加。皮下NIZ 985 TIW在晚期癌症患者中通常耐受良好，并产生与临床前观察平行的免疫激活，诱导IFN-γ和细胞毒性淋巴细胞增殖。由于在两个最高剂量水平下发生延迟SAE，在修订方案中将给药改为每周一次，作为单药治疗和与检查点抑制剂spartalizumab联合治疗。这些改变有望最大限度地发挥NIZ 985作为新型免疫疗法的潜力。NCT 02452268。
NIZ985 is a recombinant heterodimer of physiologically active interleukin (IL-)15 and IL-15 receptor alpha. In preclinical models, NIZ985 promotes cytotoxic lymphocyte proliferation, killing function, and organ/tumor infiltration, with resultant anticancer effects. In this first-in-human study, we assessed the safety, pharmacokinetics, and immune effects of NIZ985 in patients with metastatic or unresectable solid tumors. Single agent NIZ985 dose escalation data are reported from a phase I dose escalation/expansion study of NIZ985 as monotherapy. Adult patients (N=14) received 0.25, 0.5, 1, 2 or 4 µg/kg subcutaneous NIZ985 three times weekly (TIW) for the first 2 weeks of each 28-day cycle, in an accelerated 3+3 dose escalation trial design. IL-15 and endogenous cytokines were monitored by ELISA and multiplexed electrochemiluminescent assays. Multiparameter flow cytometry assessed the frequency, phenotype and proliferation of peripheral blood mononuclear cells. Preliminary antitumor activity was assessed by overall response rate (Response Evaluation Criteria in Solid Tumors V.1.1). As of March 2, 2020, median treatment duration was 7.5 weeks (range 1.1–77.1). Thirteen patients had discontinued and one (uveal melanoma) remains on treatment with stable disease. Best clinical response was stable disease (3 of 14 patients; 21%). The most frequent adverse events (AEs) were circular erythematous injection site reactions (100%), chills (71%), fatigue (57%), and fever (50%). Treatment-related grade 3/4 AEs occurred in six participants (43%); treatment-related serious AEs (SAEs) in three (21%). The per-protocol maximum tolerated dose was not reached. Pharmacokinetic accumulation of serum IL-15 in the first week was followed by significantly lower levels in week 2, likely due to more rapid cytokine consumption by an expanding lymphocyte pool. NIZ985 treatment was associated with increases in several cytokines, including interferon (IFN)-γ, IL-18, C-X-C motif chemokine ligand 10, and tumor necrosis factor-β, plus significant induction of cytotoxic lymphocyte proliferation (including natural killer and CD8+ T cells), increased CD16+ monocytes, and increased CD163+ macrophages at injection sites. Subcutaneous NIZ985 TIW was generally well tolerated in patients with advanced cancer and produced immune activation paralleling preclinical observations, with induction of IFN-γ and proliferation of cytotoxic lymphocytes. Due to delayed SAEs at the two highest dose levels, administration is being changed to once-weekly in a revised protocol, as monotherapy and combined with checkpoint inhibitor spartalizumab. These alterations are expected to maximize the potential of NIZ985 as a novel immunotherapy. NCT02452268.
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影响因子：
6.7
作者：
Barrenäs F;Hansen SG;Law L;Driscoll C;Green RR;Smith E;Chang J;Golez I;Urion T;Peng X;Whitmore L;Newhouse D;Hughes CM;Morrow D;Randall KT;Selseth AN;Ford JC;Gilbride RM;Randall BE;Ainslie E;Oswald K;Shoemaker R;Fast R;Bosche WJ;Axthelm MK;Fukazawa Y;Pavlakis GN;Felber BK;Fourati S;Sekaly RP;Lifson JD;Komorowski J;Kosmider E;Shao D;Song W;Edlefsen PT;Picker LJ;Gale M Jr
通讯作者：
Gale M Jr
DOI：
10.1158/1078-0432.ccr-17-2451
发表时间：
2018-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Miller JS;Morishima C;McNeel DG;Patel MR;Kohrt HEK;Thompson JA;Sondel PM;Wakelee HA;Disis ML;Kaiser JC;Cheever MA;Streicher H;Creekmore SP;Waldmann TA;Conlon KC
通讯作者：
Conlon KC
通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
影响因子：
15.3
作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
通讯作者：
Restifo, Nicholas P
影响因子：
4.4
作者：
Bergamaschi, Cristina;Jalah, Rashmi;Pavlakis, George N.
通讯作者：
Pavlakis, George N.
影响因子：
7.5
作者：
Felices, Martin;Kodal, Behiye;Bachanova, Veronika
通讯作者：
Bachanova, Veronika