新型IL-2细胞因子免疫激动剂(NKTR-214)是CD122依赖型的激动剂，可以通过异源二聚体IL-2受体途径(IL-2Rβɣ)提供持续的信号转导，还可以在肿瘤卫环境中通过调节性T细胞刺激CD8+ T细胞和NK细胞的增殖。本研究在局部晚期或转移性实体瘤患者中对经过NKTR-214治疗后的肿瘤微环境的免疫变化进行了评估。

        研究采用以下方法，对IV期的门诊的肿瘤患者进行q2w(两周一次)或q3w(三周一次)的NKTR-214治疗。采集血液和肿瘤组织样品，用流式细胞术、免疫组化(IHC)、T细胞克隆、基因表达分析等方法进行免疫活性的测定。

        在三周一次经NKTR-214治疗的26例患者中，接受的治疗剂量分别为4例0.003mg / kg、9例0.006 mg / kg、6例0.009 mg / kg和1例0.012 mg/kg。研究结果表明，二周一次治疗的患者有6例接受0.006 mg/kg的NKTR-214治疗。最常见的Gr1-2 TRAEs为疲劳(73%)、瘙痒(65%)、食欲不振(46%)。1例患者在最高剂量下出现Gr3昏厥和低血压反应，并以较低剂量继续治疗。没有与药物相关的AEs导致研究停止。没有观察到与免疫相关的AE或者毛细血管渗透综合征。6例(23%)的患者肿瘤发生了10-30%的缩小。3例没有接受过免疫治疗的患者在结束NKTR-214治疗后，在接受抗PD-1治疗后肿瘤明显消退。所有患者的血液样品检测治疗8天后新增殖(Ki67 +)T和NK细胞增加。流式细胞术和/或IHC显示肿瘤微环境中肿瘤CD8 + T和NK细胞的基线增加高达10倍，Treg的变化最小。PD-1表达在TIL中增加2倍。 肿瘤组织的基因表达分析显示几种免疫检查点基因、细胞毒性标志物(IFNg, PRF1, and GZMB)以及T细胞克隆性都有所增加。

        基于以上有利的安全性和生物标志物，结合NKTR-214和nivolumab的1/2期试验目前正在招募中。

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        摘要原文：

        Author(s): Chantale Bernatchez, Cara L. Haymaker, Michael E. Hurwitz, Harriet M. Kluger, Michael T. Tetzlaff, Natalie Jackson, Ivan Gergel, Mary Ann Tagliaferri, Jonathan Zalevsky, Ute Hoch, Christie Fanton, Ernesto Iacucci, Sandra Aung, Michael Imperiale, Ej Liao, Salah E Bentebibel, Nizar M. Tannir, Patrick Hwu, Mario Sznol, Adi Diab; The University of Texas MD Anderson Cancer Center, Houston, TX; Yale School of Medicine, New Haven, CT; MD Anderson Cancer Center, Houston, TX; Nektar Therapeutics, San Francisco, CA; Kanglaite Inc., San Anselmo, CA; Yale School of Medicine and Yale Cancer Center, New Haven, CT

        Effect of a novel IL-2 cytokine immune agonist (NKTR-214) on proliferating CD8+T cells and PD-1 expression on immune cells in the tumor microenvironment in patients with prior checkpoint therapy.

        Background: NKTR-214 is a CD122-biased agonist designed to provide sustained signaling through the heterodimeric IL-2 receptor pathway (IL-2Rβɣ) to preferentially activate and expand effector CD8+ T and NK cells over T regulatory cells in the tumor microenvironment. Immune changes in the tumor microenvironment after NKTR-214 treatment was assessed in patients with locally advanced or metastatic solid tumors. Methods: NKTR-214 was administered IV in an outpatient setting q2w or q3w. Serial blood and tumor tissue samples were collected to measure immune activation using immunophenotyping including flow cytometry, immunohistochemistry (IHC), T cell clonality and gene expression analyses. Results: 26 patients (pts) have been treated with NKTR-214 at q3w, 4@0.003, 9@0.006, 6@0.009 and 1@0.012 mg/kg. Six pts received 0.006 mg/kg q2w. 58% of pts had prior immunotherapy. The most common Gr1-2 TRAEs were fatigue (73%) and pruritus (65%), and decreased appetite (46%). One pt experienced Gr3 syncope and hypotension at the highest dose tested and continued treatment at a lower dose. No drug-related AEs led to study discontinuation. No immune-related AEs or capillary leak syndrome were observed. 6 pts (23%) experienced tumor shrinkage from 10-30%. Three immunotherapy naïve pts receiving sequential anti-PD1 therapy, after ending treatment with NKTR-214, experienced significant tumor regression at first scan. In all pts evaluated, blood samples showed increases in newly proliferating (Ki67+) T and NK cells 8 days post dose. Flow cytometry and/or IHC revealed an up to 10-fold increase from baseline in tumor CD8+T and NK cells in the tumor microenvironment, with minimal changes to Tregs. PD-1 expression increased 2-fold in TILs. Gene expression analysis of tumor tissue showed increases in several immune checkpoint genes, cytotoxic markers (IFNg, PRF1, and GZMB), as well as a dynamic change in T cell clonality. Conclusions: Based on a favorable safety profile and strong correlative biomarker data, a phase 1/2 trial combining NKTR-214 and nivolumab is currently enrolling.