新型IL-2細胞因子免疫激動劑(NKTR-214)是CD122依賴型的激動劑，可以通過異源二聚體IL-2受體途徑(IL-2Rβɣ)提供持續的信號轉導，還可以在腫瘤衛環境中通過調節性T細胞刺激CD8+ T細胞和NK細胞的增殖。本研究在局部晚期或轉移性實體瘤患者中對經過NKTR-214治療後的腫瘤微環境的免疫變化進行了評估。

研究采用以下方法，對IV期的門診的腫瘤患者進行q2w(兩周一次)或q3w(三周一次)的NKTR-214治療。采集血液和腫瘤組織樣品，用流式細胞術、免疫組化(IHC)、T細胞克隆、基因表達分析等方法進行免疫活性的測定。

在三周一次經NKTR-214治療的26例患者中，接受的治療劑量分別為4例0.003mg / kg、9例0.006 mg / kg、6例0.009 mg / kg和1例0.012 mg/kg。研究結果表明，二周一次治療的患者有6例接受0.006 mg/kg的NKTR-214治療。最常見的Gr1-2 TRAEs為疲勞(73%)、瘙癢(65%)、食欲不振(46%)。1例患者在最高劑量下出現Gr3昏厥和低血壓反應，並以較低劑量繼續治療。沒有與藥物相關的AEs導致研究停止。沒有觀察到與免疫相關的AE或者毛細血管滲透綜合征。6例(23%)的患者腫瘤發生了10-30%的縮小。3例沒有接受過免疫治療的患者在結束NKTR-214治療後，在接受抗PD-1治療後腫瘤明顯消退。所有患者的血液樣品檢測治療8天後新增殖(Ki67 +)T和NK細胞增加。流式細胞術和/或IHC顯示腫瘤微環境中腫瘤CD8 + T和NK細胞的基線增加高達10倍，Treg的變化最小。PD-1表達在TIL中增加2倍。 腫瘤組織的基因表達分析顯示幾種免疫檢查點基因、細胞毒性標誌物(IFNg, PRF1, and GZMB)以及T細胞克隆性都有所增加。

基於以上有利的安全性和生物標誌物，結合NKTR-214和nivolumab的1/2期試驗目前正在招募中。

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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.