重组人白细胞介素-15在癌症患者中的首次人体临床试验期间的再分布、过度增殖、自然杀伤细胞和CD8 T细胞的激活以及细胞因子产生
Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer.
作者信息
Conlon Kevin C, Lugli Enrico, Welles Hugh C, Rosenberg Steven A, Fojo Antonio Tito, Morris John C, Fleisher Thomas A, Dubois Sigrid P, Perera Liyanage P, Stewart Donn M, Goldman Carolyn K, Bryant Bonita R, Decker Jean M, Chen Jing, Worthy Tat'Yana A, Figg William D, Peer Cody J, Sneller Michael C, Lane H Clifford, Yovandich Jason L, Creekmore Stephen P, Roederer Mario, Waldmann Thomas A
机构信息
Kevin C. Conlon, Steven A. Rosenberg, Antonio Tito Fojo, John C. Morris, Thomas A. Fleisher, Sigrid P. Dubois, Liyanage P. Perera, Donn M. Stewart, Carolyn K. Goldman, Bonita R. Bryant, Jean M. Decker, Jing Chen, Tat'Yana A. Worthy, William D. Figg Sr, Cody J. Peer, and Thomas A. Waldmann, National Cancer Institute; Enrico Lugli, Hugh C. Welles, Michael C. Sneller, H. Clifford Lane, and Mario Roederer, National Institute of Allergy and Infectious Diseases, Bethesda; Jason L. Yovandich and Stephen P. Creekmore, National Cancer Institute, Frederick, MD; and Hugh C. Welles, Columbian College of Arts and Sciences, George Washington University, Washington, DC.
出版信息
J Clin Oncol. 2015 Jan 1;33(1):74-82. doi: 10.1200/JCO.2014.57.3329. Epub 2014 Nov 17.
PURPOSE
Interleukin-15 (IL-15) has significant potential in cancer immunotherapy as an activator of antitumor CD8 T and natural killer (NK) cells. The primary objectives of this trial were to determine safety, adverse event profile, dose-limiting toxicity, and maximum-tolerated dose of recombinant human IL-15 (rhIL-15) administered as a daily intravenous bolus infusion for 12 consecutive days in patients with metastatic malignancy.
PATIENTS AND METHODS
We performed a first in-human trial of Escherichia coli-produced rhIL-15. Bolus infusions of 3.0, 1.0, and 0.3 μg/kg per day of IL-15 were administered for 12 consecutive days to patients with metastatic malignant melanoma or metastatic renal cell cancer.
RESULTS
Flow cytometry of peripheral blood lymphocytes revealed dramatic efflux of NK and memory CD8 T cells from the circulating blood within minutes of IL-15 administration, followed by influx and hyperproliferation yielding 10-fold expansions of NK cells that ultimately returned to baseline. Up to 50-fold increases of serum levels of multiple inflammatory cytokines were observed. Dose-limiting toxicities observed in patients receiving 3.0 and 1.0 μg/kg per day were grade 3 hypotension, thrombocytopenia, and elevations of ALT and AST, resulting in 0.3 μg/kg per day being determined the maximum-tolerated dose. Indications of activity included clearance of lung lesions in two patients.
CONCLUSION
IL-15 could be safely administered to patients with metastatic malignancy. IL-15 administration markedly altered homeostasis of lymphocyte subsets in blood, with NK cells and γδ cells most dramatically affected, followed by CD8 memory T cells. To reduce toxicity and increase efficacy, alternative dosing strategies have been initiated, including continuous intravenous infusions and subcutaneous IL-15 administration.
目的
白细胞介素-15（IL-15）作为抗肿瘤CD8 T细胞和自然杀伤（NK）细胞的激活剂，在癌症免疫治疗中具有巨大潜力。本试验的主要目的是确定转移性恶性肿瘤患者连续12天每日静脉推注重组人IL-15（rhIL-15）的安全性、不良事件谱、剂量限制性毒性和最大耐受剂量。
患者与方法
我们进行了一项关于大肠杆菌产生的rhIL-15的首次人体试验。将IL-15以每天3.0、1.0和0.3 μg/kg的剂量连续12天推注给药于转移性恶性黑色素瘤或转移性肾细胞癌患者。
结果
外周血淋巴细胞的流式细胞术显示，在给予IL-15后数分钟内，NK细胞和记忆性CD8 T细胞从循环血液中大量流出，随后流入并过度增殖，导致NK细胞扩增10倍，最终恢复至基线水平。观察到多种炎症细胞因子的血清水平升高达50倍。在接受每天3.0和1.0 μg/kg剂量的患者中观察到的剂量限制性毒性为3级低血压、血小板减少以及ALT和AST升高，导致确定每天0.3 μg/kg为最大耐受剂量。活性迹象包括两名患者肺部病变的清除。
结论
IL-15可安全地给予转移性恶性肿瘤患者。给予IL-15显著改变了血液中淋巴细胞亚群的稳态，其中NK细胞和γδ细胞受影响最为显著，其次是CD8记忆T细胞。为降低毒性并提高疗效，已启动替代给药策略，包括持续静脉输注和皮下给予IL-15。
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