van den Heuvel Michel M, Verheij Marcel, Boshuizen Rogier, Belderbos José, Dingemans Anne-Marie C, De Ruysscher Dirk, Laurent Julien, Tighe Robert, Haanen John, Quaratino Sonia
Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands.
Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands.
J Transl Med. 2015 Jan 27;13:32. doi: 10.1186/s12967-015-0397-0.
NHS-IL2 (selectikine, EMD 521873, MSB0010445) consists of human NHS76 (antibody specific for necrotic DNA) fused to genetically modified human interleukin 2 (IL-2) and selectively activates the high-affinity IL-2 receptor. Based on an evolving investigational concept to prime the tumor microenvironment with ionizing radiation prior to initiating immunotherapy, 2 related studies were conducted and are reported here. The first, a preclinical study, tests the systemic effect of the immunocytokine NHS-IL2 and radiotherapy in a lung carcinoma animal model; the second, a phase Ib trial in patients with metastatic non-small cell lung carcinoma (NSCLC), was designed to determine the safety and tolerability of NHS-IL2 in combination with radiotherapy directly following first-line palliative chemotherapy.
Tumor-bearing C57Bl/6 mice were treated with NHS-IL2 alone (5 mg/kg; days 7-9), fractionated radiotherapy (3.6 Gy; days 0-4) plus cisplatin (4 mg/kg; day 0), or the triple combination. Metastatic NSCLC patients who achieved disease control with first-line palliative chemotherapy were enrolled in the phase Ib trial. Patients received local irradiation (5x 4 Gy) of a single pulmonary nodule. Dose-escalated NHS-IL2 was administered as 1-h intravenous infusion on 3 consecutive days every 3 weeks.
NHS-IL2 plus radiotherapy induced immune response activation and complete tumor growth regressions in 80%-100% of mice. In patients with metastatic NSCLC treated with NHS-IL2 (3, 3, and 7 patients in the 0.15-mg/kg, 0.30-mg/kg, and 0.45-mg/kg cohorts, respectively), maximum tolerated dose was not reached. Most frequently reported adverse events were fatigue, anorexia, and rash. Transient increases in leukocyte subsets were observed. In 3 patients, thyroid gland dysfunction occurred. No objective responses were reported; long-term survival was observed in 2 patients, including 1 patient with long-term tumor control.
Combining NHS-IL2 with radiotherapy achieved synergistic antitumor activity in preclinical studies, supporting the use in lung cancer patients. This combination was well tolerated and 2 of 13 patients achieved long-term survival.
ClinicalTrials.gov NCT00879866.
NHS-IL2（selectikine，EMD 521873，MSB0010445）由与基因改造的人白细胞介素2（IL-2）融合的人NHS76（对坏死DNA特异的抗体）组成，可选择性激活高亲和力IL-2受体。基于在启动免疫治疗前用电离辐射预处理肿瘤微环境这一不断发展的研究概念，进行了两项相关研究并在此报告。第一项是临床前研究，在肺癌动物模型中测试免疫细胞因子NHS-IL2和放疗的全身效应；第二项是转移性非小细胞肺癌（NSCLC）患者的Ib期试验，旨在确定NHS-IL2与一线姑息化疗后直接进行的放疗联合使用时的安全性和耐受性。
对荷瘤C57Bl/6小鼠单独给予NHS-IL2（5mg/kg；第7 - 9天）、分割放疗（3.6Gy；第0 - 4天）加顺铂（4mg/kg；第0天）或三联组合治疗。一线姑息化疗实现疾病控制的转移性NSCLC患者被纳入Ib期试验。患者接受单个肺结节的局部照射（5×4Gy）。剂量递增的NHS-IL2每3周连续3天作为1小时静脉输注给药。
NHS-IL2加放疗在80% - 100%的小鼠中诱导免疫反应激活和肿瘤生长完全消退。在接受NHS-IL2治疗的转移性NSCLC患者中（0.15mg/kg、0.30mg/kg和0.45mg/kg队列分别有3、3和7例患者），未达到最大耐受剂量。最常报告的不良事件是疲劳、厌食和皮疹。观察到白细胞亚群短暂增加。3例患者出现甲状腺功能障碍。未报告客观缓解；2例患者观察到长期生存，包括1例长期肿瘤控制的患者。
在临床前研究中，NHS-IL2与放疗联合实现了协同抗肿瘤活性，支持在肺癌患者中使用。这种联合耐受性良好，13例患者中有2例实现长期生存。
ClinicalTrials.gov NCT00879866。
