NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy

Journal of Translational Medicine

Sonia Quaratino²  John Haanen¹  Robert Tighe⁶  Julien Laurent⁴  Dirk De Ruysscher⁷  Anne-Marie C Dingemans³  José Belderbos⁵  Rogier Boshuizen¹  Marcel Verheij⁵  Michel M van den Heuvel¹ 

[1] Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands;Present address: Novartis Pharma, Basel, Switzerland;Department of Pulmonology and GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands;Merck KGaA, Darmstadt, Germany;Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands;EMD Serono, Billerica, MA, USA subsidiary of Merck KGaA, Darmstadt, Germany;Department of Radiation Oncology, Maastro, Maastricht, The Netherlands and University Hospitals Leuven/KU Leuven, Leuven, Belgium

关键词: Phase Ib;    Radiotherapy;    Immunotherapy;    NHS-IL2;    Lung cancer;   

Others  :  1137697
DOI  :  10.1186/s12967-015-0397-0

 received in 2014-10-03, accepted in 2015-01-13,  发布年份 2015

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Trial registration

ClinicalTrials.gov NCT00879866 webcite

【 授权许可】

   
2015 van den Heuvel et al.; licensee BioMed Central.

【 图 表 】

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