title: NHS-IL2 combined with radiotherapy: preclinical rationale and phase Ib trial results in metastatic non-small cell lung cancer following first-line chemotherapy.
abstract: 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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00879866.
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands. m.vd.heuvel@nki.nl.
authors.forename: Michel M
authors.initials: MM
authors.lastname: van den Heuvel
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands. m.verheij@nki.nl.
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands. r.boshuizen@nki.nl.
authors.forename: Rogier
authors.initials: R
authors.lastname: Boshuizen
authors.affiliation: Department of Radiation Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, The Netherlands. j.belderbos@nki.nl.
authors.forename: José
authors.initials: J
authors.lastname: Belderbos
authors.affiliation: Department of Pulmonology and GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. a.dingemans@mumc.nl.
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.affiliation: Department of Radiation Oncology, Maastro, Maastricht, The Netherlands and University Hospitals Leuven/KU Leuven, Leuven, Belgium. dirk.deruysscher@uzleuven.be.
authors.forename: Dirk
authors.initials: D
authors.lastname: De Ruysscher
authors.affiliation: Merck KGaA, Darmstadt, Germany. Julien.Laurent@merckgroup.com.
authors.forename: Julien
authors.initials: J
authors.lastname: Laurent
authors.affiliation: EMD Serono, Billerica, MA, USA subsidiary of Merck KGaA, Darmstadt, Germany. robert.tighe@emdserono.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Tighe
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121 1066 CX, Amsterdam, The Netherlands. j.haanen@nki.nl.
authors.forename: John
authors.initials: J
authors.lastname: Haanen
authors.affiliation: Merck KGaA, Darmstadt, Germany. sonia.quaratino@novartis.com.|Present address: Novartis Pharma, Basel, Switzerland. sonia.quaratino@novartis.com.
authors.forename: Sonia
authors.initials: S
authors.lastname: Quaratino
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002277:Carcinoma; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D019583:Dose Fractionation, Radiation; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009336:Necrosis; D010166:Palliative Care; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; C578499:EMD 521873; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D002945:Cisplatin