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

J Transl Med. 2015 Jan 27;13:32. doi: 10.1186/s12967-015-0397-0.

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.

Trial registration: ClinicalTrials.gov NCT00879866.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / radiotherapy
  • Aged
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / radiotherapy
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • Combined Modality Therapy
  • Dose Fractionation, Radiation
  • Female
  • Humans
  • Immunotherapy
  • Interleukin-2 / metabolism*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / radiotherapy*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Necrosis
  • Palliative Care
  • Recombinant Fusion Proteins / administration & dosage*

Substances

  • Antineoplastic Agents
  • EMD 521873
  • Interleukin-2
  • Recombinant Fusion Proteins
  • Cisplatin

Associated data

  • ClinicalTrials.gov/NCT00879866