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.

Trial registration: ClinicalTrials.gov NCT00879866.

Figures

Figure 1

Mouse model (LLC in C57/Bl6) study design (A) and observed tumor growth inhibition (B). Mice received the indicated treatments when tumors had reached volume of 81 mm3 to 137 mm3 7 days after implantation. Cisplatin 4 mg/kg was administered only on day 0. The dose of radiotherapy was 3.6 Gy and the dose of NHS-IL2 was 5 mg/kg. Each treatment group comprised 10 mice through day 14, and 6 mice thereafter; 4 mice from each group, selected around the mean, were sacrificed on day 14 for mechanistic endpoints. The experiment was repeated 3 times with similar results. Cis, cisplatin; RTX, radiotherapy.

Figure 2

Clinical trial design (A) and observed NHS-IL2 serum concentrations (B). Patients with metastatic NSCLC after first-line platinum-based therapy (4–6 cycles) were treated with radiotherapy followed by NHS-IL2 at escalating doses of 0.15 mg/kg, 0.30 mg/kg, or 0.45 mg/kg. Mean serum concentration of NHS-IL2 is depicted by dose level during the first, second, and fourth treatment cycles. CTX, chemotherapy; NSCLC, non-small cell lung cancer; PR, partial response; Pt, platinum; SD, stable disease.

Figure 3

Time course of leukocyte subpopulations in metastatic NSCLC patients treated with NHS-IL2 (by dose group). Absolute counts (109 cells/mm3) are shown for total leukocytes, lymphocytes, neutrophils, monocytes, basophils, and eosinophils from NSCLC patients treated with NHS-IL2 at dose levels 0.15 mg/kg, 0.30 mg/kg, and 0.45 mg/kg. Geometric mean values of absolute counts are shown for each dose level. Blood was drawn 7 days before start of treatment and at days 1 and 8 of each cycle until discontinuation. The arrow identifies the first of the 3 consecutive days of NHS-IL2 infusion. NSCLC, non-small cell lung cancer.

Figure 4

Time course of lymphocyte subsets (median by treatment group). Percentage change from baseline (day –7) based on absolute count values (cells/mm3) on days 1 and 8 during the first and second treatment cycles for: (A) proliferative CD4 T cells (CD3 + CD4 + Ki67+) and memory CD4 T cells (CD3 + CD4 + CD197–CD45RA–); (B) proliferative CD8 T cells (CD3 + CD8 + Ki67+) and memory CD8 T cells (CD3 + CD8 + CD197–CD45RA–); and (C) immature NK cells (CD16–CD56brightCD3–) and mature NK cells CD16 + CD56 + CD3–. (D) sIL-2Ralpha serum concentrations (pg/mL) at baseline and on days 1 and 8 during the first cycle. Graphs show the individual values from 12 NSCLC patients treated with NHS-IL2 at doses of 0.15 mg/kg, 0.30 mg/kg, and 0.45 mg/kg. Bars represent geometric mean values. NK, natural killer; NSCLC, non-small cell lung cancer; sIL-2Ralpha, soluble IL-2 receptor alpha.