Recombinant Human Interferon-β (rHuIFN-β) and Radiation Therapy for Inoperable Non-Small Cell Lung Cancer

Fifteen patients with stage II, IIIA, and MB non-small cell lung cancer (NSCLC) received subcutaneous (s.c.) recombinant, glycosylated, human interferon-β1a (Rebif; rHuIFN-β1a) on each day of conventionally fractionated radiation therapy (RT) given in 2.0 Gy fractions to 60 Gy in 6 weeks. The rHuIFN-β1a was generated in CHO cells by recombinant DNA technology and is identical to natural IFN-β produced by fibroblasts in primary sequence and glycosylation. Cohorts of three patients each were treated with escalating doses of rHuIFN-β1a: 1.5, 3, 6,12, and 24 MIU/m² per treatment day. Acute toxicity was assessed according to modified WHO criteria; late toxicity was graded using RTOG late toxicity criteria. The maximum tolerated dose (MTD) of rHuIFN-β1a was defined as the dose level immediately below that in which dose-limiting toxicity occurred in≥two of six patients. Immunomodulatory effects and antigenicity of rHuIFN-β1a were assessed by 2-5A synthetase, β₂-microglobulin, and neopterin levels and by measurement of anti-rHuIFN-β antibodies, respectively. Fourteen of fifteen patients experienced grades 1–3 acute (early) toxicity (≤90 days), which was primarily gastrointestinal: dysphagia/esophagitis (14/15), nausea/vomiting (12/15), anorexia (7/15), and liver transaminasemia (6/15). One of three patients treated with 24 MIU/m2 per treatment day (total rHuIFN-β1a dose 672 MIU) died of complications secondary to pneumonia, sepsis, adult respiratory distress syndrome (ARDS), and radiation pneumonitis. Twelve patients were evaluable for late toxicity (>90 days). Maximum toxicity was grade 0 in five patients, grade 1 in four patients, and grade 5 in one patient (radiation pneumonitis). Clinical responses from the combination were 1/15 CR, 6/15 PR, 6/15 stable disease, and 1/15 progressive disease. The MTD of rHuIFN-β1a has been estimated at 12 MIU/m² per treatment day when given daily during conventional RT to 60 Gy in 6 weeks. Biologic response by rHuIFN-β1a alone was reflected by significant and dose-related increases in 2-5A synthetase, β₂-nncroglobulin, and neopterin. Radiation therapy alone had no effect on these immune response parameters and did not diminish their augmentation by rHuIFN-β1a. There was no association of biologic modulation with clinical response or survival.