The incidence and clinical significance of antibodies to interferon-a in patients with solid tumors

It is well known that natural and recombinant proteins can cause antibody formation in the host. We have studied the incidence of binding and neutralizing antibodies in carcinoid patients (n = 327). All together 204 patients received interferon-alpha 2b (Intron-A), median does 15 MU range 9-35 MU/week subcutaneously and 51% of the patients developed binding antibodies by immunoassay and 17% showed positive neutralization assay but high titer antibodies (> 800 NU/ml) were only found in 4% of the patients. The median time until the development of binding antibodies was 26 months and neutralizing antibodies 25 months. Twenty-nine patients received interferon-alpha 2a (Roferon), median does 18 MU/week subcutaneously and 45% developed binding antibodies, 38% had positive neutralization assay and 28% presented high titer antibodies. Binding and neutralizing antibodies occurred at the same time after median six months of treatment. Patients treated with Wellferon (n = 45) and leukocyte interferon (n = 48), median dose of 15 MU/week subcutaneously did not develop any neutralizing antibodies. The majority of the interferon-alpha 2 antibodies were of the IgG isotype. The clinical relevance of the development of high titer neutralizing antibodies was evaluated in the patients. All together 17 patients developed high titer neutralizing antibodies and of these 12 patients showed loss of antitumor response measured as increased level of tumor markers and of tumor progression. In nine of these patients a switch to human leukocyte interferon reinstituted an antitumor response. Neutralizing antibodies against recombinant interferon-alpha 2a and 2b might occur in patients with carcinoid tumors. The incidence of high titer neutralizing antibodies is significantly higher in patients treated with interferon-alpha 2a compared to interferon-alpha 2b. A significant number of patients lost the antitumor effect during development of neutralizing antibodies at high titers, but human leukocyte interferon can be used as rescue treatment.