The pharmacodynamics and biologic activities of recombinant human interferon-beta (rHuIFN-beta) derived from chinese hamster ovary (CHO) cells were examined during long-term therapy in 7 melanoma patients. The CHO-derived rHuIFN-beta was given s.c. in a dose of 3 x 10(6) U three times per week for 24 weeks. Serum levels of IFN could not be detected before and 48 h after the s.c. injections. 2'-5'-Oligoadenylate synthetase (2-5 OAS), beta 2-microglobulin, and neopterin levels increased significantly 48 h after application, with a maximum after 96 h. Subsequently, the values decreased and remained only slightly elevated during the long-term therapy. Natural killer (NK) cell activity increased in the first 96 h significantly and fell below pretreatment values after 4 weeks. The decrease of biologic response could not be attributed to the occurrence of anti-IFN-beta antibodies because only 2 of the 7 patients developed neutralizing antibodies after 16 and 24 weeks of treatment, respectively. This trial confirms the biologic potency of CHO-derived rHuIFN-beta. However, the selected parameters demonstrate that immunostimulation is only possible over a short treatment period.
In A 6-month open adjuvant trial, we treated 21 patients with melanoma with natural interferon-ß (IFN-ß) (Fiblaferon, Rentschier, Laupheim, Germany), and a further 7 patients with recombinant (r)IFN-ß (Betaferon, Rentschier, Laupheim, Germany). With both IFN-ß preparations, the course consisted of three subcutaneous injections of 3 million IU per week given each week for a total of 24 weeks. All patients had stage II malignant melanoma (UICC 1979), and had had all detectable metastases removed surgically before enrollment in the trial.Patients were monitored for neutralizing antibodies against IFN-ß at the beginning of the study, and then every 4 weeks for the next 24 weeks, as well as at 24 and 48 weeks after the end of the treatment period. Neutralizing antibody formation was detected by a cytopathic effect reduction assay. The levels of ß2microglobulin, 2',5'-oligoadenylate synthetase and neopterin were also monitored before and during the treatment.Of the 21 patients treated with natural IFN-ß, 20 (95%) had developed significant levels of anti-IFN-ß antibodies after the 24-week treatment period, which contrasts with only 2 of the 7 patients (29%) treated with recombinant IFN-ß (Table 1 ). These antibodies persisted for a considerable time; 24 weeks and 48 weeks after the cessation of therapy, respectively, 80% and 60% of patients still had neutralizing antibodies. In some patients, the titers increased after cessation of therapy. There was no apparent correlation between the maximum antibody titer and the persistence of antibodies (Table 2). 2,',5'-OHgoadenylate synthetase, ß2-microglobulin, and neopterin levels increased greatly in all the patients when treatment with IFN-ß was initiated. In the patients treated with natural IFN-ß, these levels fell back to pretreatment levels after 8-12 weeks. This was not the case in the patients treated with recombinant IFN-ß, in whom the levels remained markedly elevated throughout the whole treatment period, and returned to normal levels only after treatment was discontinued. We saw a clear correlation between the formation of neutralizing antibodies and the decrease in ß2 microglobulin, 2',5'-oligoadenylate synthetase and neopterin levels, which shows that there was a drop in the biological activity of the injected IFN-ß in the presence of the antibodies. We found complete cross-reactivity between the antibodies formed against the natural IFN-ß and those against Betaferon (which is a glycosylated recombinant IFN-ß, produced in Chinese hamster ovary cells), perhaps because both are glycosylated at identical sites, even though with a different pattern of sugars. Thus, we cannot advocate a switch from treatment with natural IFN-ß to recombinant IFN-ß if antibodies are detected.However, it remains to be determined whether Betaser, a nonglycosylated IFN-ß preparation produced in Escherichia coli, might still be effective.Neutralizing antibodies against IFNs have previously been found to have clinical significance mainly in patients with hematological disorders and in those...
The effect of 13-cis-retinoic acid and highly purified human leukocyte interferon alpha (Alphaferon) therapy for metastatic melanoma was studied. A group of 17 patients with disseminated malignant melanoma were treated over a 6-month period. They received 60 mg 13-cis-retinoic acid/day continuously and ten cycles of interferon alpha (IFN alpha). IFN was administered by subcutaneous injection, at a daily dose of 6 x 10(6) IU Alphaferon. The 5-day treatment period was followed by an IFN-free interval of 2 weeks. We were able to observe an overall response rate of 30% with 12% complete responses (2 out of 17 patients). Sites of response included the skin, lung, liver and lymph nodes. All responses have now lasted over 6 months. Therapy was generally well tolerated and could be performed on an outpatient basis. Side-effects of this combination therapy did not exceed the established side-effects of the two substances. We also studied 2'-5'-oligoadenylate synthetase, beta 2-microglobulin and neopterin levels during the whole treatment course. All patients were within the normal range before treatment and a sharp rise occurred during each IFN cycle. The maximum being observed 24 h after the third injection. This indicates a high biological activity of IFN alpha administered cyclically during the whole treatment course. This finding also corresponds well with the absence of neutralizing antibodies before and after the whole treatment period.
The incidence and clinical significance of therapy-induced neutralizing interferon beta (IFN beta) antibodies was studied in a group of 21 melanoma patients treated with natural IFN beta and 7 patients treated with recombinant IFN beta. They were treated subcutaneously with 3 x 10(6) IU three times per week in an adjuvant open trial for 24 weeks after surgical removal of all detectable metastases. Of the 21 patients treated with natural IFN beta, 95% developed significant levels of neutralizing antibodies after 24 weeks. In comparison, 28% of the 7 patients treated with recombinant IFN beta developed neutralizing IFN beta antibodies. Cross-reactivity of the antibodies could be demonstrated. Persistence of antibody titers was seen in 80% of the patients 24 weeks after cessation of treatment with natural IFN beta. No correlation between the maximum antibody titers and the antibody persistence after cessation of therapy could be established. We detected a clear correlation between the formation of neutralizing antibodies and the decrease in beta 2-microglobulin and 2',5'-oligoadenylate synthetase and therefore the drop in biological activity. In this adjuvant trial there was no difference in relapse rate and time until relapse between antibody-positive and antibody-negative patients. No difference in clinical outcome could be established between the patients treated with natural IFN beta and recombinant IFN beta.
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