Robert J. Spiegel

Low incidence of serum neutralizing factors in patients receiving recombinant alfa-2b interferon (intron a)

The development of serum neutralizing factors against recombinant alfa-2b interferon (Intron A) was reviewed in a large clinical experience. In 537 patients receiving systemic therapy, neutralizing factors developed in only 13 (2.4 percent). In 1,326 patients who received intranasal administration and 154 with intralesional administration, the incidence was less than 1 percent. Patients in whom antibody developed had no predisposing characteristics that could be identified, no particular types of patients with cancer had a high rate of neutralizing factors, and two of 10 patients with cancer in whom neutralizing factor developed were still able to show clinical responses. In patients in whom neutralizing factor was present, there was no discernible difference in the incidence or severity of interferon side effects as compared with patients who had no demonstrable neutralizing factor levels. This form of recombinant alpha-2 interferon appears to have a very low antigenic potential.

Treatment of Kaposi's sarcoma with interferon alfa‐2b (Intron® A)

The activity of the alpha interferons against AIDS‐related Kaposis sarcoma (KS) has been demonstrated in numerous clinical trials. Unfortunately, most reports have involved small patient cohorts and a variety of dosages and schedules of administration. We report here a series of Phase II trials with interferon alfa‐2b (Intron® A, Schering Corp., Kenilworth, NJ) involving 114 patients using three dose regimens. Patients received 50 × 106 IU/m2 intravenously (high dose), 30 × 106 IU/m2 subcutaneously (intermediate dose), or 1 × 106 IU/m2 subcutaneously (low dose). Clinical responses were seen in all regimens and, overall, 35% of the patients obtained complete or partial remissions. The response rates in the low‐, intermediate‐, and high‐dose groups were 33%, 28%, and 45%, respectively. In addition, high‐dose therapy was associated with more rapid time to response. Patients with low‐stage (I or II) disease and those who lack B symptoms were more likely to respond to therapy; i.e., response rates for patients without B symptoms were 38%, 44%, and 60% in the low‐, intermediate‐, and high‐dose groups, respectively. Seventy (61%) patients had died at the time of data collection, with a median survival of 15 months. Disease stage and the presence of B symptoms significantly affected mortality. Responders enjoyed significantly longer survival (P < 0.10) than did nonresponders both overall and when adjusted for disease stage. Interferon alfa‐2b was generally well tolerated, although almost all patients experienced flu‐like symptoms. No lifethreatening toxicities occurred and only six (6%) patients discontinued treatment due to adverse reactions. No significant improvement in immunologic parameters was detected during this study. These studies suggest that, in this disease setting, interferon alfa‐2b may be acting through direct antiproliferative effects rather than as an immunomodulator, and higher doses appear to be more effective than very low doses.

Clinical overview of alpha interferon. Studies and future directions

The clinical development of the alpha interferons has now progressed through initial Phase I and II trials into extensive controlled clinical trial designs. Alpha interferon has been a prototype of other biological agents that are now in clinical development. These agents operate through fundamentally different mechanisms of action than conventional chemotherapy and have produced a unique profile of side effects as well as response patterns. Time to response is generally longer than with chemotherapy, and dose‐response and schedule‐dependency questions continue to be explored for most tumor types. Although response rates have been low against most solid tumors when alpha interferon is used as a single agent, it has demonstrated a surprisingly wide range of efficacy in hematologic malignancies. These include tumors of presumed B‐cell, T‐cell, and myeloid lineages. In some diseases, e.g., hairy cell leukemia and chronic myelogenous leukemia, alpha interferon is broadly effective; it appears to considerably reduce or occasionally eliminate the malignant clone while normalizing the peripheral blood counts in most patients. In other diseases, alpha interferon appears destined to play a major role as part of combination therapy or in maintenance or consolidation therapy. In other disease settings, alpha interferons role continues to be explored as part of combination therapy, adjuvant therapy, or as local—regional therapy. The full potential of alpha interferon as an antineoplastic agent will not be determined for many years. In this paper, the results from the first 5 years of widespread clinical testing are reviewed.

Alpha interferons: A clinical overview

The development of the recombinant alpha interferons has provided a prototype for the clinical development of biological compounds. Over 5,000 patients have now been treated with alpha interferons, and from this experience, some general principles relating to the phase I-III testing of biologicals have emerged. Clinical trials of alpha interferon have suggested dose-response relationships and provided a clearer picture of schedule dependence. These trials have also indicated that the extent of tumor burden and identification of sensitive patient subtypes may be critical factors affecting the potential activity of biological compounds. Recent studies using interferon in the treatment of chronic viral hepatitis have also generated promising results, suggesting an even greater antiviral role for the drug. The toxicity profile of the alpha interferons is unusual. Fever and influenza-like symptoms occur in almost all patients at all doses and schedules, and are usually dose limiting. Somnolence and other generally mild CNS effects occur in a small percentage of patients. Hematologic toxicity occurs but is minimal at lower doses and is noncumulative and rapidly reversible at all doses. Gastrointestinal toxicity is mild. No other unusual or unexpected toxicities have been reported, and early reports of cardiovascular toxicity have not been confirmed in large trials. The full role of alpha interferon in antineoplastic and antiviral therapy will be resolved in the coming years. This review summarizes existing safety and efficacy data for the alpha interferons.

Role of recombinant interferon alpha2 and cimetidine in patients with advanced malignant melanoma

SummaryFollowing recent reports suggesting that the addition of eimetidine to interferon may enhance response rates in patients with metastatic malignant melanoma, we have completed a Phase II study of the use of recombinant alpha2 interferon and cimetidine in patients with advanced malignant melanoma and who had progressive disease following interferon therapy alone. We observed two partial responses, no complete responses, and two patients had stable disease. Toxicity encountered was analogous to that of interferon alone. We conclude that the additional of cimetidine to alpha interferon is not beneficial in the treatment of advanced metastatic malignant melanoma.

On the updated ECCO consensus guidelines for medical management of Crohn's disease

Dear Sir, During the 2009 annual meeting of the European Crohns and Colitis Organisation (ECCO), the updated consensus guidelines for medical management of Crohns disease (CD) were presented. ECCO deserves recognition for using a rigorous, evidence-based approach in developing these guidelines. However, whilst we acknowledge our own interests as marketing authorisation holder and distributor of Remicade, we would like to respectfully point out our objections to an assumption of a class effect between anti-TNF agents, as the updated guidelines and in particular section 5I suggest: “ All currently available anti-TNF therapies appear to have similar efficacy and adverse-event profiles, so the choice depends on availability, route of delivery, patient preference, cost and national guidance [EL5, RG D]. ” Firstly, the different biologics targeting TNF-α have different molecular structures and seem to have different clinical effects. For example, the anti-TNF drug etanercept, although currently indicated for use in other inflammatory diseases, was not efficacious in CD clinical trials, and is not indicated for treatment of CD.1 Likewise, development of the monoclonal anti-TNF antibody CDP571 in CD was stopped …

Interferons in oncology : current status and future directions

The European School of Oncology has formed a study group to consider the present status of interferons in oncology. This position paper summarizes the discussions and conclusions of the first meeting of this study group.

Interferon: Current concepts of mechanisms of action

Almost 30 years ago Isaacs and Lindenmann [1] discovered that the supernatant obtained from cells incubated with heat-inactivated influenza virus contained a substance capable of preventing the growth of active virus. This substance, named interferon (IFN), was later shown to be composed of a system of structurally related proteins that act directly on the target cells, not on the virus, and are produced by many types of animal cells in response to various external stimuli (e.g., viruses, certain types of double-stranded RNA, antigens, or mitogens). Three classes of IFNs have been described that differ in their amino acid sequences, as well as immunochemical and physicochemical properties: alpha (leukocyte), beta (fibroblast), and gamma (immune) IFN. Alpha and beta IFNs have also been designated as type I (acid-stable) and gamma IFN as type II (acid-labile). The alpha IFNs, which are produced by a variety of different cells including macrophages, null cells (non-B- and non-T-lymphocytes) and transformed B-cell lines, are a family of at least 14 species that share a 75% or greater amino acid sequence homology. Beta IFN, which shares ca30% amino acid sequence homology with alpha IFNs, is produced mainly by fibroblasts and epithelial cells, but may also be produced by human tumor cells derived from leukocytes (e.g., the Namalwa cell line). Gamma IFN is predominantly a product of T-cells and natural killer (NK) cells and shares little homology with type I IFNs.

Approval Standards for Alfa Interferon Subtypes

The quality and potency of recombinant proteins is peculiarly dependent on numerous factors in the manufacturing process. The producing strain, the plasmid, and the production process from fermentation to final purification have a profound influence on the impurities in the drug substance as well as on the structure of the compound, particularly its tertiary structure, which has implications for receptor-binding, mechanism of action and, ultimately, clinical safety and efficacy. The molecule produced from a defined strain and process must also be fully characterized to determine whether impurities or compounds related to the encoded protein may be present that can affect quality, safety, efficacy, and antigenicity. Even when a new product meets specifications comparable to those of an approved reference product, however, the active substance and the profile of impurities will probably differ since both the nature of the active substance and the impurity profile are process-dependent. Since many variables can affect biologic activity as well as clinical safety and efficacy, controlled clinical trials must be conducted to establish safety and efficacy. This review describes scientific issues regarding production, characterization, quality assurance, biologic activity, and clinical safety and efficacy, which relate specifically to recombinant alfa interferons but also have broader application for approval standards for other recombinant proteins produced by a new manufacturer using a completely different manufacturing process.

Interferon alfa-2b/melphalan/prednisone in previously untreated patients with multiple myeloma: a phase I-II trial.

SummaryInterferon alfa-2b (Intron A; Schering Plough) has been shown to be active in advanced previously treated multiple myeloma (MM). Recent in vitro evidence has suggested synergy between cytotoxic agents and interferon alfa-2b. This phase I–II protocol was initiated to study interferon alfa-2b in combination with melphalan and prednisone. Groups of five patients received interferon alfa-2b twice-weekly for two weeks at dose levels of 0.5, 1.0, 2.0, 5.0 and 10.0×106 IU/m2. During week 2, melphalan (9 mg/m2) and prednisone (40 mg/m2) were administered concurrently with interferon alfa-2b followed by a rest period during nadir myelosuppression, the cycles being repeated every 28 days. Thirty patients were entered of whom 21 were Stage III, 3 Stage II and 6 Stage I. Median nadir WBC/mm3 and platelets/mm3 at the various dose levels are given in the table.Serious adverse reactions while on study included myocardial infarction, renal failure and leukopenia-related sepsis. Early response information is available. Twenty-six patients are evaluable for response. Seven have had progressive disease and 19 (69%) a partial response, the median duration was 11+ months. Interferon alfa-2b does not appear to antagonize melphalan/prednisone effectiveness and may be additive or synergistic. Full evaluation of this combination will be undertaken in randomized controlled trials which are now underway.