Interferons
Overview
The body’s immune system normally rids itself of aberrant cells before they have a chance to multiply, colonize, or metastasize. Immunotherapy takes advantage of these natural host defense mechanisms through several classes of agents: monoclonal antibodies that target aberrant proteins on cancer cells; cytokines that increase or activate host immune cells, such as T cells, macrophages, and natural killer (NK) cells (large granular lymphocytes that bind to and kill cells by releasing cytotoxins); or vaccines that activate specific host T-cell or antibody responses that attack the cancer cells.
The only immunotherapy agent in current use for chronic myelogenous leukemia is the cytokine interferon-alpha (interferon-a). Cytokines are low-molecular-weight secreted proteins produced by many different cell types. These proteins are involved primarily in regulating the immune response and are necessary for the biochemical communication involved in wound healing, immunosurveillance, and inflammatory responses. The IFNs are a family of naturally occurring cytokines produced in response to viral infections, antigens, mitogens, and other cytokines. Three types of interferons have been identified: interferon-alpha (produced by leukocytes and macrophages), interferon-beta (produced by fibroblasts), and interferon-gamma (produced by T lymphocytes).
Mechanism Of Action
The direct anti tumor effect of IFNs derives from their ability to inhibit cell-cycle progression, induce a reduction in tumor-cell protein synthesis, and inhibit late progenitor colonies. IFNs can also produce indirect anti-tumor effects by modulating immunomodulatory and anti-angiogenic responses. Their immunomodulatory role involves inducing the expression of major histocompatibility antigens and modulating the expression and function of T cells, monocytes, and natural killer cells. Both the direct and indirect effects of IFNs result from induction of a subset of genes called the IFN-stimulated genes (ISGs).
Interferon-Alpha
Interferon-a is used to treat approximately 30 different diseases, both alone and in combination with chemotherapeutic and biological agents. Several types of interferon-a are available although not all are licensed in all countries for the treatment of chronic myelogenous leukemia. Interferon-a was considered standard first-line treatment until December 2002, when the FDA approved imatinib for the first-line treatment of chronic myelogenous leukemia.
Interferon-a may exert a direct antiproliferative effect. Alternatively, it may exert an indirect effect on the immune system through nonspecific enhancement of antileukemic cell-mediated response. interferon-a may increase human leukocyte antigen (HLA) molecule expression on Ph-positive cells; this increased expression enables more-efficient recognition of the HLA-linked leukemic peptide by antigen presenting cells (APCs) and T-lymphocytes. The binding of interferon-a to its membrane receptor activates a number of signaling pathways that eventually modulate the transcription of several genes. Many of these pathways are the same as those that are constitutively activated by the leukemia-specific BCR-ABL tyrosine-kinase oncoprotein. An important difference between the effects of interferon-a and BCR-ABL is that ICSBP (interferon consensus sequence binding protein) is downregulated in BCR-ABL-expressing cells and upregulated by interferon-a. Mice lacking ICSBP expression develop a myeloproliferative syndrome resembling chronic-phase chronic myelogenous leukemia.
Why some Ph-positive cells are or become resistant to interferon-a is unknown. Clinical observation indicates that interferon-a’s therapeutic effect decreases over time. interferon-a’s effect is much greater in early rather than in late chronic-phase disease, and it is minimal in disease that progresses from chronic to the accelerated or blastic phases. This declining effect implies the development
of other genomic abnormalities that make the cells more resistant to interferon-a. Sensitivity to interferon-a may depend primarily on the amount of BCR-ABL tyrosine-kinase oncoprotein present in the blood. The identification of other genomic abnormalities that play a role in determining response may provide a basis for a more rational use of interferon-a, either alone or in combination.
The use of interferon-a in chronic myelogenous leukemia was first evaluated by the Houston group at the M.D. Anderson Cancer Center almost 20 years ago. Since then, several studies by single-institution or cooperative groups using recombinant interferon-a-2a, -2b, or -2c have confirmed the efficacy of interferon-a in chronic myelogenous leukemia. The M.D. Anderson Cancer Center used a dose of 5 MIU/m2 daily for the treatment of 274 patients with early chronic-phase chronic myelogenous leukemia. Of these patients, 80% achieved a CHR and 58% displayed a cytogenetic response (complete, 26%; major, 38%). The median survival was 89 months. Achieving a cytogenetic response after 12 months of therapy was associated with a statistically longer survival. At five years, the survival rates were 90% for cytogenetic response, 88% for major cytogenetic response, and 76% for minor response.
Several randomized studies have investigated the relationship of duration of the chronic phase and survival to interferon-a treatment dose and schedule. An Italian study involving 322 patients demonstrated a 6-year survival rate of 50% with interferon-a compared with 29% with chemotherapy (Italian Cooperative Group on Chronic Myeloid Leukemia, 1994). The median survival of the 218 patients who were assigned to interferon-a and the 104 patients who were assigned to chemotherapy was 76 months and 52 months, respectively. The proportion of the patients who were projected to be alive after ten years was 29% in the interferon-a arm and 17% in the chemotherapy arm. The median time from diagnosis to progression was 74 months with interferon-a and 46 months for chemotherapy. The median survival and the 10-year survival rate of Sokal’s low-risk patients achieving hematologic and cytogenetic responses were 104 months and 47%, respectively, in the interferon-a arm versus 64 months and 30%, respectively, in the chemotherapy arm.
A worldwide collaborative overview of 1,554 patients randomized and assigned to treatment in seven trials aimed to establish whether patients benefit from treatment with interferon-a (Chronic Myeloid Leukemia Trialists’ Collaborative Group, 1997). The regimens that involved interferon-a produced statistically significantly better survival than those that involved hydroxyurea or busulfan. The five-year survival rates were 57% with interferon-a and 42% with chemotherapy.
Two French multicenter trials studied the potential benefit of combining interferon-a and LDAC (IFN+LDAC) as first-line treatment. Patients were randomized to receive interferon-a 5 MU/m2 or the same dose of interferon-a plus monthly courses of LDAC at a dosage of 10 mg/m2/day for 10 days. Of 207 evaluable patients after a median follow-up of 85 months, 29 of 103 patients (28%) in the IFN+LDAC group achieved a cytogenetic response, whereas 21 of 104 patients (20%) treated with interferon-a obtained this result; median survival was 77 months in the IFN+LDAC group and 65 months in the interferon-a group.
In the second study, the dose of cytarabine was increased to 20 mg/m2/day. The trial enrolled 810 patients; 721 were studied (360 randomly assigned to the IFN+LDAC group and 361 to the interferon-a group). An update of this trial showed that the probability of achieving an major cytogenetic response at 24 months was significantly higher in the IFN+LDAC group. In addition, the patients in the IFN+LDAC group survived significantly longer than those in the interferon-a group. At three years, the estimated survival rates were 85.7% and 79.1% for the IFN+LDAC group and the interferon-a group, respectively.
The Italian Cooperative Study Group on chronic myelogenous leukemia conducted a similar randomized trial. Five hundred and forty evaluable patients were randomized to IFN+LDAC (275) and to interferon-a alone (265). At 12 months, the combination resulted in a higher major cytogenetic response rate (28% versus 18%). Although this difference was significant, it did not translate to better survival.
A Phase III trial using genetic randomization compared allo-Stem-cell transplantation with “best available therapy” — interferon-a. Genetic randomization uses the availability of a sibling donor or a matched unrelated donor to determine the treatment of the patient — all patients with an appropriate donor would receive allo-Stem-cell transplantation. A preliminary report of this trial found that the projected three-year survival was 64% for the related donors and 80% for the drug therapy group; in the drug therapy group, the three-year survival for patients with a low-risk Sokal or Hasford score was 90%. These results support the findings of a registry-based study concluding that the survival benefit of allografting over interferon-a becomes apparent only between five and ten years after treatment. Prior to this time, patients treated with interferon-a have superior survival.
Interferon-a has several shortcomings. It has an extremely slow onset of action, it is poorly tolerated (patients often develop flu-like symptoms), and it requires daily injections. Therapy must be discontinued in 15-25% of patients and the dose reduced in up to 50%. Because hematologic responses take several months to occur, other agents such as hydroxyurea are often used prior to interferon-a therapy to rapidly reduce the leukocyte counts.
This post has been viewed 262 times.