One of the main approaches to cancer immunotherapy involves cytokines, which serve as messengers for the immune system. Immune cells secrete cytokines, which are proteins or glycoproteins, to strengthen or suppress normal immune functions. Researchers are attempting to take advantage of this regulatory role to boost the activity of macrophages and natural killer cells, as well as the T and B cells of the adaptive immune system. Cytokines tend to function in collaboration with other molecules, so it is difficult to judge the efficacy of an isolated cytokine in a clinical trial. Some cytokines that don’t have anti-cancer functions, such as interleukin 1 beta, help mediate the negative effects of cytokines, such as interleukin 2, that can fight tumor growth.
Some cytokines have proven ineffective in treating cancer even when used in combination with other therapies. For example, tumor necrosis factor causes severe hypotension when used systematically despite its promising name. Interleukin 4 was shown to be toxic when used in high doses and interleukin 6 proved to be a growth factor for myeloma cells despite its activity against other cancer cells. In addition, granulocyte-macrophage colony-stimulating factor has generated some controversy in terms of its ability to treat melanoma.
Despite the mixed results found in some trials, a few cytokines have become very important in immuno-oncology. The Food & Drug Administration (FDA) has approved interleukin 2 and interferon-alfa 2b for use in the treatment of cancer, and a handful of others are currently under evaluation for their role in cancer therapy.
Interleukin 2 and Cancer Immunotherapy
A T cell growth factor, interleukin 2 binds to a specific receptor on the cells and causes proliferation. At high doses, the cytokine has a high response rate but also high toxicity due to capillary leak syndrome, which is like a state of septic shock. This toxicity, however, is manageable and reversible. The treatment has been primarily associated with renal cell carcinoma, which may respond to interleukin 2 administered at low does to avoid toxicity. One
large study involved 425 patients on low-dose interleukin 2 alone and in combination with interferon-alfa. Researchers found that response rate was significantly higher when the two cytokines were used in unison, although no difference in overall survival was apparent.
Interleukin 2 was approved for use in renal cell carcinoma because of duration of response rather than achievement of response. Patients with the disease who had an objective response to treatment were still alive and either stable or progression-free one year after treatment. The cytokine is also indicated for melanoma. Responsive patients have been progression-free from five to 15 years after treatment.
Treatment Using Interferon-Alfa
The term interferon-alfa refers to a group of molecules encoded on chromosome 9. The family consists of 150 or so amino acids that bind to the surface of immune cells and have very diverse effects on gene expression. Interferon-alfa upregulates tumor antigens and adhesion molecules and additionally promotes B and T cell activity. The cytokine can stimulate both dendritic cells and macrophages to destroy tumor cells. Research has shown that interferon-alfa has a small but consistent response rate in kidney cancer of about 5 to 10 percent. The treatment has become standard, especially in patients that cannot tolerate interleukin 2. However, interferon-alfa is still not approved by the FDA for use in kidney cancer.
The FDA has approved interferon-alfa for the treatment of metastatic melanoma. When patients with stage 3 and 2B resected high-risk melanoma were treated with interferon-alfa, definite disease-free and overall survival benefits were evident. The treatment provided essentially another year of life. At the seven-year follow-up, survival had increased by 27 percent with interferon-alfa. The cytokine was also approved for treatment of hairy cell leukemia after a study found significant survival benefits.
GM-CSF and Interleukin 12
Granulocyte-monocyte colony stimulating factor (GM-CSF) is a cytokine primarily used in stem cell and bone marrow transplants to replace the myeloid series, but data has positioned it as a potential melanoma monotherapy. Scientists theorize that the cytokine would reconstitute antigen-presenting cells and thus better prepare the immune system for a focused response. With the therapy, overall and disease-free survival were significantly increased in a 48-patient trial. However, the results of this trial have been called into question because the matched controls came from an older database that was built before the advent of sophisticated staging and treatment measurements. More studies will need to be conducted to determine if GM-CSF caused the therapeutic effect or whether benefits were simply reaped from four decades of treatment improvement.
Another cytokine that may have therapeutic benefit is interleukin 12, a heterodimeric protein that increase activity in T cells and natural killer cells. In addition, the cytokine is a growth factor for B cells. In mouse models, the treatment has achieved antitumor activity, but only when used as an adjuvant. When paired with peptide vaccines in patients with resected stage 3 and 4 melanoma, interleukin 12 boosts response. GM-CSF may also help boost response to vaccines.