Integrative Cancer Immunotherapy with Interleukine-2 (IL-2)
Cancer is one of the most common lethal diseases in the world. Recently there has been a breakthrough in harnessing the immune system to treat malignant tumors. Cytokines are small glycoproteins that bind to cell surface receptors and regulate the development, survival, and function of immune cell. Thus, cytokines have been extensively studied as potential therapeutic agents to manipulate the immune response to tumor cells.
IL-2 is one of the key cytokines with pleiotropic effects on the immune system. Interleukin 2 (IL-2) is required for the activation, growth, and differentiation of several families of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells.
Current main indications of rIL-2 include the treatment of metastatic renal cell carcinoma and melanoma for which high-dose intravenous regimens are recommended.
Timeline in understanding the biology and therapeutic application of IL-2.
The signaling pathway of IL-2
IL-2 binds to its receptors at different affinities. Binding of IL-2 to the IL-2Rbg or IL-2Rabg complex leads to the activation of multiple signaling pathways with initial signal transduction involving the recruitment of Janus family tyrosine kinases (JAK1 and JAK3) to the cytoplasmic domains of IL-2Rbg or IL-2Rabg. The activation of JAK kinases results in the recruitment and phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, STAT5A, and STAT5B. Then, three major downstream signaling pathways including the STAT signaling pathway, the phosphoinositide 3-kinase (PI3K-AKT) signaling pathway, and the mitogen-activated protein kinase (MAPK) signaling pathway are activated. These pathways have
mediated the survival, proliferation, differentiation, activation, cytokine production etc. in different types of immune cells.
Signaling pathways of IL-2.
The application of IL2 in cancer immunotherapy
IL-2 was the first cytokines to be successfully used in the treatment of cancer. This was because it can promote T cells as well as NK cells. IL-2 can induce T cell proliferation and differentiation and
also cause its activation.
Large trials on bio-chemotherapy involving combination of chemotherapeutic agent with IL-2 several large trials (metastatic melanoma) have consistently shown better overall response rates with early clinical benefit as compared with chemotherapy.
With targeted therapy
Targeted therapy has deeply revolutionized the current strategy for cancer treatments, especially after the discovery of BCR-ABL in leukemia and EGFR mutation in non-small-cell lung cancer (NSCLC).
The role of IL-2 activation in the restoration of the immunocompetence of lymphocytes against lung cancer
has been demonstrated. EGFR-TKI affects the cancer-related networks of pro-inflammatory cytokines
and activates the lymphocytic responses, which suggested a possible synergism between the EGFR molecular pathway inhibition and immune system modulation in tumor shrinkage.
For subcutaneous injection- Minor toxicities were observed including fatigue, transient fever and digestive disorders. Patients can develop transient subcutaneous nodules at the injection sites. These side effects never required hospitalization nor discontinuation of therapy. A dose-dependent and sustained increase in peripheral blood eosinophils and lymphocytes was observed.
Chatchai Sribundit, M.D.
Dr. Chatchai Sribundit is the distinguished founder of Akesis Life. His education, training and community support is highly regarded worldwide. Dr. Chatchai traveled extensively during the past two decades in order to bring the best possible integrative cancer treatments to Thailand. His primary concern is the well-being of his patients through kindness and care.