BY ROBERT G. BELL
We continue our discussions with two of the heavyweights of cancer immunotherapies, monoclonal antibodies and cytokines. Monoclonal antibodies (MAbs) for cancer therapies are bioengineered antibodies that are constructed to bind to specific antigens that are expressed on the surface of cancer cells. MAbs are usually made by injecting animals with human antigens. The antibodies produced are then harvested and fused with a myeloma cell (cancerous B cell) to produce a fusion cell known as a hybridoma (each hybridoma divides to produce identical daughter cells or clones [monoclonal]).
The commercial development of MAbs is complex and includes (but is not limited to) the characterization of the physical, chemical, and biological properties of the antibody, antigen expression specificity, immune effector functions, signaling pathway effects, in vivo antbody localization and distribution, antibody chimerization and humanization, biodistribution, and the in vivo therapeutic activity, safety, and efficacy. MAbs mimic the actions of antibodies produced naturally by our bodies’ immune systems (B cells, T cells).
The Food and Drug Administration approves MAbs function by several mechanisms. Some MAbs work by stimulating the immune system (rituximab [PDF], alemtuzab [PDF]), or binding to receptors (ipilimumab [PDF]), or inhibiting cancer growth factors (bevacizumab [PDF], cetuximab, panitmumab, trastuzumab [PDF]) or use of immunoconjugates (90Y-ibritumomab tiuxetan [PDF], ado-trastuzumab emtansine [PDF]) to facilitate apoptosis in the cancer cells.
Cytokines are small cell signaling proteins (5–20 kilodaltons) produced by white blood cells to regulate immune responses, inflammation, and hematopoiesis. Cytokines are produced in macrophages, B and T lymphocytes, fibroblasts, mast, endothelial, and stromal cells, and produce a diverse set of proteins that include chemokines, interferons, interleukins, lymphokines, and tumor necrosis factor.
Several types of cytokines are used in cancer therapy, which include interferons (IFNs), interleukins (ILs), and hematopoietic growth factors. By activating natural killer and dendritic cells, α-IFN can enhance a patient’s immune response to cancer cells by inhibiting cancer growth and apoptosis. The ILs, like other cytokines, are not stored within cells but are secreted rapidly in response to a stimulus like an infectious agent and bind to the infectious cell’s surface triggering a cascade of signals within the target cell that alter the cell’s biology.
IL-2 (T-cell growth factor) increases the proliferation of white blood cells, including cytotoxic T cells and natural killer cells, leading to an enhanced anticancer immune response and has been approved (aldesleukin) for the treatment of metastatic kidney cancer and metastatic melanoma. Hematopoietic growth factors promote the growth of various blood cell populations including platelets and red blood cells and allows patients to continue chemotherapy regimens that might otherwise be stopped or modified due to low blood cell numbers. Available hematopoietic growth factors include erythropoietin, which stimulates the formation of red blood cells, granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte stimulating factor (G-CSF), which increases the number of white blood cells (and T cells), and IL-11 (oprelvekin), which increases platelet production.
MAbs and cytokines are the current success stories of precision medicine and will continue to be so as we gain a better understanding of cancer biology and immune regulation. MAbs and cytokines, in conjunction with conventional cancer therapies or novel immunologic treatments such as cancer vaccines, protein therapy, checkpoint inhibitors, and gene therapies, hold the hope of preventing cancer and commuting the death sentence once associated with cancer to a chronic and manageable disease.