The immunostimulatory activity of IL-2 has proven beneficial in the treatment of some cancer types. An effective anti-cancer agent would prove not only medically valuable, but also commercially very successful. In the developed world, an average of one-in-six deaths is caused by cancer. In the USA alone, the annual death toll from cancer stands in the region of half a million people.
There exists direct evidence that the immune system mounts an immune response against most cancer types. Virtually all transformed cells express (a) novel surface antigens not expressed by normal cells or (b) express, at greatly elevated levels, certain antigens present normally on the cell at extremely low levels. These 'normal' expression levels may be so low that they have gone unnoticed by immune surveillance (and thus have not induced immunological tolerance).
The appearance of any such cancer-associated antigen should thus be capable of inducing an immune response, which, if successful, should eradicate the transformed cells. The exact elements of immunity responsible for destruction of transformed cells remain to be fully characterized. Both a humoral and cell-mediated response can be induced, although the T-cell response appears to be the most significant.
Cytotoxic T cells may play a role in inducing direct destruction of cancer cells, in particular those transformed by viral infection (and who express viral antigen on their surface). In vitro studies have shown that cytotoxic T-lymphocytes obtained from the blood of persons suffering from various cancer types are capable of destroying those cancer cells.
NK cells are capable of efficiently lysing various cancer cell types and, as already discussed, IL-2 can stimulate differentiation of NK cells forming LAK cells, which exhibit enhanced tumouricidal activity. Macrophages, too, probably play a role. Activated macrophages have been shown to lyse tumour cells in vitro, while leaving untransformed cells unaffected. Furthermore, these cells produce TNF and various other cytokines which can trigger additional immunological responses. The production of antibodies against tumour antigens (and the subsequent binding of the antibodies to those antigens) marks the transformed cells for destruction by NK/LAK cells and macrophages - all of which exhibit receptors capable of binding the Fc portion of antibodies.
Although immune surveillance is certainly responsible for the detection and eradication of some transformed cells, the prevalence of cancer indicates that this surveillance is nowhere near 100 per cent effective. Some transformed cells obviously display characteristics that allow them to evade this immune surveillance. The exact molecular details of how such 'tumour escape' is achieved remains to be confirmed, although several mechanisms have been implicated, including:
• Most transformed cells do not express class II MHC molecules and express lower than normal levels of class I MHC molecules. This renders their detection by immune effector cells more difficult. Treatment with cytokines, such as IFN-y, can induce increased class I MHC expression, which normally promotes increased tumour cell susceptibility to immune destruction.
• Transformed cells expressing tumour-specific surface antigens that closely resemble normal surface antigens may not induce an immune response. Furthermore, some tumour antigens, although not usually expressed in adults, were expressed previously during the neonatal period (i.e. just after birth) and are thus believed by the immune cells to be 'self'.
• Some tumours secrete significant quantities of cytokines and additional regulatory molecules that can suppress local immunological activity. TGF-P (produced by many tumour types), for example, is capable of inhibiting lymphocyte and macrophage activity.
• Antibody binding to many tumour antigens triggers the immediate loss of the antibody-antigen complex from the transformed cell surface, either by endocytosis or extracellular shedding.
• The glycocalyx (carbohydrate-rich outer cell coat) can possibly shield tumour antigens from the immune system.
Whatever the exact nature of tumour escape, it has been demonstrated, both in vitro and in vivo, that immunostimulation can lead to enhanced tumour detection and destruction. Several approaches to cancer immunotherapy have thus been formulated, many involving application of IL-2 as the primary immunostimulant.
Experiments conducted in the early 1980s showed that lymphocytes incubated in vitro with IL-2 could subsequently kill a range of cultured cancer cell lines, including melanoma and colon cancer cells. These latter cancers do not respond well to conventional therapies. Subsequent investigations showed that cancer cell destruction was mediated by IL-2-stimulated NK cells (i.e. LAK cells). Similar responses were seen in animal models upon administration of LAK cells activated in vitro using IL-2.
Clinical studies have shown this approach to be effective in humans. LAK cells originally purified from a patient's own blood, activated in vitro using IL-2 and reintroduced into the patient along with more IL-2, promoted complete tumour regression in 10 per cent of patients suffering from melanoma or renal cancer. Partial regression was observed in a further 10-25 per cent of such patients. Administration of high doses of IL-2 alone could induce similar responses, but significant side effects were noted (discussed later).
IL-2-stimulated cytotoxic T cells appear even more efficacious than LAK cells in promoting tumour regression. The approach adopted here entails removal of a tumour biopsy, followed by isolation of T-lymphocytes present within the tumour. These tumour-infiltrating lymphocytes (TILs) are cytotoxic T-lymphocytes that apparently display a cell surface receptor which specifically binds the tumour antigen in question. They are thus tumour-specific cells. Further activation of these TILs by in vitro culturing in the presence of IL-2, followed by reintroduction into the patient along with IL-2, promoted partial/full tumour regression in well over 50 per cent of treated patients.
Further studies have shown additional cancer types, most notably ovarian and bladder cancer, non-Hodgkin's lymphoma and acute myeloid leukaemia, to be at least partially responsive to IL-2 treatment. However, a persistent feature of clinical investigations assessing IL-2 effects on various cancer types is variability of response. Several trials have yielded conflicting results, and no reliable predictor of clinical response is available.
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