Tumour defence system boosts immunotherapeutic R&D
interferes with the cells that are trying to kill them. These
results raise the possibility of new drug targets for cancer such
as those that may transport free fatty acids out of the tumour.
Immunotherapeutic methods are often not effective at removing established tumours for a number of reasons including a loss of the ability of the cytotoxic T lymphocytes to recognise the tumour and a physical barrier separating the lymphocytes and the tumour.
Several forms of anti-cancer therapy rely on immunotherapeutic anti-cancer strategies, therapies that encourage the body's natural defences, such as cytotoxic T lymphocytes, to aid in destroying tumours.
Examples include interleukins, interferons, haematopoietic colony stimulating factors and proinflammatory factors such as tumour necrosis factor (TNF). Such cytokines operate on lymphocytes by stimulating them to proliferate by this means boosting a host's immune response.
Examples of cytokines include interleukins (IL-2, IL-7, IL-12), interferons (IFN), hematopoietic colony stimulating factors (GM-CSF) and proinflammatory factors such as tumour necrosis factor (TNF). Such cytokines operate on lymphocytes by stimulating them to proliferate by this means boosting a host's immune response.
The researchers, from the Torrey Pines Institute for Molecular Studies in San Diego, discovered that tumours secrete fatty acids, which inhibit the cytotoxic T lymphocytes' ability to kill tumour cells.
"We found that the most common type of free fatty acids, which at normal levels are essential for life, at high levels prevents the cytotoxic T lymphocytes from destroying tumour cells," said Dr Alan Kleinfeld, co-lead researcher.
"The second thing is that human breast cancer cells, but not normal tissue from the same breast, produce very large amounts of the type of free fatty acids that block the cytotoxic T lymphocytes," he added.
This discovery means that the cancer may have a way of defending itself against attack by the immune system, thereby reducing the potential efficacy of novel anti cancer therapies that rely on a functioning immune system.
These results suggest that free fatty acid levels in the blood could be used to help gauge the aggressive potential of a tumour,
The researchers also discovered that free fatty acids act against cytotoxic T lymphocytes by blocking a number of the lymphocytes' signalling events. For example, they keep certain proteins from being phosphorylated and they also prevent an increase in intracellular calcium that is essential for the cytotoxic T lymphocytes to kill the tumour cells.
Kleinfeld said that he suspected that these signalling events were being blocked at the cells' membranes.
The concept of utilising the immune system for the treatment of cancer has been tried for some time without any direct breakthrough success. So far "passive" immunotherapy has experienced most success, with antibody and cytokine therapy leading the way.
One example is Rituxan, a drug that has seen its revenue grow from $152 million in 1998 to more than $1 billion in 2002.
Other immune-based therapies that have already reached the market are Zevailn, Bexxar, Campath, OncoVax and Erbitux. Other cancer vaccine strategies that are already available include Actimmune, Allovectin-7, Avicine, BEC2, Canvaxin, CeaVac, Gastrimmune, GMK, LymphoCide, Melacine, Ovarex, Oncophage and Osidem.
Although the potential of this strategy remains solid, the efficacy of immunotherapy should and could be improved as Kleinfeld's research demonstrates. Indeed more simple protocols are now being exchanged for more sophisticated ones, and novel solutions are continuing to emerge.
