Immune cycle


The immune cycle is a natural homeostatic oscillation of the immune system when chronic inflammation is occurring. Similar to the menstrual cycle, the exact wavelength and waveform of each particular individual patient is different. That is, different people have different immune cycles although each cycle is typically repeated every seven days.
C-reactive protein levels in the blood need to be measured every few days in order to have enough time points to show a repeating fluctuation. This is caused by the synchronous division of T cells over time, with T-effector cells boosting immune activity followed by T-regulatory cells suppressing the immune response.
Although the exact reason for the immune cycle is not yet clear, it appears to be a result of repeating and alternating stimulation and inhibition of the immune response, which has been demonstrated to exist in cancer patients. Many cycles occur in the body - like temperature regulation and hormone levels - and the exact cause for these cycles is also unknown, but it is thought to involve the hypothalamus.
The process used to identify this cycle is called 'immune cycle mapping', while the process that uses this cycle in treatment is called 'immune synchronisation'. It is important to note that the immune cycle and immune synchronisation still "require a lot more testing" before treatment methods can become viable because the "research is still in its early stages".

History

The idea of an immune cycle has existed for well over a hundred years. In 1891, Dr William Coley noticed that some of his patients responded better to treatment than other patients, even with complete responses. Almost a century later, in 1975, physicist George Irving Bell developed a mathematical equation to predict a hypothetical immune cycle. Dr Robert North, writing in the 1980s, demonstrated that chemotherapy encouraged the growth of tumors in mice, whose immune systems are very similar to humans. Unfortunately, these pioneers of the immune cycle were unable to establish its existence, particularly since the necessary technology had not yet come into existence.
In the late 1990s, Associate Professor Brendon Coventry noticed that some of his patients responded better to a Melanoma vaccine than other patients despite receiving identical treatment. When local cancer tumours where injected with the vaccine, cancers that had not been injected began to shrink as well, thus indicating an immunogenic relationship. These observations led him to speculate that the immune system operates in a cyclical manner, with peaks and troughs. Operating on this theory, Coventry was able to increase complete response rates to treatment of advanced melanoma from 7% to 17% and without noticeable negative side effects to chemotherapy and radiotherapy.
In 2004, Associate Professor Manfred W. Beilharz et al. from the University of Western Australia began reporting on similar patterns in the treatment of HIV/AIDS infected mice. In 2005, Mr. Martin Ashdown, a minor contributor to this 2004 paper, claimed to have discovered this cycle in 2002, although this is inconsistent with the historical record.
The 2009 publication of CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool? in the Journal of Translational Medicine, of which Coventry was lead author, signalled for the first time that the immune cycle existed in some form. Speaking on ABC radio in 2010, Coventry explained the reasoning behind how the cycle was discovered by numerous practitioners and researchers:

Current scientific status

In 2010, Professor Michael Quinn from the Royal Melbourne Hospital announced that trials would be conducted on women suffering from ovarian cancer. Dr Roxana S. Dronca et al. from the Mayo Clinic found that the immune cycle is also evident in fluctuations beyond C-reactive protein, as it can be seen in "infradian immune biorhythms of both immune cell subpopulations and cytokines." Speaking to the Daily Express newspaper in the UK, Quinn said
However, in 2014, Dr Mutsa Madondo et al. were unable to replicate the results of the 2009 Coventry et al. paper. They discovered that "he statistical analysis used showed no evidence of periodic oscillation". In 2015, Coventry - in a team that included Professor Maciej Henneberg - argued that cancer had become highly developed over time and could counter mainstream cancer treatments by manipulating the immune cycle:
In late 2016, one of the patent holders, Biotempus Limited - whose Chief Scientific Officer, Mr. Martin Ashdown, was involved in the 2009 paper - went into administration and liquidation. The other patent holder, the Mayo Clinic in the US, is presently conducting a clinical trial into immune synchronisation.

Immune synchronised cancer treatments

The use of the immune cycle in treatment through immune synchronisation remains in the very early stages of research, as demonstrated above. According to a 2012 article in Cancer Management and Research, a well timed treatment and the use of agent Interleukin 2 could force the immune system into overdrive, expanding and maximising the period of T-effector cell activity. According to Coventry, "he immune system works in waves that seems to be switching on and off constantly. And now what we're trying to do is see whether we can identify periods or phases in that cycle where we could target more effectively..."
However, the research can also apply to Chemotherapy and Radiotherapy more generally because it is applicable to the treatment of cancers that are, or are likely to be, immunogenic. What this shows is that a patient's treatment outcome may be largely determined by when treatment is administered in relation to their immune cycle, making treatment more a game of chance than a game with fixed rules. Crucially, the ability to administer treatment at the most effective time in a patient's immune cycle means that significantly smaller dosages of chemotherapy can be used, which in turn means far fewer negative side effects to treatment or, possibly, no significant side effects.

Public Awareness

The Australian Melanoma Research Foundation has undertaken many initiatives to promote this research and the potential benefits it could have on cancer patients, as well as advertising clinical trials. Australian Senator Nick Xenophon has helped raise public awareness about this research, a fact that has been noted in the acknowledgements of numerous journal articles.
Numerous submissions and presentations on these findings were made to committees of the Parliament of Australia. In a 2014 submission to the Standing Committee on Health into Skin Cancer in Australia, the Australian Melanoma Research Foundation stated that without the application of the new knowledge on the immune cycle cancer treatment was a "mathematically random" process. It was also revealed that treatment on mice with the new knowledge resulted in a "complete eradication of established tumours in 60% of mice". Their 2015 submission to the Senate Standing Committee on Community Affairs Inquiry into the Availability of New, Innovative and Specialist Cancer Drugs in Australia states that the 5 year survival rate of patients with advanced cancer is consistent with statistical probability that a patients treatment will be administered at exactly the right place in their immune cycle.
In 2013, Dr Svetomir Markovic of the Mayo Clinic gave a public lecture in which he described the immune cycle and the potential developments to medicine it provides.