Immune cycle

The immune cycle is a natural homeostatic oscillation of the immune system when chronic inflammation is occurring.^[1] Similar to the menstrual cycle, the exact wavelength and waveform of each particular individual patient is different.^[1] That is, different people have different immune cycles although each cycle is typically repeated every seven days.^[1]

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 (a wave-like cycle).^[1][2] 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.^[2]

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'.^[1] 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".^[3][4]

History

First to note fluctuations in responses to treatments and speculate on a possible cycle, Dr William Coley.

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.^[2] 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.^[2] Unfortunately, these pioneers of the immune cycle were unable to establish its existence, particularly since the necessary technology had not yet come into existence.^[2]

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.^[5] 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.^[6] These observations led him to speculate that the immune system operates in a cyclical manner, with peaks and troughs.^[2] 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.^[7][8]

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.^[9] 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.^[10]

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.^[1] Speaking on ABC radio in 2010, Coventry explained the reasoning behind how the cycle was discovered by numerous practitioners and researchers:

"We really didn't know that it did until we started taking daily blood measurements. With these daily measurements, it revealed that the inflammatory markers in the blood are going up and down. At first we thought this was an aberration, we didn't think it was anything terribly significant at all, but when we started studying it we noticed that a cycle began to emerge and that the blood levels were going down and then going up and then going down again and going up. We then started to try and work out why this might be occurring... We're all finding the same thing, and this then compels us to want to investigate it much closer and much further, because we think there could be enormous cost savings in this. If we could deliver the right chemotherapy at the right time, then we may be able to alter the cost of cancer care and in particular alter the efficiency at which we deliver it." Coventry, ABC Radio,14 April 2010^[11]

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.^[12] 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."^[13] Speaking to the Daily Express newspaper in the UK, Quinn said

"Everyone, including non-cancer patients, has an immune cycle which fluctuates every 12 to 14 days. That’s why if someone in the family comes in with a cough or cold, only some members of the family will develop it. The immune system also attacks cancer cells, which is why we need to give chemotherapy on the right day... The concept is sensational. If you can treat people at the right time it could dramatically improve their chance of a successful outcome. The research is still in its early stages, however if we are proved right this method of treatment could be applied to all cancers and in fact all diseases." Quinn, 7 March 2010.^[14]

However, in 2014, Dr Mutsa Madondo et al. (in a team that included Professor Quinn) were unable to replicate the results of the 2009 Coventry et al. paper. They discovered that "[t]he statistical analysis used showed no evidence of periodic oscillation".^[15][16] 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:

"Clearly, the cancer cell appears as an adaptive and highly evolved entity able to switch on certain genes to survive the onslaught of radiation and chemotherapy, despite having genetic/chromosomal errors. So, in this sense it is a very sophisticated survival machine." Coventry et. al., 2015 ^[17]

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.^[18] The other patent holder, the Mayo Clinic in the US, is presently conducting a clinical trial into immune synchronisation.^[19]

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.^[1][20] According to Coventry, "[t]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 [Melanoma vaccine treatments] more effectively..."^[7]

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.^[21] 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.^[22] 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.^[2][23]

"Everything in nature exists in a delicate balance. The mammalian immune system has finely tuned opposing forces of immunity and tolerance. This balance can allow vigorous and selective responses to microorganisms and cancer while avoiding damaging responses to normal healthy tissue." Brendon Coventry et al., May 2010^[2]

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.^[24] 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.^[23]

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.^[25] It was also revealed that treatment on mice with the new knowledge resulted in a "complete eradication of established tumours in 60% of mice".^[25] 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.^[26]

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.^[27]

References

Further reading

• Coventry BJ, Baume D, Lilly C (2015). "Long-term survival in advanced melanoma patients using repeated therapies: successive immunomodulation improving the odds?". Cancer Management and Research. 7: 93–103. doi:10.2147/CMAR.S76163. PMC 4425244. PMID 25995649.
• Coventry BJ, Lilly CA, Hersey P, Michele A, Bright RJ (2014). "Prolonged repeated vaccine immuno-chemotherapy induces long-term clinical responses and survival for advanced metastatic melanoma". Journal for Immunotherapy of Cancer. 2: 9. doi:10.1186/2051-1426-2-9. PMC 4950896. PMID 27437102.
• Coventry BJ, Lilly C, "Table of Comparison of Reported Clinical Effectiveness of Treatments for Metastatic Melanoma," Australian Melanoma Research Foundation, 2014, www.melanomaresearch.com.au.
• Coventry BJ, Ashdown ML (2012). "Complete clinical responses to cancer therapy caused by multiple divergent approaches: a repeating theme lost in translation". Cancer Management and Research. 4: 137–49. doi:10.2147/CMAR.S31887. PMC 3379856. PMID 22740774.
• Coventry BJ, Ashdown ML (2012). "The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses". Cancer Management and Research. 4: 215–21. doi:10.2147/CMAR.S33979. PMC 3421468. PMID 22904643.
• Dronca RS, Leontovich AA, Nevala WK, Markovic SN (2012). "Personalized therapy for metastatic melanoma: could timing be everything?". Future Oncology. 8 (11): 1401–6. doi:10.2217/fon.12.126. PMC 4012533. PMID 23148614.
• Coventry BJ, Ashdown ML, Quinn MA, Markovic SN, Yatomi-Clarke SL, Robinson AP (2009). "CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?". Journal of Translational Medicine. 7: 102. doi:10.1186/1479-5876-7-102. PMC 2791755. PMID 19948067.