ot all patients are cured by , biological Ntherapies, radiotherapy or surgery. Some patients can have complete regression of all cancer, while others do not appear to be responding or show some level of clinical response but not enough to overcome the tumour. BAy M ARMTIN AaSHDtOWtNe andrBR EoNDOfN COTVENiTmRY e This variability has remained unex- plained for many decades, and at the end of this week about 800 Australians with cancer will be dead. In the US the numbers will be close to 12,000 per week. In May 2006, Science noted that the US cancer mortality rate had changed very little in 50 years despite the intro- duction of a multitude of often-expen- sive drugs. The annual associated cost of cancer treatment and loss to society in personal and economic terms amounts to hundreds of billions of dollars glob- ally.

What Is Cancer? Cancer is uncontrolled growth and divi- sion of genetically altered cells that typi- cally invade other tissues, may have the capacity to spread, and might eventually kill the patient. Traditional cancer therapies attempt to stop this cell division by poisoning the cancer cells when they are dividing and most vulnerable. But cancer therapy also affects normal cells as they divide, often leading to unwanted collateral toxicities such as nausea, bowel disturbances, hair loss, immune suppression, ulcers, infec- tion and even death. Cancer cells tend to divide continu- ously, and that is why chemotherapy and radiotherapy are given over a number of days, weeks or months in various forms and combinations in the hope that the therapy will eventually kill all the cancer cells. Clearly, for most cancer types, this cannot halt the progression of the disease.

Successful treatment of cancer may depend on the accurate The ’s Role timing of chemotherapy or vaccine therapies to match The notion of the body’s own immune fluctuations in each patient’s immune system. system eliminating cancer cells is not new.

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iStockphoto In 1891 William Coley, a New York emerged earlier, was left untouched by these inhibitory cells – now called T- surgeon, made the remarkable observa- the chemotherapy drug and was there- regulatory cells – are available and more tion that some patients who developed fore free to kill the tumour cells. sophisticated. streptococcal infection and fever showed Interestingly, North also noticed that The implications of these observations regression of most or all of their cancer. if the chemotherapy was given at the are potentially profound, and one could He recorded a series of similar patients, wrong day and earlier, the tumour would conclude that while chemotherapy and and even inoculated non-infected patients grow faster. Again, this ran counter to other cancer therapies are therapeutically to induce infection. This was truly the prevailing dogma that the bene!cial, they are actually modulating remarkable in an era long before the intro- chemotherapy agent was supposed to be the cancer patient’s immune system, duction of antibiotic therapies! active against the tumour – not make it releasing it from regulation rather than Coley’s daughter and grandson subse- grow faster. This gave the impression that directly killing the tumour cells. quently worked on these early pioneering the tumour was resistant to the cytotoxic Furthermore, a number of researchers observations for many years, but the tools drug. have observed that different required for dissecting the immune Recently this same timing phenom- chemotherapy agents can therapeutically system apart to understand the real mech- enon was reported by David Klatzmann’s manipulate the immune response in the anisms behind these observations group in France. In other papers, radia- cancer patient. remained lacking or rudimentary until tion therapy seemed to have the same the past few decades. effect. Emerging Evidence In a series of publications in the 1980s Everything in nature exists in a delicate Robert North, an Australian-born immu- “the timing of cancer balance. The mammalian immune system nologist based at the Trudeau Institute in has !nely tuned opposing forces of immu- therapy... could be New York, and colleagues were able to nity and tolerance. This balance can allow induce immune-based tumour regression crucial in determining vigorous and selective responses to in mouse cancer models by directing the success of microorganisms and cancer while chemotherapy at what was then called treatment”. avoiding damaging responses to normal “immune suppressor” cells rather than healthy tissue. the tumour cells. This was counter-intu- Usually this is a highly e#cient phys- itive to the existing paradigm of Consequently, to achieve a successful iological process, but if it does get out of chemotherapy directed purely at the treatment outcome for tumour-bearing balance it can result in diseases such as cancer cells. mice, the therapy had to be applied in an multiple sclerosis, arthritis, in"amma- But North’s therapeutic approach accurate and timely fashion. The mouse tory bowel disease and cancer. would only work if the chemotherapy immune system behaves almost identi- Evidence gathered over the past few was administered as a single dose 14–15 cally to the human, indicating common years has made it clear that the immune days after the tumour cells had been immune system mechanisms among system is not ignorant of the presence of implanted and had established growth. mammals. a tumour. In fact, it can fail to control While an immune response against the Why North’s work was not fully appre- the disease because the immune system tumour cells was generated in the !rst ciated at the time is perhaps understand- holds itself back, allowing the cancer to 10–12 days, it was curtailed at about day able. In personal communications with kill the host. 14–15 by the suppressor cells. This North he explained that the work "oun- Another profound observation is that immune suppression would allow the dered due to a lack of speci!c markers to the immune system, once triggered, works tumour to grow and kill the mice some 30 readily identify these suppressor/ regula- in a very controlled, sequential and time- days later. tory cells. Other researchers also doubted dependent fashion over several days. That However, when they were treated at their existence due to the di#culty of isola- is, it switches “on” and “off”. Observa- the right time, the tumours would tion and assaying. In addition, it was not tions in the mouse and human clinical completely regress. The rationale behind fully appreciated that these cells are in low situation suggest that, in a disease state the approach was to kill the suppressor numbers and their appearance is short- such as cancer, this “on/off” cycle simply cells when they were rapidly dividing and lived. repeats constantly under homeostatic hence vulnerable to typical cancer drugs. North’s papers are now commonly feedback control. In fact, the homeostatic In contrast, the activated effector arm of cited in other publications, and the assays regulation is likely to be the very problem the immune response, which had to detect the numbers and activity of that does not allow the immune system

MAY 2010 | | 19 Using these methods we have been able to correlate the timing of vaccina- tion or chemotherapy with the induc- tion of successful clinical responses. More accurately timed delivery of vaccine or chemotherapy approaches might reverse immune suppression in patients with metastatic melanoma, and cancer more generally.

Conclusions The implications of our !ndings could be profound. For a start, reduced amounts of cancer drug, radiotherapy or thera- peutic vaccine might be required to successfully treat the cancer patient if the Figure 1. Daily CRP blood levels can be measured and may identify the optimal timing for treat administration is synchronised with each ment of cancer with either vaccine (green) or chemotherapy (red) according to variations in the patient’s immune cycle. This could result immune cycle (red dashed line) . If these putative “windows of opportunity” are missed, the patient fails to respond to therapy, as described in the mouse experiments. in a dramatic reduction in associated toxi- cities, with expensive new cancer agents to gain su#cient momentum to destroy sent repeating or cyclical immune acti- playing a lesser role in cancer treatment. the cancer. vation and suppression against the cancer, One strong possibility is that the timed Since the “on-switch” ( T-effector with a reproducible periodicity of approx- therapeutic vaccine approach, with its cells) and the “off-switch” (T-regulatory imately 6–7 days. The cancer appears to very low toxicity, might become the best cells) divide synchronously over a very cause the patient’s own immune system approach. short time frame a few days apart, they to switch “on” and then switch “off” Furthermore, inexpensive “off-patent” can be selectively killed with standard against the cancer, perhaps explaining drugs could be used more e#caciously, cancer drugs by timing the administra- some of the variability in the effective- even at low doses. This could result in a tion to when they are dividing. If the ness of many cancer treatments. Thus, dramatic reduction in the costs of cancer therapy is timed correctly, the “off- what North and Klatzmann have treatments. switch” cells can be removed, allowing described in the mouse model may apply We suspect that the unexpected the unregulated immune system to kill to humans. recovery of some advanced cancer the tumour cells. This has been achieved Putting these two ideas together – of a patients given standard therapies may in a number of mouse cancer models. persistent regulated immune response have been the result of random, chance or cycling “on and off” in cancer patients and accidental manipulation of the patient’s Timing Treatment a difference in the timing of division for own immune system. By simply being in Recently, we and colleagues reported in the two opposing immune cell populations the clinic on the right day, these patients’ the Journal of Translational Medicine the controlling this cycle – we have postulated inhibitory T-regulatory cells have been discovery of homeostatic oscillations in that the timing of cancer therapy with ablated, enabling more effective T- the human immune system in the form respect to this cycle could be crucial in effector responses to occur. of repeating “immune cycles”. Using serial determining the success of treatment. Clinical investigations of this phenom- (near daily) blood measurements of C- By sequentially measuring CRP before enon are underway and, with appropriate reactive protein (CRP), a commonly used and around the time of vaccination or funding and trial design, the preliminary in"ammatory marker that rises and falls chemotherapy, we were able to establish !ndings may be veri!ed in a matter of over several days with the initiation and the position of the patient’s underlying only weeks rather than the often-quoted termination of the immune response, we immune curve (Fig. 1). Timing with 10–15 years. have been able to observe oscillations in respect to this cycle appears to be critical Time, or rather “timing”, will tell. the in"ammatory/ immune response in for modulating the immune system with Martin Ashdown is a Research Fellow at the University of late-stage cancer patients. each intervention, and pivotal to the Melbourne’s Faculty of Medicine. Brendon Coventry is Associate Professor of Surgery at the University of Adelaide/ Royal Adelaide These immune cycles most likely repre- success of the therapy. Hospital.

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