Modern drugs have reduced the toxicity of many treatments but have not significantly improved complete response rates which are still currently only about 7% across many types of cancers and using many different types of treatment.

This, we believe, is not due to fundamental problems with the agents themselves. Rather, it is due to the random timing of their application. Drug treatments are at present scheduled according to a range of clinical and non-clinical considerations but not with regard to what Biotempus has identified as the most important factor: the dynamics of the individual patient’s immune system.

In 2002 Biotempus Chief Scientific Officer Martin Ashdown made a remarkable observation: that the immune system of a cancer patient fluctuates over an approximately seven-day cycle.

The immune system is a massively complex one. Indeed, immunology has over the past decade or more become one of the most intensely studied and exciting areas of medical science. Every new discovery in the field reveals the ever greater complexity of the system’s interlocking mechanisms. However, the key aspect of Martin’s observation is fundamentally simple. It relies on the fact that the immune system has two aspects: a means of attacking disease and a means of limiting that attack.

The attack mechanisms of the immune system are remarkably efficient. We routinely encounter external and sometimes novel threats in the form of bacteria (think of an infected wound) and viruses (colds and flu). The attack (effector) system responds to antigens and thus identifies, kills and clears off these invaders. When it has done so, the other side of the immune system—the regulatory system—steps in to call off the attack. Good regulation of the system is crucial. The effector system is potent and, unless it is reined back, can create havoc. An unregulated immune system is the cause of autoimmune diseases (rheumatoid arthritis, type 1 diabetes, multiple sclerosis and many more) in which the body relentlessly attacks itself.

Martin noted that certain molecules in blood samples taken daily or near-daily from cancer patients rose and fell over a repeating period of about seven days.

This correlated with changes in the effector and regulatory aspects and cells of the immune response. This dynamic cycling showing the two-sided immune system can be tracked by monitoring the concentration of the biomarker molecules.

The discovery of a seven-day cycle of an immune system under stress is an important one. It is a biological cycle similar to the well-known 28-day human menstrual or the 24-hour cortisol cycle. Individuals might deviate marginally from the average—some women have slightly shorter or longer menstrual cycles but a population average emerges. On average, there is a one-in-14 chance that at any given time the effector side of the immune system of a cancer patient will be at or near its peak. And the same one-in-14 chance that the regulatory side and cells will be at or approaching their maximum number.

Here is the equation: Let us assume that the regulatory peak is somewhere within a 12-hour window. We don’t know—and don’t need to know—down to the hour or minute where the peak is. If it occurs each seven days (168 hours) and lasts for 12 hours, that’s 168 divided by 12, which gives 14. Thus any given 12-hour period has a one in 14 chance of being that patient’s peak. One in 14 is 7%. There is a 7% chance that chemotherapy administered on any random day will coincide with the patient’s peak regulatory side immune activity.

A sophisticated analysis of reported late-stage cancer treatment involving many types of cancer and many types of treatment has shown that the complete response rate is about 7%. That is, about 7% of patients are apparently rendered free of the disease. We don’t believe this is coincidence. It points to chemotherapy being remarkably effective if it is given at the right time. That right time is when treatment will cause major disruption to the regulatory side of a patient’s immune activity.

Chemotherapy is a blunt instrument. It is intended to kill rapidly dividing cells (the hallmark of an out-of-control cancer) but it is non-selective.

Its well-known toxic side-effects are the result of its indiscriminate destruction of rapidly dividing cells throughout the body, including the effector and regulatory cells that are dividing in large numbers as they approach their respective seven-day population peaks.

A disrupted regulatory system cannot perform its task of reining back the effector side of the system. The effectors are left free to get on with their work: attacking the cancer. This at-present inadvertent action can be harnessed to the patient’s advantage.

The cycle has been detected in patients in a range of cancers: melanoma, ovarian, colorectal, brain, bladder, multiple myeloma, breast, oesophageal, lung, prostate and mesothelioma. This indicates that the phenomenon is a universal one and that the immune system is involved regardless of cancer type. We expect that the implication of our forecasts can be as simple as moving a proposed treatment by a few days—from a Tuesday to a Thursday, for example—to coincide with a patient’s individual cycle.

Additional benefits include a dramatic reduction in the quantity of agents required and the frequency of treatment.

Our approach is not limited to more efficient application of chemotherapies. Indeed, modern approaches to cancer treatment focused on immune modulating agents benefit equally from our understanding of immune system dynamics. These and older agents such as interleukin 2 (IL2) have also been shown to be effective in about 7% of patients. Our view is that they too disturb the immune system but depend for their random success on application at a point when the immune system is coincidentally primed towards tumour responsiveness

biotempus-technology-21

Some clinical observations

A sophisticated analysis of reported late-stage cancer treatment involving many types of cancer and many types of treatment has shown that the complete response rate is about 7% . That is, about 7% of patients are apparently rendered free of the disease.

We don’t believe this is coincidence. It points to chemotherapy being remarkably effective if it is given at the right time. That right time is when treatment will cause major disruption to the regulatory side of a patient’s immune activity.

Chemotherapy is a blunt instrument. It is intended to kill rapidly dividing cells (the hallmark of an out-of-control cancer) but it is non-selective. Its well-known toxic side-effects are the result of its indiscriminate destruction of rapidly dividing cells throughout the body, including the regulatory cells that are dividing in large numbers as they approach their seven-day population peak.

A disrupted regulatory system cannot perform its task of reining back the effector side of the system. The effectors are left free to get on with their work: attacking the cancer. This at-present inadvertent action can be harnessed to the patient’s advantage.

Biotempus’s strength is our unique understanding of using the immune cycle to forecast greatly optimised treatment windows.

The cycle has been detected in patients in a range of cancers: melanoma, ovarian, colorectal, brain, bladder, multiple myeloma, breast, oesophageal, lung, prostate and mesothelioma. This indicates that the phenomenon is a universal one and that the immune system is involved regardless of cancer type. We expect that the implication of our forecasts can be as simple as moving a proposed treatment by a few days—from a Tuesday to a Thursday, for example—to coincide with a patient’s individual cycle.

Additional benefits include a dramatic reduction in the quantity of agents required and the frequency of treatment.

Our approach is not limited to more efficient application of chemotherapies. Indeed, modern approaches to cancer treatment focused on immune modulating agents benefit equally from our understanding of immune system dynamics. These and older agents such as interleukin 2 (IL2) have also been shown to be effective in about 7% of patients. Our view is that they too disturb the immune system but depend for their random success on application at a point when the immune system is coincidentally primed towards tumour responsiveness.

Why has this previously been overlooked?

First, as an historical accident. It has long been thought that in distinguishing between self and non-self the immune system does not recognize cancer as a foreign antigen. This is increasingly being shown to be untrue. The immune system does recognize and attack cancer but that effort is constrained by the regulatory mechanisms. Thus the system alternates between attack and retreat—the persistent rise and fall cycle we have described.

Second, because no one previously has taken daily measurements and accurately mapped the immune response over two to four weeks. Researchers typically take two or three data measurements in the first week of an experiment, one measurement in the second week and one in the third or final week. They then attempt to join the dots. But essentially the detail has been missed.

We did the detailed measurements. After animal laboratory testing was complete, the first human clinical trials began in Australia and at the Mayo Clinic in the United States in 2008.

The data obtained led to the grant of patents for using the cycle to guide therapy. These patents are central to Biotempus’s clinical, research and commercialization focus.

With the knowledge of the immune cycle, the confounding variable results from previous experimental data can be interpreted. Certain immune hormones (cytokines) and cellular receptors have a bimodal activity. Many cytokines/receptors are both pro-inflammatory and immune suppressive and so have paradoxically opposing roles. This has made it difficult to know how to use various immune modulating agents therapeutically to either stimulate or restrict the immune response. Appreciating that these cytokines work transiently in the time domain, and in an opposing way, has allowed Biotempus to explain the patient population response rate spectrum—to appreciate why some patients respond and others don’t. The Biotempus proprietary technology can be used to optimize timing of treatment and significantly improve patient outcomes.