Australasian Science Magazine

Researchers hope to fool the immune system into thinking that cancer is part of an infection caused by external invaders. frentusha/iStockphoto

By Alexander D. McLellan

The efficiency of anti-cancer vaccines can be improved by exposing immune cells to harmless bacteria found in the throat.

The primary reason we evolved immune systems was to protect us from small creatures of the microbial world that wanted to feast on our flesh. Bacteria and fungi like to grow on our body surfaces, where they cause no harm, but some microbes like to invade deeper into our tissues, slurping up the nutrient-rich juices inside and between our body cells, while viruses hijack our cells and use them as factories to create more viruses.

These microbes cause sickness and death, ranging in severity from the common cold to the bubonic plague, but most of the time our immune system is waiting to hit back with antibodies to knock out the invaders, or with killer white blood cells to destroy infected host cells.

A surprising additional function of the immune system is its ability to destroy our own cells should they become cancerous. In a lifetime, our immune system can destroy potentially cancerous cells millions of times. The reason for this is that cancer cells can overproduce antigens that make them look different to other harmless cells. In this way cancerous cells may be detected and destroyed by the immune system as soon as they arise.

One of the best strategies is to vaccinate people against cancer before it arises so that the immune system is primed to attack a small mass of cells that could turn into tumours. Vaccination induces an adaptive (memory) immune response so that the immune system responds more vigorously the next time it encounters a particular antigen.

Vaccination against cancer is already possible. For example, the success of the human papillomavirus vaccine cancer has been a major breakthrough in cervical cancer prevention.

However, vaccines targeting other tumours are of limited benefit to the majority of patients with advanced disease, and are generally expensive or limited to clinical trials. In general, vaccination against large established tumours is much more difficult than preventing the cancer that arises from small cell masses.

Tricking the Immune System to Attack Cancer

The immune system is very effective in destroying invaders that cause inflammation. Inflammation acts as an alarm signal that alerts white blood cells and other molecules of the immune system to a potential problem. Immune cells then enter a state of heightened alertness and become much more effective at finding and destroying agents that would do us harm.

However, cancer cells do not usually provoke inflammation, so the immune system may ignore them. Furthermore, the destruction of cancer cells becomes more inefficient when tumours begin to grow into larger cell masses. Why is this?

The most obvious thing we know about the immune system is that it is reluctant to attack parts of our own body, including cancerous cells. Although large tumours can overproduce tumour antigens, they also tend to resemble large “self” organs that, unlike tiny pockets of isolated cancer cells, can engender “tolerance” by the immune system.

The great hope of cancer treatment is that we can break this immune tolerance through a process of “immunotherapy”. In essence, immunotherapy attempts to boost the immune response to attack the cancer.

My research involves tricking the immune system into reversing immune tolerance and entering attack mode long enough to destroy all cancerous cells. One way we do this is to fool the immune system into thinking that cancer is part of an infection caused by external invaders.

Something the immune system does very well is to become extremely hyperactive in response to agents that cause inflammation. Bacteria are an obvious choice of weapon to use against cancer since they evoke very strong inflammatory responses that would be useful if directed against cancer.

We recently found that certain types of bacteria greatly increased the efficiency of anti-cancer vaccines. The bacteria we studied were harmless commensals that normally live in most people’s throats. However, exposing immune cells to a cancer antigen in the presence of these bacteria greatly enhanced the anti-tumour response.

Prof Franca Ronchese of the Malaghan Institute in New Zealand has taken a different approach to trick the immune system into attacking tumours. She has discovered that injecting uric acid crystals, which cause gout, together with bacteria into the areas around skin or breast tumours recruits immune cells to destroy the cancer. The benefit of this approach is that cancer that has spread to other sites is also destroyed by the treatment of the primary tumour.

Recruiting Natural Killer Cells

We showed that a particular type of white blood cell called a natural killer (NK) cell was important for the bacterial stimulation of the anti-cancer response. NK cells are well-known for their ability to destroy infected cells, and they do this independently of the adaptive immune response. For this reason, they were long considered dispensable for vaccine efficacy. Essentially, the NK cell was thought to be more important for virus infections and dispensable for adaptive or memory responses induced by vaccination.

We and other groups have revisited the importance of NK cells in the anti-cancer response. NK cells are prodigious producers of a class of immune hormones called cytokines, and we showed that a cytokine called interferon-gamma is essential for the efficacy of bacteria-based immune responses.

Our new research suggests that NK cells are important for generating immune responses when tiny fragments of tumour cells are released into the body’s lymphatic system. NK cells seem to be able to amplify the response to these tumour fragments, turning on the immune system to fight the living tumour cells.

One of the greatest problems facing immunotherapy is keeping the immune system in anti-cancer attack mode long enough to rid the body of the cancer. Although many clinical studies can demonstrate that their vaccine has induced an anti-tumour response, these studies often report disappointing results for the long-term survival of cancer patients.

One compounding problem is the generalised weakening of the immune response during the latter stages of cancer progression and chemotherapy. This may predispose patients to infections, and also make their immune systems less capable of fighting the cancer. Even if anti-cancer responses are switched on in cancer patients, the natural tendency is for the immune system to switch off for a period of time.

The immune system has evolved to attack microbial invaders and then shut itself down as soon as the invaders have been destroyed. The reason for the shutdown is to avoid prolonged inflammatory responses, which lead to debilitating conditions including autoimmunity. However in anti-cancer immunotherapy the aim is to prolong the immune response against the cancer.

A major breakthrough in the past couple of years has been the validation of two new drugs that stop the immune system from shutting down during an anti-cancer immune response. Molecules called PD-1 and CTLA-4 normally pull on the brakes during an immune response against cancer. Newly available drugs block the natural action of these molecules and ensure that anti-cancer immune responses are prolonged.

History Revisited

While our laboratory and others around the world are discovering more effective ways to use bacteria to activate the immune system, the use of bacteria in the treatment of cancer is actually more than 120 years old. William Coley was a New York-based surgical oncologist specialising in sarcomas. Dismayed at the death of a patient due to sarcoma, he began researching cases where tumours had spontaneously regressed. He noted that a certain type of skin infection called erysipelas was often associated with tumour regression. Using “Coley’s toxins” – preparations of heat-killed bacteria similar to those that caused the infections – Coley was apparently able to induce high fevers and tumour regression in a number of cases.

However, the presentation of his results as a series of case studies cast uncertainty about the interpretation of his results. Great leaps forwards in the discovery and development of chemotherapy and radiation to treat cancer further sidelined research into Coley’s treatments, and the production of Coley’s toxins was discontinued in 1963.

Recent understanding of the way that bacteria activate the immune system have led Canadian company MBVax Bioscience to renew production of Coley’s toxins under the name Coley Fluid. However, due to drug-licensing problems, the preparations are not widely available internationally.

Despite these setbacks in the use of bacteria in immunotherapy, we are encouraged by the clinically acceptable practice of treating bladder cancer with bacteria. Since the 1970s, the BCG vaccine strain against tuberculosis has been the standard therapy for the treatment of bladder cancer. Patients are simply treated by introducing live bacteria into the bladder. The immune activation that follows from the bacteria in the bladder throws the local immune system into a state of “red alert”. In the process of recognising the bacteria, which are in fact rather harmless, the immune system seems to realise there is also a cancer present. The immune system then destroys the cancerous cells. The treatment is often effective and has a good success rate for superficial cancers.

Are we on the verge of finding a cure for cancer? The first problem is that cancer is a collection of very different diseases ranging from blood-derived leukaemias to solid tissue cancers such as sarcomas or melanomas. Because of this heterogeneity in cancers, there are many types of therapies designed to kill different types of cancer. Thus a “cure for cancer” is unlikely to involve all types of cancer.

Nevertheless, we assume that all cancer cells are capable of being destroyed by the immune system – it’s just a matter of finding their Achilles heel. Tumours differ in their presentation of tumour antigens, and for some tumours we have yet to identify specific antigens that we could use to turn the immune system against them.

On a positive note, we now know that the success of chemotherapy requires a contribution from the immune system. Chemotherapy was once thought to be a primarily toxic mechanism to destroy cancer cells. However, certain types of chemotherapy not only destroy tumour cells but also kill the cells in such a way that the dead cell fragments activate the immune system, resulting in an anti-tumour immune response.

Combining both chemotherapy and immunotherapeutic strategies will no doubt give us new ways to combat the very heterogeneous class of disease that we know as cancer.

Alexander McLellan is Associate Professor in Microbiology and Immunology at the University of Otago in Dunedin, New Zealand.