14 July 2017
In this article, we profile two projects where Garvan’s cancer and immunology teams are working together on what might be the beginning of a paradigm shift in drug development that could truly transform healthcare.
Garvan researchers are collaborating to recruit the body’s own defence mechanism, the immune system, to improve outcomes for cancer patients. Focusing on the area of ‘cancer immunotherapy’, the teams aim to identify and develop new and more effective cancer therapies, prevention strategies, and perhaps even discover biomarkers that will pave the way for new diagnostic tests.
Professor Stuart Tangye, head of the Garvan Institute’s Immunology Division says that by understanding the immune system, and how it influences cancer development and progression, a relatively new approach to the treatment of cancer is evolving.
“We all owe our survival to our immune system. It protects us from a constant barrage of attacks, whether they come from outside the body, like bacteria, viruses and fungi, or from inside in the form of cancer. One of the many questions we are investigating is, how do cancers and infectious diseases evade the immune system’s sophisticated protective mechanisms?”
Harnessing the power of the immune system
While the concept of cancer immunotherapy is not new, the growing field is proving it to be a very powerful approach. Current research is focused on examining interactions between the immune system and a cancer as it begins and progresses, and if it recurs. Progress is also being made in understanding how the immune system might be involved in preventing cancer in the first place.
“Most traditional cancer drugs target the tumour. This exciting new approach to cancer treatment involves creating drugs that target cells of the immune system, not the cancer. Basically, we are taking the immune system – something that exists naturally in the body – and strengthening it to protect against, or attack a specific tumour type,” explains Professor Tangye.
Antibodies play a vital role in cancer immunotherapy. Antibodies are remarkable proteins in being able to recognise and bind to specific proteins called antigens (foreign intruders that do not belong within the body). Once attached, antibodies call on other parts of the immune system to destroy the cells containing the antigen. Researchers can design antibodies in the lab, known as monoclonal antibodies, which target very specific antigens like those found in cancer cells.
The problem with cancer is that it is only partially foreign because it develops from our own tissues. An immune response is limited to the mutations in cancer cells that result in altered proteins, and it is these altered proteins that the immune system identifies as foreign.
The more mutations a cancer has, the more likely it is to produce changes that can be ‘seen’ by the immune system. This is why cancer immunotherapy has proven successful in some forms of melanoma. People diagnosed with melanoma have usually had a lifetime of exposure to UV light, meaning there has been plenty of time for many mutations to develop. Similarly, smoking-related lung cancer has seen promising results from immunotherapy because a lifetime of exposure to cigarettes produces a lot of mutations and, therefore, a lot of changes that can be ‘seen’ by the immune system.
Garvan’s cancer immunotherapy work has been supported by research grants from Cancer Council NSW for a number of years, and this support was recently renewed when Professor Tangye received the Susan and John Freeman Cancer Research Grant. This grant allows Professor Tangye to study patients with primary immunodeficiencies, hoping to understand how errors in specific genes can cripple their immune system, and increase their susceptibility to developing cancer.
This research aims to guide strategies to enhance anti-viral and anti-cancer immunity. Professor Tangye says, “I hope that this research will not only help people with immune deficiencies, but also those with an increased risk of developing cancer. My ultimate goal for this research is that it will help in the development of vaccines that can protect people with immune deficiencies from getting cancer.”
Another cancer immunotherapy project at Garvan is being led by Professor Jonathan Sprent, and aims to find ways to improve results of a treatment approach known as Dendritic Cell Therapy.
Dendritic cells function by absorbing antigens from cancer cells and presenting small pieces of antigen in stimulatory form to the immune system. In this way, dendritic cells make cancer antigens visible to the immune system. However, cancer cells can make dendritic cells defective, compromising the immune system’s ability to ‘see’ that there is something invading the body.
Dendritic Cell Therapy is essentially a way of boosting the power of dendritic cells. It involves growing dendritic cells in tissue culture, then adding cancer antigens to these cells. These antigen-bearing cells are then injected into a patient. Trials of Dendritic Cell Therapy have been underway for 20 or 30 years, and while some patients do well, the majority see little benefit.
Professor Sprent says, “There are a number of possibilities as to why success with Dendritic Cell Therapy has been limited. One possibility is that, when you grow dendritic cells and add cancer antigens, you have to do it in tissue culture in the lab. This may create problems because when removed from the tissue culture and injected into the body, the cells may die or become trapped in tissues like the lungs. They never make it to the lymphoid tissues and, as a result, the cellular immune response is never activated.”
The technique that Professor Sprent and his team are using involves preparing and growing large quantities of dendritic cells in tissue culture. He explains, “Then we prepare tiny pieces, called nanoparticles, from the surface of these dendritic cells and load them with small bits of cancer antigen. We can also add other things to the surface of the nanoparticles in order to make the immune response to the cancer antigens more powerful.
“Next, we inject the nanoparticles carrying the cancer antigens into a mouse. This approach stimulates a good immune response and leads to effective rejection of tumours.
“I think this approach is promising because, being so small, the nanoparticles we create can move throughout the body easily, whereas whole dendritic cells cannot. So, the nanoparticles are ideal for reaching the lymphoid tissues and inducing a good immune response to the tumour.”
The road ahead
Immunotherapy has galvanised interest around the world, primarily in the treatment of cancer, and there are so many possibilities to explore.
Professor Sprent says one major challenge is how to make immunotherapy effective in the treatment of other cancers.
“While immunotherapy is proving useful in the treatment of diseases like melanoma and smoking-related lung cancer, where the mutations develop over time, other cancers with less mutations do not respond. For example, cancer of the colon tends to have less mutations, so the immune system can’t ‘see’ the cancer as easily.
“So, the big challenge is, how can we stimulate the immune system to attack tumours like colon cancer? I think this will preoccupy us for some time to come.”