Why is the same immunotherapy ineffective one moment and works well and indefinitely in the same patient half a year later? And how can we make immunotherapy work for more cancer types? These are questions Karijn Suijkerbuijk focuses on as professor of immunotherapy of solid tumours. Her appeal: put the immune system at the centre, not the cancer.
On Friday 19 April, Karijn held her inaugural speech as professor of Immunotherapy of solid tumours. She took her audience into the wonderful world of immunotherapy. ‘I have become fascinated by this world, in which we can cure patients who used to have a poor prognosis from metastatic cancer,’ Karijn says. ‘But it is also a world in which we have to learn to look from a different perspective: not that of the cancer, but that of the immune system.’
In immunotherapy, cancer is fought by strengthening our immune system. Every day, millions of cells in our body are dividing. In this process, mistakes commonly occur, accidental or due to external factors, such as UV radiation or smoking. As a result, cells can start dividing in an uncontrolled manner and cancer can develop. Fortunately, our army of immune cells is smart and strong enough to clean up many of these wildly dividing cells. But cancer cells are also nimble because they can block these immune cells.
For a long time, we had no solution for this. Until the advent of immunotherapy, so-called ‘checkpoint inhibitors’. Karijn: ‘You can actually imagine this immunotherapy as a kind of helmet, which protects the immune cell and ensures that it can no longer be blocked by cancer cells. With that helmet, the immune cells can do their job again and clear the cancer cells.’ This has been a huge breakthrough in the fight against cancer.
About 10 years ago, melanoma (an aggressive form of skin cancer) was the first cancer type in which immunotherapy showed promise. This was much needed at the time because no effective treatment existed for metastatic melanoma, causing most patients to die within a year. ‘At that time, I was just starting my training as an oncologist and became fascinated by this treatment, the effects of which persisted for years after treatment was stopped.’
Currently, there are different forms of immunotherapy, that are used in different tumour types. But we have also found out that the immune responses to treatment very widely between patients. Some people have few side effects, while others have severe side effects that require them to stop immunotherapy. For some, immunotherapy kicks in immediately, while for others it doesn’t. And, to complicate matters further, in the same patient, immunotherapy can cause very heavy side effects one time, while being tolerated perfectly fine by the same patient one year later.
These side effects of immunotherapy, such as intestinal or liver inflammation, can often cause patients to have to stop immunotherapy early. Karijn: ‘I explain this to patients as follows: when we give immunotherapy, we stimulate the immune system to work harder. As a reaction the immune system can go in overdrive, causing too strong immune reactions in the body resulting in side effects. We then must put a brake on the immune system with immunosuppressive drugs to calm it down a bit again.’
For a long time, it was thought that a high dose of those immunosuppressive drugs would do no harm to the efficacy of immunotherapy. Karijn and her team have found out that this widespread assumption is wrong. ‘We were the first to convincingly show that patients who received high doses of immunosuppressive drugs or multiple types at the same time lived up to 2 two times shorter on average,’ Karijn explains. ‘I am proud that our work in this field is acknowledged internationally and am convinced that our studies are going to lead to changes in international guidelines and better treatment of side effects.’
Coming of age in the world of immunotherapy also includes better support for patients who live longer and even are cured as a result. Now that we know that people live for 20, 30 or maybe even 50 years after being treated with immunotherapy, we need to start taking more account of long-term effects. For example, what are actually the long-term effects of immunotherapy on fertility and on the cardiovascular system?
Much of the research Karijn is involved in focuses on predicting in which patients’ immunotherapy will work. ‘Of patients with metastatic melanoma, for example, almost half benefit long-term from immunotherapy. That also means that the other patients do not obtain benefit from the treatment, while they still do experience the side effects,’ Karijn says. ‘If we could predict their response, we could spare them the nasty side effects and offer another treatment right away.’
In the PREMIUM project, for example, Karijn and her colleagues are investigating whether they can predict even before treatment starts which patients with metastatic melanoma will or will not respond to immunotherapy. The analysis is using AI to analyze clinical data of 2,000 patients, their CT scans and microscope images.
One remarkable finding in PREMIUM: people with a low muscle mass and high levels of abdominal fat are less likely to respond well to immunotherapy. Furthermore, the PREMIUM project also showed that the amount of immune cells in and around the tumour can predict the effect of immunotherapy: the more immune cells are in the tumour, the higher the success rate. ‘Again, therefore, the key lies not with the cancer cell, but with the immune cell.’
It appears that lifestyle factors can also influence the success rate of immunotherapy, according to a growing body of research. Factors such as stress, diet and exercise can also affect our immune system. ‘Every day, patients ask me what they can do themselves, and this research helps to give them advice,’ Karijn explains. For example, patients who exercise intensively at the start of immunotherapy were found to have fewer side effects and live longer.
‘Only by doing well-designed research we can learn more and more about the complex rules in the chess game between the immune system and cancer. This is about what a patient can do to maximize the chance of effect, but also what we as doctors can do or, on the contrary, should leave out to give immunotherapy the chance to work for a long time,’ Karijn concludes. ‘Also, there are still many cancers for which immunotherapy often does not work yet, such as breast, colon and prostate cancer. By combining immunotherapy with other treatments, we hope to change that in the future.’
