Immunotherapy – A revolution in cancer treatment.
Interview: Matthias Geering
Professor of Oncology Alfred Zippelius conducts research at the University Hospital of Basel in the field of immunotherapy as a means of treating cancer. As deputy director of medical oncology, Professor Zippelius applies this new therapy in treating patients. He is convinced that we are about to experience a revolution in dealing with certain types of cancer.
For many years, the question of whether the immune system had any effect on the development of cancer was a subject of intense debate. Only at the end of the 90s was it possible to prove, on the basis of numerous experiments, that the human body is able actively to fight off cancer cells. It was also discovered then, however, that tumors are able to block the body’s defensive cells – the so-called T-cells or killer cells. After long and intensive research, scientists established how tumors are able to block the human immune system and override it. In response to this blocking ability, scientists developed an effective treatment: With immunotherapy, the body’s own “killer cells” are reactivated using artificially manufactured protein structures, so-called “monoclonal antibodies”. This ensures that a tumor can once again be recognized by the immune system. The body’s own killer cells can then attack the cancer cells and destroy them, or halt their growth. Research in this field is booming. At the University Hospital of Basel, too, several clinical trials are currently being conducted to examine the effectiveness of combinations of immunotherapy, radiation, and chemotherapy.
UNI NOVA: Alfred Zippelius, in 2013 the research journal “Science” declared immunotherapy the scientific discovery of the year. As a researcher and as a practicing oncologist using this therapy at the University Hospital of Basel, you are at the very forefront in this field. What is happening at the moment in your area of research?
ALFRED ZIPPELIUS: There are countless new developments. Not only are new immune-therapeutic approaches being developed, we are also working on combining immunotherapy with already existing forms of therapy. We are seeing that such combinations massively improve patient response rates. The task for research is to examine these combinations mechanistically, since conventional therapies such as chemotherapy can also compromise the body’s immune defenses. This is, it must be said, an extremely competitive field. Almost all of the larger pharmaceutical companies are working on active substances whose efficacy can be proven in trials and which will very soon be approved for use.
UNI NOVA: Is this dynamism coming exclusively from the market place?
ZIPPELIUS: Not at all. There is also a sense of revolution in medical oncology. We have discovered an important approach to reactivating the immune response. This presents us with great challenges in research. The patients learn of these new therapeutic possibilities and hope that they too will respond well to the new drugs.
UNI NOVA: In Switzerland, only one drug has so far been approved. In co-operation with the pharmaceutical industry, you are using active substances that are about to be approved. What exactly do you do?
ZIPPELIUS: With regard to some tumors, we have already made great progress. In the future, we want to use the drugs more widely for a range of tumors and to improve the effectiveness of the drugs. In addition, we test these substances both in early clinical trials and also in larger studies against established standards in oncology, such as chemotherapy.
UNI NOVA: Conventional wisdom has been that the more quickly the cancer is discovered the better. How important is early diagnosis?
ZIPPELIUS: The assumption used to be that tumors should be as small as possible to respond to a therapy. That was probably not far wrong since earlier treatments worked like a vaccination, through which killer cells are activated. Immunotherapy as it is used today, however, is based on antibodies that essentially “release the brakes” on the killer cells and so make it possible for these killer cells to work again. Even with larger tumors there is a good chance of success: If we can manage to release these brakes, then the body’s own defense system can get to work again. If the killer cells are reacti vated, then the size of the tumor is really not very important.
UNI NOVA: So in the case of larger tumors, too, you can stop their growth?
ZIPPELIUS: For a certain percentage of patients not only do we stop the growth, we even reduce the size of the tumor. In ideal circumstances the tumor disappears completely. Sadly, this is not the case for all patients! The response rate for lung cancer is currently around 20 percent, for malignant melanoma it is between 30 and 40 percent. When we combine the antibodies, the response rate is even better.
UNI NOVA: But then the number of side effects would also increase!
ZIPPELIUS: That’s true. Here the issue is inflammatory, autoimmune side effects. Every human being has defensive cells and these can also attack their own body. If we are healthy, then we can control these well. In the course of immunotherapy, activation of the defensive cells may occur, and the defensive cells may then also attack healthy organs.
UNI NOVA: You conduct translational research, from “bench to bedside” – as this kind of research has been described.
ZIPPELIUS: Yes, indeed. But in our case it goes in both directions; that is, from the hospital bed back to the laboratory bench. This is precisely our strength: The proximity of the lab to the hospital, the proximity, that is, of the medical oncology department to the tumor center at the University Hospital of Basel. We can therefore develop the therapies very quickly and efficiently.
UNI NOVA: Is this a field in which it is almost impossible for the pharmaceutical in dustry to conduct research alone because the research is so dependent on the patients?
ZIPPELIUS: The pharmaceutical industry does, of course, need close contact to hospitals and to research because these drugs have to be tested on the patients. And for us, this contact provides us with the opportunity to work with highly interesting active substances, allowing us to conduct innovative research. In addition to all this, conducting clinical trials has become so complex that without the support of industry such trials would no longer be possible in most cases.
UNI NOVA: You work very closely with the pharmaceutical industry and the companies ultimately wish to be successful on the market with their products. Who profits if, thanks to your research, there is a major breakthrough? How is the issue of intellectual property regulated?
ZIPPELIUS: A number of patents have been established within the framework of our immunotherapy research with the industry. In these cases, clear guidelines are determined in co-operation with the university’s technology transfer department “Unitectra”. The deciding factor here, however, is that we are not developing any new active substances. We are more interested in researching new effect mechanisms in an academic setting. On the basis of this research, we then suggest certain combinations with existing forms of therapy such as radiation or chemotherapy. We are not involved in product development – we want to understand the immunology in terms of which tumors respond to an active substance and which patients we can treat with it.
UNI NOVA: The costs of immunotherapy are very high. What makes this therapy so expensive?
ZIPPELIUS: There is always an enormous amount of research behind such drugs. Money is invested in a large number of potentially useful substances that never actually reach the market. Those drugs that do become approved are the tip of the iceberg. The price of a drug is, however, also a function of the added value that it creates. If you have a drug that extends life only briefly, then it is has relatively little value and the price is therefore lower. If, however, you have a substance with a high response rate even for patients for whom conventional drugs are no longer effective, then the value of this substance is accordingly higher. This is especially true if the new therapy makes it possible to make the tumor disappear permanently.
UNI NOVA: If this therapy is so expensive, then this form of treatment will surely benefit only a small group of people!
ZIPPELIUS: Actually, no. Immunotherapy is in fact already in widespread use. Currently, the treatment is organized so that the therapy is made available to the patient on a permanent basis rather than for only a few months.
UNI NOVA: Why can treatment not be discontinued once the tumor has vanished?
ZIPPELIUS: This is currently under research. We do not yet know the answer. We’ll have to find it through conducting trials. Early studies, however, indicate that the reoccurrence of the tumor is relatively stable. That is to say that among the few patients in whose cases the medication was discontinued during trials, the remission persists. This gives us reason for optimism.
UNI NOVA: Who currently decides who will receive this therapy and who not? Is it the doctor? The patients?
ZIPPELIUS: Treatment is offered in keeping with international guidelines, which are decisive for our medical procedures. In addition to this, medical trials have clearly defined criteria for inclusion and exclusion, and these prescribe which patients we may treat.
UNI NOVA: Costs are already high because you use the drugs widely and also continue to treat patients who have already been healed.
ZIPPELIUS: In many tumor cases, the pharmaceutical industry currently makes the drugs available to us free of cost for research purposes. These active substances are still waiting to be approved for the market. Once these drugs have been approved, however, we shall no longer receive them free of charge. Then we will have to pay for them. In the case of lung cancer, we expect this to happen very soon.
UNI NOVA: Then the health system can expect high costs – and subsequently difficult decisions: Who will then decide who is to receive these new, expensive drugs and who not?
ZIPPELIUS: Ultimately, we as a society must decide how much we are prepared to pay for this medication. Oncologists, naturally, wish to do as much as possible for their patients. The task for research is, however, to optimize the therapy. If we can determine right at the start of treatment which patients will respond to therapy, then we can target this treatment more accurately and thus save money.
UNI NOVA: Where is research currently heading – where do you hope to make the next breakthrough?
ZIPPELIUS: Immunotherapy has huge potential. We want to understand exactly what these drugs do in the body so that we can target their use precisely. It is also crucial to define the combination of radiation, chemotherapy, and immunotherapy not only on the basis of empirical data but also on the basis of factors that can be calculated exactly. If we can do that, then we can further substantially increase response rates.
UNI NOVA: Dare to make a prognosis – where will we be in five years?
ZIPPELIUS: I think we shall see gigantic steps forward in fighting many kinds of tumors. In the case of malignant melanoma, survival times have already increased greatly. This will also be the case for other tumors. There will, of course, also be some disappointments in relation to some tumor types. This is because there are complex constellations in which it is not that easy to reactivate the immune system using this therapy. Here, we’ll have to combine immunotherapy with other therapies in order finally to achieve success.
As deputy director of medical oncology at the University Hospital of Basel, Professor Alfred Zippelius’ research focuses on tumors of the lungs, skin, head and neck. He also heads the Laboratory for Cancer Immunology.