What is missing from current cancer treatments

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Interview: Matthias Geering

Oncology professor Alfred Zippelius conducts research at the University Hospital Basel in the field of cancer immunotherapy. He treats patients with this new therapy and is convinced that we will see a revolution in the treatment of certain types of cancer.

For a long time it was controversial whether the immune system has an influence on the development of cancer. Only in the late 1990s was it possible to demonstrate in numerous experiments that the human body can actively fight off cancer cells. At that time, however, it was also discovered that tumors can block these defense cells - so-called T cells or killer cells.

After long, intensive research, scientists have found out how tumors can block and disable the human immune system. In response, they have developed an effective treatment: In immunotherapy, the body's own "killer cells" are reactivated using artificially produced protein structures, so-called monoclonal antibodies. In this way, the tumor is recognized by the immune system again, and the body's own killer cells attack the cancer cell, destroy it or stop it from growing.

Research is in full swing, and several clinical studies are currently underway at Basel University Hospital, in which the effectiveness of combinations of immunotherapy, radiation and chemotherapy is being investigated.

UNI NOVA: Alfred Zippelius, the research magazine “Science” selected immunotherapy as the scientific discovery of the year in 2013. As a researching and treating oncologist who uses this therapy at the University Hospital Basel, you are at the forefront. What is currently happening in your research area?

ALFRED ZIPPELIUS: There are countless new developments. Not only are new immunotherapeutic approaches being developed, but we are also working on combining immunotherapy with existing treatment concepts. It has been shown that this combination of therapies can massively increase the response rate in patients. The task of research is to investigate these combinations mechanistically, since conventional therapies such as chemotherapy can also impair the immune system. We experience an extremely competitive environment. Almost all large pharmaceutical companies are working on active ingredients that have proven themselves in studies and will be approved very soon.

UNI NOVA: Does the dynamic come exclusively from the market?

ZIPPELIUS: No, there is also a spirit of optimism in medical oncology. We discovered an important approach to reactivating the immune response. This presents us with major research tasks. This is how the patients learn about these therapeutic options and hope that they too will respond to the new drugs.

UNI NOVA: Only one drug has been approved in Switzerland. In cooperation with the pharmaceutical industry, you use active ingredients that are about to be approved. What exactly are you doing there?

ZIPPELIUS: We have already made great strides for some tumors. In the future, we want to use the drugs more widely on various tumors on the one hand, and improve their effectiveness on the other. To this end, we test these substances both in early clinical studies and in large studies against established standards in oncology such as chemotherapy.

UNI NOVA: Up until now it was always said: the sooner the cancer is discovered, the better. How important is early diagnosis?

ZIPPELIUS: It used to be assumed that tumors had to be as small as possible in order for them to respond to therapy. Perhaps that wasn't all that wrong because previous treatments worked like a vaccination that activated killer cells. The immunotherapy as we use it today, however, relies on antibodies that, so to speak, release the brakes on the killer cells and thus enable these killer cells to work again. Even with a large tumor, you can be quite successful: If we manage to release this brake, the body's own defense system can work again. And when these killer cells are reactivated, the size is rather unimportant.

UNI NOVA: So you can also stop the growth of large tumors?

ZIPPELIUS: In a certain percentage of patients, we not only stop tumor growth, we even push the tumor back. Ideally, it disappears completely. But unfortunately not with all patients! We currently have a response rate of around 20 percent for lung cancer and 30 to 40 percent for black skin cancer. And when we combine the antibodies, we're even better.

UNI NOVA: But then the rate of side effects also increases!

ZIPPELIUS: That is correct, these are inflammatory autoimmune side effects. Everyone has immune cells that can attack their own body. When we are healthy, we can control them well. As part of this therapy, immune cells can be activated, which can also attack healthy organs.

UNI NOVA: You do translational research, “from bench to bedside” - from the laboratory to the bedside - as this form of science is paraphrased.

ZIPPELIUS: Yes, but with us it goes in both directions, including from the hospital bed back to the laboratory. This is exactly our strength: It is the proximity of the laboratory to the clinic, i.e. medical oncology, to the tumor center at the University Hospital Basel. This enables us to further develop the therapies very quickly and efficiently.

UNI NOVA: Is this an area in which the pharmaceutical industry can hardly do research on its own because it depends on the patient?

ZIPPELIUS: Of course, the pharmaceutical industry needs close contact with hospitals and research, because these drugs have to be studied on patients. Conversely, this contact allows us to work with highly interesting active ingredients and thus carry out innovative research. In addition, conducting clinical studies has become so complex that in most cases we can no longer do it without industrial support.

UNI NOVA: You work very closely with the pharmaceutical industry, which ultimately wants to be successful in the market with its products. Who benefits if your research makes a big breakthrough? How is the subject of “intellectual property” regulated?

ZIPPELIUS: As part of our immunotherapy research with industry, a number of patents have been created. The university technology transfer office “Unitectra” has defined clear framework conditions for these cases. What is crucial, however, is that we do not develop any new active ingredients here. Rather, we are concerned with researching new mechanisms of action in an academic environment. Based on this, we then suggest certain combinations with existing forms of therapy such as radiation or chemotherapy. We do not develop any products - we want to understand immunology: which tumors respond to an active ingredient and which patients can we treat with them.

UNI NOVA: The costs for immunotherapy are very high. What makes this therapy so expensive?

ZIPPELIUS: There is always an enormous amount of research behind such drugs. Investments are made in many potential active ingredients without being ready for the market. Those drugs that get approved are the tip of the iceberg. The price of a drug is of course also based on the added value it generates. If you have a drug that only lasts for a short time, its value is low and the price is low. But if you have a substance that has a high response rate even in patients on whom the conventional drugs were no longer effective, then the value of these new substances is of course correspondingly higher. This is especially true if this new therapy can permanently make the tumor disappear.

UNI NOVA: If this therapy is so expensive, then this form of treatment will only benefit a small group of people!

ZIPPELIUS: No, immunotherapy is already being used very widely. Treatment is currently designed in such a way that patients will not only take the therapy for a few months, but rather permanently.

UNI NOVA: Why can't immunotherapy be discontinued when the tumor has disappeared?

ZIPPELIUS: This is the subject of current research. We do not yet know the answer and must be investigated in studies. In the first studies, however, one can see that the tumor suppression is relatively stable, i.e. in the few patients in whom the drugs were discontinued during studies, the remission persists. This is hopeful.

UNI NOVA: Who decides today who receives this therapy and who doesn't? Is it the doctor? The patient?

ZIPPELIUS: The treatment is carried out in accordance with international guidelines that are decisive for our medical practice. In addition, clinical studies have clear inclusion and exclusion criteria that dictate which patients we can treat.

UNI NOVA: Are there already high costs because you use these drugs on a broad basis and cured patients continue to be treated?

ZIPPELIUS: For many tumors, the drugs for study purposes are currently still being made available to us by the pharmaceutical industry. These active ingredients are still awaiting approval for the market. As soon as these drugs are approved, however, we will no longer receive them free of charge; they will then be billed. We expect this for lung cancer in the very near future.

UNI NOVA: Then there will be huge costs for the healthcare system - and with them difficult decisions: Who will then decide who will be given these new, expensive drugs and who will not?

ZIPPELIUS: Ultimately, we as a society have to decide how much we are willing to pay for these drugs. Of course, the oncologist wants the maximum for his patients. However, it is the task of research to optimize therapy. If we could determine at the very beginning of the treatment which patients respond to a therapy, then we could use this treatment in a much more targeted and thus more cost-saving manner.

UNI NOVA: In which direction are you currently researching - where do you hope for the next breakthrough?

ZIPPELIUS: Immunotherapy has great potential. We want to understand what exactly these new drugs do in the body so that we can then use them in a targeted manner. It is also crucial that we define the combination of radiation, chemotherapy and immunotherapy not only on the basis of empirical data, but also on the basis of precisely calculable factors. If we can do that, then we can significantly increase the response rates again.

UNI NOVA: Dare to predict - where will we be in five years?

ZIPPELIUS: I believe that we will see huge advances in combating many types of tumors. Survival times for black skin cancer have already increased significantly, and other tumors are following suit. Of course, we will also experience disappointments with some types of tumor. Because there are complex constellations in which the immune system cannot be activated so easily with this therapy. Here we have to combine immunotherapy with other therapies in order to ultimately be successful.

As Deputy Head of Oncology at the University Hospital Basel, Professor Alfred Zippelius' research focuses on lung tumors, skin tumors and head and neck tumors. He also heads the tumor immunology laboratory.

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