Yes, we can repeat the cancer every day. In short, the human immune system is able to distinguish cancer cells from normal body cells and then deliberately destroy them. Degenerated cells even send suicidal emergency calls to the body's defenses, so that immune cells find and destroy them so that no adult tumor can develop. Nevertheless, the cancer cells sometimes succeed in disrupting emergency communication and delaying the immune system.
For years, the biologist James Allison at the MD Anderson Cancer Center in Houston, Texas, researched these blocks of the immune system called "checkpoints", as well as the Japanese Tasuku Honjo at the University of Kyoto. Both developed a completely new treatment concept for cancer that has saved many lives of many cancer patients for a number of years, previously considered incurable. Both researchers have already received prizes in abundance and also collectively. Now the most important honor a researcher can get is the Nobel Prize in physiology or medicine. "What Allison and Honjo discovered has revolutionized oncology," says Dirk Jäger, cancer immunologist at the German Cancer Research Center in Heidelberg. The price was "to be expected".
The first serious tests of the treatment concept started in 2001. Previously, the researchers had developed antibodies against the immune system inhibition, Allison against the "CTLA-4" brake pad, Honjo against "PD-1". Both are signaling molecules located in the envelope of T cells, important immune cells. They work approximately as a checkpoint, a checkpoint. Usually they transmit the distress signals from degenerated cells so that the body's defenses are activated. But some cancer cells can prevent this, so the emergency calls do not arrive and an attack on the cancer cells is missing.
First die, then mother
With their antibodies against the control points CTLA-4 and PD-1 Allison and Honjo are able to release these immune brakes and reactivate the cancer cessation. This was initially achieved in laboratory tests and then in the first patients. With spectacular results. As in the case of a 26-year-old with so-advanced black skin cancer, for example, that the lungs had already been affected by secondary tumors and hardly a doctor of the young woman wanted to predict more than a few months of survival. After only one injection of an antibody against the CTLA-4 brake – the now approved drug ipilimumab (Yervoy) – the cancer literally dissolved. "A few years later she showed me pictures of her first baby," reported Allison some time ago at the Tagesspiegel, when he was awarded the Paul Ehrlich and the Ludwig Darmstaedter Prize. It would not have come to this or the Nobel Prize, if after the individual case not many other treatment successes would have been: every fifth patient with advanced black skin cancer is permanently cured. The concept of prostate, bladder and kidney cancer is also successful.
Old idea of immune stimulation
For the first time in Europe, Charité doctors used checkpoint inhibitors, also known as these tools to unleash the immune system in jargon, in 2006, says Ulrich Keilholz, director of the Charité Comprehensive Cancer Center. Meanwhile about one third of the patients, about one thousand a year, receive treatment based on the research of Allison and Honjo.
Mobilizing the immune system against cancer is an idea that doctors and biologists have long had before Allison and Honjo. In 1866, the Bonn surgeon Wilhelm Busch had already noticed that the cancer had withdrawn from a patient after she had become infected with bacteria and had reactivated her body defenses. Later, the pioneer of immunology, Paul Ehrlich, speculated that cancer can often develop in the body, but only break out when the immune system can no longer fight these "nests". But attempts to translate that knowledge into therapies failed time and time again. "We have tried to stimulate the immune system again and again, but that has never worked," says Keilholz.
It was not until the end of the twentieth century that immunologists understood the fine regulation of the release and slowing down of the body's defenses. This also revealed how the immune system prevents excessive reactions that can also target the body's own structures in certain diseases. This is the case, for example, with multiple sclerosis. However, this overreaction is also one of the dreaded side effects of award-winning cancer therapy. Raising the brake on the T cells also means that the body loses some of its control over the immune response. "That was always a problem in the beginning," says Keilholz, but in the meantime you can counteract the exaggerated reactions. "That almost does not happen anymore."
Signals for the defense
In the meantime, the new therapies are mostly used in combination with conventional treatment methods, ie surgery, radiotherapy and chemotherapy, says Dirk Jäger of the DKFZ. In some tumors, such as the lungs, they are already used alone and as a replacement for chemotherapy.
However, the therapy does not work well for all patients – about one-third of patients with black-spot cancer treated with control-point inhibitors do not respond, Keilholz says. "We first need to understand why these patients do not respond to treatment," adds Jäger. One of the reasons seems to be that tumors often have their own "anti-immune system" in their immediate environment, with cells that suppress the immune response. Jaeger & # 39; s research group has developed a signaling drug therapy that attacks here, so that checkpoint inhibitors gain access to tumors in the first place. Large pharmaceutical companies such as BMS and MSD are currently working on medicines, says Jäger.
Understand the tumor to fight it
"The balance between immune response and tumor growth is extremely complex and immune cells are also very complex in the tumor," the researcher adds. Depending on the type of tumor and the patient, there can be very large differences: "In the future we will have to understand the patients, their immune system and their tumors individually very much, to treat them precisely because we have to know which mechanisms of the tumor each time. "This is the only way to find ways to help the immune system recognize and attack the tumor.
Combinations of new therapies can help more people in the future. For those who did not respond to Allisons antibody ipilimumab alone, one could also use another therapy, says Lars Bullinger, tumor immunologist at the Charité. Significantly, such an approach is the combination with antibodies against PD-1. So it is a therapy that brings the findings of Allison and Honjo together.
A big problem now, as always, is the money. The costs are "too high", says Ulrich Keilholz. "Initially the pharmaceutical companies had only expected about 5000 patients in Germany, so the price calculated according to a niche indication." But now there are safely 50,000 per year in Germany alone, which would be treated with ipilimumab and similar medicines. The production costs are too low, because the calculation could not be adjusted, says Keilholz: "It's time."