A new opportunity in the battle against cancer?

If you want to understand a solution, you should first understand the problem. Such is the case with cancer and the emerging new form of therapy which most likely places at the disposal of physicians a new and truly effective weapon against the disease.  But first, a mental experiment is called for here: There is a gang of thieves running amok in a small town. The police have found out just in time about the imminent threat, but have only been given vague information: All members of the gang are male and have brown hair. Because the situation is urgent, the security forces take into custody all brown-haired men within the town – and discover that they are nevertheless powerless to prevent the dreaded burglaries due to the fact that one of the perpetrators unfortunately might have dyed his hair at the last moment.  

Similar to the manner in which the mental-experiment police deal with the culprits, physicians today are combating cancer. For example chemotherapy, which is used in the treatment of tens of millions of patients worldwide every year, makes use of an imprecise selection process of elimination similar to hair colour in human beings. The chemotherapeutic agent attacks those cells in particular that divide frequently, thus eliminating the majority of the cancerous cells. But other cells within the organism divide frequently as well, among them the cells in the hair-roots, the intestinal tract and the immune system. “Chemotherapy is extremely non-specific, and the side-effects are respectively huge. And the successful cases remain within narrow limits,” says Rienk Offringa, director of the field “Molecular Oncology of Gastrointestinal Tumors” at the German Cancer Research Center in Heidelberg (DKFZ). The other two established therapy options against cancer – surgical removal of the tumour or local irradiation – are indeed concentrated on a specific region of the body but they also destroy healthy tissue, and all circulating and/or dispersed cancer cells within the body are left behind.

As do thousands of medical professionals, chemists and biologists throughout the world, Offringa is conducting research within a rather young field that gives promise of finally producing a targeted weapon against cancer – cancer immunotherapy. As the name implies, this therapeutic approach integrates the body’s own immune defence system or some of its mechanisms. The biggest advantage here is that the immunological processes, with which research scientists work, are highly selective. In this manner, tumour cells throughout the entire body could be specifically targeted for the first time.

Under the auspices of a special and highly promising subdivision of cancer immunotherapy, so-called T cells are currently in the spotlight. They are able to recognise exogenous (foreign) cells and either attack them or alarm other immune cells. A tumour consists however of endogenous (the body’s own) cells, which, although they have been altered through mutations, are not pronounced enough to be recognised by the T cells as foreign. In order to change this situation, research scientists have discovered two different methods.

On the one hand, an attempt can be made from the outside to incite the immune system, the T cells in particular, to attack the cancerous cells. For this purpose, certain antibodies, for example, can be administered. They block an inhibitory signalling pathway – also known as the “checkpoint” – within the immune system. In this manner they “release the brakes”, as it were: The immune cells are now uninhibited and take action against minimal deviations in the body’s own cells. This allows them to strike primarily at – the tumour itself. Not only are universities and research facilities conducting intensive research on this mechanism, but pharmaceutical companies as well are investing hundreds of millions of euros into these efforts. The obvious reason for this: They intend to earn money later on from their invested time and effort. This is because the antibodies that stimulate the immune system are the same for each person, which allows a targeted therapeutic drug to be mass-produced at low cost.

Rienk Offringa from the DKFZ is going one step further in his research. He is not attempting to block the inhibitory signalling pathways in the immune system; rather, he is promoting those signalling pathways that activate the immune system. These stimulating factors have thus far been researched even less thoroughly than the checkpoint inhibitors – but if it is possible to activate them, they are in the end clearly more effective. Offringa explains this using the example of a car: “When I take my foot off the brake, the car can go faster or at least roll away. But when I press on the gas-pedal – that’s even more effective: Then it jumps forward abruptly.”

The second way that T cells can be used in immunotherapy is considerably more specific: One takes blood from the patient and extracts a few T cells from it. In the laboratory, these cells are then outfitted, by means of genetic modification, with a so-called tumour-specific receptor and reproduced. Once they are placed back into the body, the small army of modified T cells is able to detect the tumour and destroy it. That, of course, sounds easier than it really is, because the biggest challenge for scientists lies currently in the search for suitable structures on the surface of the tumour cells – particular tumour characteristics, upon which they are able to align the T cells. Specifically, if they select structures that also appear on healthy cells, the T cells will attack healthy tissue as well – the advantages of the targeted therapy would then be gone.

For this reason, several working groups at the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Charité in Berlin are currently focussing on tumour characteristics that arise from mutations – i.e. random genetic alterations. This suggests itself since mutations are causal for the emergence of tumours and are consequently found only in cancer cells.

“At first glance, this would appear to be quite time-consuming and expensive, because each individual patient receives to some extent a tailor-made therapy,” says molecular biologist and gene therapist Wolfgang Uckert at Humboldt-Universität zu Berlin, who is currently conducting research at the MDC as visiting scientist. “The tumour genome has to be analysed, in order to find the mutations that represent a suitable target for the T cells.” But Uckert is convinced that this so-called mutation-specific therapy is implementable in everyday clinical practice: “The molecular-biological methods are becoming better and less expensive all the time. Just 15 years ago it cost millions of dollars and took years to decipher the first human genome. Then that became weeks and thousands of dollars. Today it involves days and just a few hundred dollars.”

Together with, among others, Matthias Leisegang from the Charité who also works at the MDC, Uckert has already successfully aligned T cells, removed from mice, against mutations that can also be found in some skin-cancer patients. The therapy with these T cells worked highly efficiently against tumours – without side effects.

Essential for these successful trials was the development of an animal model. This means that research scientists have bred mice with a certain genetic feature. The treatment of a tumour disease in these animals makes it possible to find precisely those particular tumour characteristics that represent an effective target for T cells in the patient as well. This is because: “Not all reprogrammed T cells are effective against the tumour. It is important to outfit the T cells with the proper tumour-specific receptor, so that they are effective. Which ones that would most likely be – that can be determined by our animal model,” says Matthias Leisegang. Therefore, the animal model is highly significant for this research:  It shows research scientists, and possibly doctors later on as well, which therapeutic approach is leading them in the right direction.