“The news caught me totally unprepared, without the slightest symptoms, to a certain extent by chance and out of the blue,” is how top politician, Guido Westerwelle, described his diagnosis of acute myeloid leukemia (AML). Westerwelle spoke openly about his illness, publishing a book and giving a number of interviews. In 2016 he lost the fight against the insidious blood cancer.

As a matter of fact, the initial symptoms can seem unremarkable: tiredness, pale skin, a loss of appetite and dizziness. Despite the availability of cutting-edge treatments, this form of blood cancer can still be fatal. The Spanish tenor, José Carreras was fortunate enough to overcome this cancer back in 1988. Since then, the singer and his eponymous foundation have become involved in research into and treatments for the disease, which happily is diagnosed relatively rarely.

In the past, his foundation has also supported research by Professor Dr. med. Dimitrios Mougiakakos at the Clinic for Hematology and Oncology at Otto von Guericke University Magdeburg. For over 15 years, this specialist in internal medicine, hematology and oncology has worked to address the basic immunological mechanisms of cancerous diseases, and especially malignant diseases of the lymphatic system such as lymph node cancer and chronic lymphocitic leukemia. The oncologist is pursuing some promising approaches. He is developing a targeted treatment that ideally only takes effect on tumor cells and thus in the best case scenario should make onerous chemotherapy superfluous.

What we are talking about are known as immunotherapies, in which scientists worldwide are placing a great deal of hope in the fight against cancer. The idea behind the treatment is to program the bodily defenses of cancer patients in such a way that they recognize and combat cancer cells. But something that sounds so simple has in reality been occupying scientists worldwide for decades. This is because cancer cells have an insidious characteristic. They can hide from the immune system like the proverbial ‘wolf in sheep’s clothing’. “Tumors and cancer cells can manipulate their immediate environment to their advantage,” explains Mougiakakos.

Prospect of new cancer therapy

He mentions another challenge faced by researchers: “When it comes to the interaction between the immune system and the tumor cells, it is not a fixed system, but instead dynamic.” This means that there is always the risk that resistance could develop to immunological treatment principles. Understanding the underlying mechanisms is, according to the specialist, the basis for a new generation of promising immunotherapies against cancer and beyond. He has already succeeded in making an initial breakthrough in this connection.

Professor Mougiakakos was one of the first experts in Germany to use CAR-T-cell therapy in a clinical setting. The world’s first successful CAR-T-cell treatment of a patient with a severe form of the autoimmune disease, systemic lupus erythematosus, drew international attention. Mougiakakos, who worked on this case with researchers from the German Center for Immunotherapy at University Hospital Erlangen, recalls: “We were surprised how quickly her condition improved immediately after the infusion. After all, this innovative treatment method is currently only used with certain blood and lymph node cancers.” More patients with autoimmune diseases followed, all of whom have responded to the novel treatment.

One focus of the research is cell metabolism, its changes due to external influences and its functional effects, which are measured here in real time using flux analysis. (Photo: Jana Dünnhaupt / University of Magdeburg)

This therapy is the latest milestone in cancer treatment. Since February 2023, the method has also been used at Magdeburg University Hospital - with patients affected by certain blood or lymph node cancers or with those where conventional chemotherapy-based treatments have failed. Mougiakakos goes on to explain: “We use the patient’s own immune cells. To do so we isolate the T-lymphocytes of the patient, genetically manipulate them so that they are better able to recognize the tumor and return them to the patient, so to speak as a living drug in the form of an infusion.” Although it sounds simple, the treatment is based on highly complex immune defense processes.

According to Mougiakakos, the T-cells are among the “body’s policemen” as they discover and combat thousands of bacteria, viruses and other pathogens daily. Cancer cells are able to hide from these immune cells. “To ensure that the T-cells are able to recognize the cancer cells again despite their ‘camouflage’, in CAR-T-cell therapy, the T-cells are genetically modified so that they carry what is known as the chimeric antigen receptor (CAR) from which they take their name on their surface. This acts like a sensor - a mixture of antibody and T-cell receptor. With this sensor, the cancer cells can now be recognized and efficiently destroyed.”

These ‘optimized’ T-cells, which the patient receives back in the form of an infusion, multiply rapidly and can remain active for many years, thus preventing a relapse of the disease. For this reason, Mougiakakos is optimistic about the future: “For patients with certain forms of blood or lymph node cancer, who do not respond to conventional chemotherapy treatment and/or have suffered several relapses, these chemotherapy-free, targeted immunotherapies have thus far shown highly promising results.” However, with up to five weeks manufacturing time and costs in the order of 300,000 euros, the treatment is extremely time consuming and cost-intensive.

To develop new approaches, Mougiakakos relies first and foremost on interdisciplinary cooperation. With his team of nutritionists, biochemists, biologists and medical doctors he is especially interested in discovering how tumor cells communicate with their environment, the so-called tumor micro-milieu, and what influence that has on successfully combating the tumor. “Our research shows that metabolism and immune responses are very closely linked. The decoding of the underlying mechanisms involved should help us in the medium term both to strengthen patients’ own immune responses and to optimize the efficiency of immunotherapeutic approaches,” explains the professor, who, among other places, has conducted research at the University of Pennsylvania in Philadelphia (USA) and at the renowned Karolinska Institute in Stockholm (Sweden), which has previously been recognized by the Nobel committee.

Long road to clinical application

The team uses putative weak points in the tumor cells as possible targets for treatment. This is because, like all cells in our body, cancer cells depend on being supplied with sufficient nutrients. In comparison with normal cells, however, cancer cells are especially hungry. They grow and divide more quickly and consequently consume more energy too. “Cancer cells are thus in competition with the immune cells and deprive them of important the energetic substrates that they need for fighting tumors. Through their increased metabolic activity, moreover, tumor cells produce countless harmful metabolites. This means that the immune system is weakened because it is facing two challenges simultaneously. Part of the work being undertaken concerns bringing about a targeted intervention in the processes that are important for the growth and metabolism of tumor cells.

Using imaging techniques, the scientists can determine, among other things, how well and how often immune cells feed on tumor cells under different conditions and thus develop improved cell and immune therapies. (Photo: Jana Dünnhaupt / University of Magdeburg)

Another approach is the targeted reprogramming of the body’s own immune cells. The challenge here is that “immune cells communicate constantly with their environment and therefore cannot be controlled to the extent that we would like. It is what is known as a black box. For this reason, there are still patients who do not respond well to modern treatments,” explains Mougiakakos.

Nevertheless, in a project supported by the German Research Foundation (DFG), the working group led by Mougiakakos was able, in collaboration with researchers from Erlangen, Regensburg and Würzburg, to obtain important insights into the immune response after a stem cell transplant, a treatment that is vital for life in patients with leukemia. The working group was able to show that damage in the DNA of T-lymphocytes in the first six weeks after transplantation is associated with functional deficits, an increased risk of relapse and a poorer overall survival rate. The team is now working on improving the repair of the DNA of T-lymphocytes and thus their effectiveness in the fight against leukemia.

For Mougiakakos it is clear that with these new approaches in gene and immunotherapy, more and more treatment options will result. “This means that we can treat patients in an ever more targeted way and in the event that an individual fails to respond to certain treatments, other alternatives will be available. The road to clinical application is long for the majority of methods, as, of course, all these exciting findings have to be very intensively tested before they can be tried on patients. But, ultimately, that is precisely what science is all about.

Guericke facts

• In comparison with other cancerous diseases, such as breast or lung cancer, leukemias are relatively rare. Every year around 13,700 people fall ill with leukemia in Germany.
• The work of researchers Tasuko Honjo and James Allison, who were awarded the Nobel Prize for Medicine in 2018, provided a breakthrough in cancer treatment. They discovered two critical proteins that act as brakes in the immune defense. Subsequently, it became possible to develop new drugs, known as checkpoint inhibitors.