Radiation, chemotherapy, surgery: Classical treatment approaches for cancer still remain standard. But researchers around the world are constantly looking at new therapies. A team at the University of Cologne wants to defeat cancer with the help of our own immune system.

By Anna Euteneuer

Feeble, underweight, with a sunken face and suffering from hair loss. This is what people who fight cancer often look like. One in two people in Germany will develop cancer once in their lives. However, the overall cancer mortality rate has consistently decreased over the past twenty years. »One reason for this is the progress in research and treatment,« says Henning Walczak. However, many cancers remain hard to treat or cannot be treated.

Walczak is Alexander von Humboldt Professor at the Centre for Biochemistry of the Faculty of Medicine. He is convinced that we must first understand our body better in order to find entry points for cancer treatments. The focus of his research is not primarily on the cancer cell itself, but on the cells of the body that are located in the immediate vicinity of the disease. He sees the key to success in cancer treatment in the targeted activation of the immune system.

A master of disguise

Even before tumours are treated with surgery, chemotherapy or radiation therapy, the first hurdle for cancer is our immune system. Every day, genetic defects develop in our body which could turn into cancer. The immune system recognizes and eliminates cancer cells that divide uncontrollably. The immune process is very effective in the everyday development of early cancer cells in our body, but at some point it reaches its limits. The reason is that cancer cells can ›disguise themselves‹ – they can pretend to be something they are not. They deceive the immune system. Walczak and his team want to reactivate the immune system in cancer patients to fight the disease.

Although the immune system has mechanisms to distinguish healthy from harmful cells, cancer cells can bypass this detection. For example, so-called checkpoint proteins on their surface. These proteins interact with appropriate receptors on T cells, a type of immune cell, and inhibit their ability to attack the cancer cells. They suggest that ›everything is fine and normal here‹. Drugs such as immune checkpoint inhibitors block this interaction and allow the T cells to recognize and attack the cancer cells again. This enhances the immune response to the tumour. However, a prerequisite for the therapy is that the disguise which the tumour has chosen is known.

Immunotherapy and targeted therapeutics that activate or inhibit certain proteins are now indispensable in cancer treatment. »If something goes wrong, we can now intervene in many processes. However, this requires that we know what precisely is going wrong,« says Walczak. For a long time, most patients being treated for cancer have no longer been given just one medication. A combination of agents serves to simultaneously lift different ›covers‹ of the cancer cell or activate immune cells. Walczak is looking for ways to make the tumour cells susceptible to the powerful effect of the immune system and to achieve the desired deadly effect for the cancer cells. His research group is currently testing several entry points. Their goal: to find signals that lead to the destruction of cancer cells.

Immune checkpoint inhibitors – The immunologists James Patrick Allison and Tasuku Honjo once laid the foundation for the development of immune checkpoint inhibitors that activate the immune system to attack tumour cells. In 2018, they received the Nobel Prize in Physiology or Medicine. At first, they only wanted to understand how immune cells tick and how their regulation works.

Deadly messengers

One approach is so-called death ligands. These are the body’s own proteins that can trigger the death of cells. Among other things, Walczak’s team has identified the so-called death ligand TRAIL (Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand) as a target for cancer therapy. TRAIL is a molecule that occurs in our body and plays an important role in the control of cells. It is usually produced by our immune system to detect and eliminate diseased or damaged cells in our body. If TRAIL encounters a TRAIL receptor on the surface of a cell, it signals to the cell that it should destroy itself. The affected cell follows the signal and decomposes into small parts that can be easily disposed of by other cells without causing damage.

TRAIL is only one of several death ligands, but it has a decisive advantage. Unlike the so-called Tumour Necrosis Factor (TNF) or Fas ligand, the administration of TRAIL is not toxic to the body. Although the reason for the good tolerability of this death ligand is not yet understood, it renders TRAIL particularly attractive as a new cancer therapeutic.

In some cases, Walczak’s team attempts to re-enable an immune attack on the tumour by blocking a death ligand. This allows immune cells that can specifically recognize and kill tumour cells to survive. »Our goal is to integrate knowledge about death receptors and death ligands and the associated signalling processes into tumour therapy in the best possible way,« says the researcher.

An important aspect of the work of Walczak’s team is to make the death of the tumour cells triggered by the therapy usable for the immune system: The immune cells are supposed to ›learn‹ to recognize and eliminate similar cells in the future. »Many conventional and newer, targeted therapies kill many tumour cells, and that’s generally a good thing. But some tumour cells survive this attack, then multiply, and the resulting tumour is usually resistant to the original therapy. We have to design the way in which we kill these tumour cells in such a way that their death is suitable for ›training‹ the immune cells, so to speak. In this way, the tumour cells that remain in the body can be specifically detected and killed by the immune system,« says Walczak.

From bench to bedside and back

The combination of targeted therapies and immunotherapy would be the researcher’s ›dream team‹ against cancer. In order to achieve this goal, Walczak says that in addition to new immunotherapies that his team is researching, it is also necessary to improve targeted therapies and to test them in the clinic. This is because patients should benefit as quickly as possible from the results of basic cancer research.

Both the CANTAR network and the National Centre for Tumour Diseases (NCT) are helping the UoC scientists to realize the project. The researchers can test their therapeutic approaches and at the same time evaluate patient data: Does the approach work? And if so: For which patients does it work best, for which less well? What would be the better treatment for the group with these particular molecular features? The scientists are asking themselves these questions, including in Walczak's team. »I can only recommend anyone with a tumour to participate in a clinical trial, if possible,« says Walczak. This allows access to new treatment options that may be more effective or safer than existing therapies and could improve the quality of life or better control the disease. Importantly, clinical trials also contribute to medical research and to improving cancer care in the future by providing invaluable insight on why the new therapy works or does not work in an individual patient.

CANTAR – The oncological research network CANcer TARgeting has set itself the goal of developing new substances to identify and neutralize specific driving pathways of cancer diseases, and to investigate how cancer can ›escape the immune system‹. CANTAR will receive a total of 19.4 million euros for the funding period from August 2022 to July 2026 from the state of North Rhine-Westphalia. The University of Cologne’s share amounts to 8.4 million euros.

The recent successes in immunotherapy and targeted therapies show that this is a promising path for cancer research and therapy. Henning Walczak summarizes: »My team and I are convinced that continuous research will enable further breakthroughs. Ultimately, we want to enable the immune system to keep tumour cells permanently in check.«

NCT West
Once the biology is understood, the knowledge must reach the patients. The National Centre for Tumour Diseases (NCT) is helping to achieve this. Since February 2023, the university hospitals of Cologne and Essen have been the location of NCT West and are funded by the German Federal Ministry of Education and Research.
The centre offers scientists the opportunity to initiate so-called Investigator Initiated Trials quickly. This type of clinical trial is initiated and conducted by independent researchers or research institutions – in contrast to industry-funded clinical trials in which pharmaceutical companies bear the primary responsibility.
At NCT West, scientists and physicians are working together to transfer the results from the research laboratories to the clinic and then back to the laboratory. This network bridges the gap between laboratory discoveries and clinical trials and promotes the implementation of promising ideas into clinical practice.

Further information:
Website Prof. Dr. Henning Walczak