ETH researchers take major step towards personalized cancer immunotherapy

Cells belonging to the body's immune system can help fight tumors. This has allowed for several years for oncologists to use drugs called checkpoint inhibitors to encourage T cells to clear tumor cells. Last year, the two scientists who discovered this therapeutic approach received the Nobel Prize in Medicine.

While physicians are experiencing some initial success with this method, particularly with respect to melanoma and many other types of cancer, immunologists and cancer researchers are working to develop this approach. What they have in mind, is a vaccine that would cause the multiplication of cancer-fighting T cells in the body, thus strengthening the body's immune defenses. The big question is which molecules are appropriate for a vaccine? Researchers from the team of Manfred Kopf, professor of molecular biomedicine, have developed a method of identifying such molecules.

The search for a relationship between immune cells and tumor cells

Since, on the one hand, the tumors differ considerably from one patient to another and that, on the other hand, there are not two identical people (except identical twins), the future cancer vaccination system is a complex example of personalized medicine. The goal is to develop an individual vaccine for each patient.

Potential vaccines include protein fragments, called peptides, that are found only in tumors due to mutation. As T cells are specific and still recognize only one particular peptide, just as a key is only suitable for one lock, another prerequisite for such a vaccine is that the patient has T cells capable of to recognize these cancer peptides. Therefore, before physicians can immunize a cancer patient, laboratory tests must be performed to find the corresponding pairs of T cells and peptides. A peptide recognized by a T lymphocyte can be used for personalized immunization. The vaccine must then activate the body's T cells, which only recognize this peptide (and therefore the tumor cells). These T cells should eventually eliminate the tumor.

The ETH researchers' method allows a lab to determine which T cells recognize which peptide. Until now, this has been incredibly difficult. Scientists used tumors in mice to show that their approach worked well. Then they want to demonstrate the effectiveness of their approach to treating tumors in humans.

Each patient receives his own set of reporter cells

At the heart of this new method is a collection of several million reporter cells, each of which has on its surface one of the many peptides found in a tumor. The reporter cells are designed to become green as soon as a T cell interacts with it because of the recognition of the peptide presented. This allows scientists to identify tumor peptides recognized by the T cells of a cancer patient. This involves mixing the reporter cell collection with the T cells extracted from the patient's tumor, isolating the reporter cells that become green and identifying the peptide that they carry.

Since each person (and each vertebrate in general) has a unique immune system and each tumor carries a unique pattern of mutations, scientists must produce a different set of reporter cells for each patient. "One option is to determine the genetic sequence of the tumor and compare it to the gene sequence of healthy cells in the patient," says Kopf. This allows researchers to determine how well the tumor differs from healthy tissue, and then transfer the genetic information with precisely these tumor-specific differences in the reporter cells.

Experimental test

As Kopf explains, "other scientists are using computer predictions to determine which anti-cancer peptides are suitable for this type of immunization." But this approach is as effective as the algorithms used – and for the moment On the contrary, we have developed an experimental test that badures us that T cells recognize patients' tumor peptides. "

Early tests involving a bad cancer model in the mouse showed Kopf and his colleagues that their method worked. In immunized mice, the immune system actually attacked the tumor; this has not been the case in non-immunized mice used by scientists.

Scientists have already patented this method five years ago. In 2015, their promising discovery earned them the Spark Award from ETH Zurich. Their work was recently published in the journal Immunology of nature.

To develop commercial applications of this technique, scientists have founded a spin-off of ETH called Tepthera. This start-up intends to demonstrate the effectiveness of its approach by also using tumors in humans.

Just as interesting for autoimmune diseases

"Our technique and personalized immunization are promising for the treatment of all cancers – especially in combination with checkpoint inhibitors," says Kopf Type 1 diabetes.

Unlike the immune system of healthy people, the immune system of people with autoimmune diseases attacks not only foreign or mutated cells, but also the body cells of the autoimmune patient. In the case of many of these conditions, it is not yet known against which native molecules the autoimmune response is directed. This is something that can now be studied using the new method. Unlike cancer, where the idea is to use vaccination to activate killer cells for autoimmune diseases, the goal is to develop a vaccine that moderates the immune system.