Fighting cancer with the body's own defense system - this is the approach on which immunotherapy is based. Prof. Helmut Salih heads the Clinical Cooperation Unit (KKE) Translational Immunology at the University Hospital Tübingen (UKT) and the DKFZ and is a pioneer in this field. At the KKE, 15 immunotherapies developed in-house are already being evaluated in clinical trials.
Every year, around half a million people in Germany are diagnosed with cancer. Somewhere in their bodies, cells begin to multiply uncontrollably. The classic treatment methods used to be surgery, radiotherapy or chemotherapy. However, strategies have now also been established to mobilize the body's own immune system in order to cure the cancer.
The antibody forge
"Immunotherapy was ridiculed for a long time", says Helmut Salih, who has been researching the topic for more than 25 years. First in Munich, where he met his mentor Gundram Jung, then in the USA and finally, again together with Jung, in Tübingen. Their perseverance has paid off - it is now clear that the immune system is one of the best weapons against cancer.
The body's own defense system has evolved to enable higher organisms to survive in a world full of viruses and bacteria. The immune cells have no mercy on pathogens - anything that is foreign is attacked. But tumors can also be eliminated by the immune system - provided the immune cells are shown the way.
Together with a team of doctors and scientists, Salih is developing so-called bispecific antibodies in the Clinical Cooperation Unit (CCU) Translational Immunology, which bind different proteins simultaneously with their "two arms": With one arm, they recognize the tumour cells. With the other, they stimulate the so-called T-cells, the most potent defense cells of the immune system, which then kill the tumor cells.
To date, bispecific antibodies have been particularly successful when the tumor cells are easily accessible to the immune system, such as in the case of blood cancer or lymphoma. In the case of solid tumors, the vast majority of cancers, the immune cells have a harder time. "We have to get the T cells to leave the blood vessels and migrate into the tumor", explains Salih. To do this, the team is developing antibodies that not only recognize the tumour cells themselves, but also the tumour's blood vessels. This improves their effectiveness.
Helmut Salih is a pioneer, yet in some respects he longs to return to earlier times. At the end of the 1990s, when Salih first met Jung, it was still possible for researching doctors to develop a drug in the laboratory and then quickly use it on seriously ill patients with no other treatment option. Due to ever-increasing regulations, the development and clinical testing of drugs at public institutions is now almost impossible to finance. As a result, some potentially life-saving ideas never make it from the laboratory to the patient. Helmut Salih is not satisfied with this: "Like Paul Ehrlich, Jung and I always wanted to be both a doctor and a drug developer. I also believe that expertise from the laboratory can make a significant contribution to being able to better assess effects and, above all, side effects in the clinic."
This is exactly what is possible at Tübingen University Hospital. In 2019, the CCU Translational Immunology was established here, which Helmut Salih now heads together with Juliane Walz, Professor of Peptide-Based Immunotherapy. "The founding of the CCU in 2019 was a visionary decision by the University Hospital" says Salih. "An innovative structure was created here so that cancer patients can benefit from the results of research more quickly."
The CCU works closely with the various specialist departments at the University Hospital. For example, together with the Department of Urology, the CCU team identifies suitable patients for therapy with an antibody against prostate cancer, while immunotherapy studies for colon and liver cancer are carried out with colleagues from the Department of Gastroenterology. Patients benefit from the new structure: "We now have 15 clinical trials at CCU with immunotherapeutics for various cancers that we have developed at public institutions, which I think is quite unique and helps us to become faster and better for our patients," explains Salih with a little pride.
One example: A trial with an antibody in patients with advanced prostate cancer has been running at the CCU since 2019. Almost all patients responded, but only briefly. "We know that T cells require two different signals for a sustainable immune response. The first activates them against the tumor, the second so-called costimulatory signal ensures that they remain active and proliferate. The latter is important in order to be able to sustainably combat large tumors that consist of a large number of malignant cells," explains Salih. However, bispecific antibodies available to date only provide the first signal. Based on early pioneering work by Jung, the team has now developed a combination of two bispecific antibodies, each of which binds different target molecules on tumor cells with one arm and activates one of the two T cell receptors with the other arm. This allows an increase in tumor specificity and thus a reduction in side effects, but above all a long-lasting immune response. This combination therapy will be tested in an initial clinical trial in 2024. Helmut Salih will again accompany this therapy from the laboratory to the patient's bedside.