Immunotherapy has been a revolution in cancer treatment by harnessing the immune system to attack tumor cells. However, not all patients respond favorably to this therapy, and effectiveness also varies depending on the type of cancer. Now, research led by the Cancer Center Clínica Universidad de Navarra and the German company Catalym has clinically demonstrated that the neutralization of GDF-15 protein enhances treatment with immunotherapy, at least in a fraction of patients whose tumors had become resistant to conventional treatments.
GDF-15 is a substance produced mainly by the tumor that acts as a repellent for the cells of the immune system, preventing their penetration into the cancerous tissue. This protein, which is probably used by the placenta to prevent the rejection of antigens inherited from the father, is used by tumors to resist the attack of the immune system.
The results, published in the journal ‘Nature’, show that, when GDF-15 crashesthe cells of the immune system that are capable of recognizing and destroying tumors overcome the obstacle and attack it efficiently until it reduces its size or even disappears. «GDF-15 becomes a very important drug target in the treatment of oncological diseases. We are facing results that, potentially, can transform the way cancer is treated, although studies will still have to be carried out with a larger number of patients to be sure of the scope of the new combined treatment,” says Dr. Ignacio Melero, co-director of Immunology and Immunotherapy at Cima and at the University of Navarra Clinic.
The phase I-II clinical trial has also been carried out in hospitals in Madrid and Barcelona – highlighting the participation of VHIO and START Madrid CIOCC – and has tested the treatment in approximately 200 patients with solid tumorsthathad shown resistance to treatment with anti-PD-(L)1 antibodies. It is, in many cases, the best treatment available to patients, since it consists of neutralizing the PD-1 or PD-L1 proteins, which are involved in the main mechanism that tumors use to evade the immune response.
«Despite the revolutionary results of PD-(L)1 blockade, the majority of patients do not respond to treatment or do so temporarily, with resistance appearing. In this trial, participants received escalating doses of the monoclonal antibody visugromab (a monoclonal antibody developed by Catalym that neutralizes GDF-15) in combination with nivolumab (which neutralizes PD-1), and tumor biopsies were subsequently obtained at different times to analyze the change in behavior of the immune system cells during treatment,” explains Dr. Melero.
The study has shown that the combination of both drugs induces antitumor responses with excellent tolerability and, in addition, laboratory analyzes clearly reveal the mechanism of action. “We have observed objective reductions in tumor burden that are profound and lasting in a fraction of the treated patients, as well as some complete responses with disappearance of all measurable tumor lesions in patients who had not previously responded to multiple treatments,” says the doctor. Melero.
Progress against cachexia
Cancer-induced cachexia produces a serious loss of weight and muscle mass that frequently occurs in the body of people with advanced oncological diseases. Specifically, the GDF-15 protein acts on the central nervous system, causing a decrease in appetite and an increase in energy expenditure.
For this reason, Dr. Melero states that “inhibiting this protein has results that seem clinically relevant, since they also contribute to helping patients gain weight.” This fact has recently been demonstrated in another clinical trial published in the ‘New England Journal Of Medicine’ and in which the effectiveness of another monoclonal antibody to combat the tumor cachexia.
Dr. Melero explains that “in our clinical trial we observed that patients with high levels of GDF-15 in serum experienced weight gain after treatment with visucromab, suggesting that the use of this medication could have positive effects to help to cancer patients, also from a nutritional point of view, although we have not included patients with cachexia in our study.
#Spanish #researchers #discover #enhance #immunotherapy #resistant #tumors
