A work led by scientists from the Center for Applied Medical Research (CIMA) and the University Clinic of Navarra demonstrates in mice that, by blocking the protein called tumor necrosis factor (TNF) during a potent treatment of immunotherapy against cancer (therapy that combines two drugs: anti-PD-1 and anti-CTLA-4), it is possible to improve its effectiveness and reduce toxicity. The research is published in the journal Nature.
TNF serves to mediate inflammation, induces the destruction of some tumor cells and activates white blood cells, the cells of the immune system. The blocking of this protein in immunotherapy is not new, but its prophylactic application in this anti PD-1 and anti CTLA-4 therapy is.
“We have found in mice that prophylactic blocking of TNF during immunotherapy prevents adverse effects and improves their response to treatment. This allows us to better adjust the doses of the medication and thus achieve a more robust anti-tumor efficacy,” adds Pedro Berraondo, researcher at CIMA.
“We have identified that the immunoregulatory function of TNF is dispensable and, to a certain extent, damages the antitumor activity of this dual immunotherapy,” explains Ignacio Melero, senior researcher at CIMA and co-director of the Immunology Department of the University Hospital of Navarra.
Elisabeth Pérez Ruiz, from the Costa de Sol Hospital and first author of the work, highlights the usefulness of this approach in the context of prevention. The next step, the experts point out, is to transfer this research to the clinic.
According to Melero, “if the data in patients are analogous, an important paradigm in the therapeutic approach to cancer will be changed. However, despite the promising results, we must be very cautious about their interpretation, since these are observations in animal models that we will not know with certainty if they will reproduce in the patients included in the ongoing clinical trials or those that are going to start soon.”
Novelty in anti-TNF treatment
Research in cancer treatment seeks to extend the benefits of immunotherapy to a greater number of patients. The latest advances in this field consist in uniting several of these treatments. Among them, “the combination of PD-1 and CTLA-4 inhibition drugs achieves extraordinary efficacy against the most aggressive skin cancer (melanoma), kidney and lung cancer. However, 40% of patients suffer serious side effects,” says Melero.
PD-1 and CTLA-4 are proteins that are found in a type of immune cells, the T lymphocytes, and their mission is to prevent these cells from destroying other cells, such as cancer cells, thus acting as “brakes” in the control of the immune system. By inhibiting these molecules, the action of these “brakes” is eliminated and the defense action of the organism is stimulated.
Melero recalls that “this dual immunotherapy has demonstrated its effectiveness in patients with metastases in melanoma or renal cancer. Currently, it is being tested with very promising results against other types of cancer. However, the treatment should be interrupted in more than a third of the cases due to adverse autoimmune effects and that is why it is so important to prevent these side effects in the way that our study contributes.”
“Our results in the laboratory, together with previous clinical experience, suggest the conduct of clinical trials to verify the safety and efficacy of the treatment,” says Berraondo.
In fact, Melero points out: “We are evaluating a possible clinical trial protocol to study the effect of prophylactic TNF blocking in the treatment with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in humans.”