Pretreatment with TNF inhibitors may improve outcomes of combination cancer immunotherapy
A collaborative experimental study, published in Nature and led by researchers at the University of Navarra, suggests TNF blockade may dissociate efficacy and toxicity in the use of combined immunotherapy in animal models
Credit: Cima Universidad de Navarra
Pamplona (Spain), May 2nd, 2019. A collaborative experimental study, led by researchers at Cima and Clinica Universidad de Navarra, proposes a new therapeutic approach against cancer that dissociates efficacy and toxicity in the use of combined immunotherapy in animal models. This clinical strategy consists of blocking a protein involved in the regulation of the immune system (called tumor necrosis factor, TNF) while applying combination immunotherapy treatment (inhibition therapy of PD-1 and CTLA-4, other proteins that “slow down” the immune response). Nature, the leading international weekly journal of science, publishes this research in its latest issue.
“In this study, we have identified that the immunoregulatory function of TNF is dispensable and, to a certain extent, harmful to the antitumor activity of this combined immunotherapy,” explains Dr. Ignacio Melero, a senior researcher at Cima and co-director of the Department of Immunology at Clinica Universidad de Navarra. “We have verified that the prophylactic blocking of TNF before applying immunotherapy avoids adverse effects and improves the response to treatment in these animal models. This allows us to adjust the doses of the medication better and thus achieve a more robust anti-tumor efficacy, “adds Dr. Pedro Berraondo, a researcher at Cima. Dr. Elisabeth Perez Ruiz, from Hospital Costa del Sol and first author of the work, highlights the usefulness of this approach “since in prevention context it means using what we already use in routine practice to treat the autoimmune adverse effects.”
The next step pointed out by the experts, is to transfer this research to the clinic. According to Dr. Melero, “if we obtain the results of this study in patients, it will change the paradigm for treating cancer. However, despite these promising results in animal models, we must be very cautious about their interpretation, because we don’t know with certainty if they will be reproduced in the patients that are included in the ongoing clinical trials or in 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 more significant number of patients. The latest advances in this field consist of uniting several of these treatments. Among them, “the combination of PD-1 and CTLA-4 inhibition drugs achieves remarkable efficacy against the most aggressive skin cancer (melanoma), kidney and lung cancer. However, 40% of patients suffer serious side effects,” says Dr. Melero. “That is precisely why preventing them as achieved in this study is so important for the success of this combined immunotherapy,” adds the expert.
PD-1 and CTLA-4 are a type of immune cells proteins (the T lymphocytes) responsible for preventing these cells from destroying other cells, such as cancer cells. Thus, they act as “brakes” in the control of the immune system. By inhibiting these molecules, the “brakes” are unplugged, and the defenses of the organism are stimulated.
The tumor necrosis factor (TNF) serves to mediate inflammation, induce the destruction of some tumor cells, and activate the 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. “The clinical evidence is modest, but points to an excellent safety of TNF inhibition in advanced cancer patients,” says Dr. Berraondo. “Our results in the laboratory along with previous clinical experience suggest conducting a clinical trial to test the safety and efficacy of this combined immunotherapy treatment. In fact, we are evaluating a potential clinical trial protocol to study the effect of prophylactic TNF blockade upon treatment with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in humans,” adds the expert.
This research has been supported by the International Immuno-Oncology Network, a global peer-to-peer collaboration formed by Bristol-Myers Squibb; the Spanish association against cancer (AECC), various European funds and other financial grants such as the aids from “la Caixa”. In addition to Cima and the Clinica Universidad de Navarra, researchers from several institutes collaborated. They were part of the Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), the Hospital General Universitario Gregorio Marañon, the Hospital Costa del Sol, the Hospital Universitario Virgen de la Victoria, the Navarra Institute for Health Research (IDISNA), the Instituto de Investigacion Biomedica de Malaga (IBIMA), the Centro de Investigaciones Medico-Sanitarias (CIMES) y Universidad de Malaga.
Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy
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About Clinica Universidad de Navarra
Clinica Universidad de Navarra, with more than 2.800 full-time commitment professionals in both of its locations Pamplona and Madrid, is a research hospital and a model in personalized medicine in our country. Our hospital is renowned for its research and teaching labor, for its prestigious professionals and its career in the diagnosis and treatment of complex pathologies.
Furthermore, it is a high-resolution hospital due to its diagnosis speed, that it is possible thanks to a multidisciplinary work and the acquisition of the latest technology. With all that, Clinica Universidad de Navarra is capable of providing 46 clinical and surgical specialties.
For the fifth consecutive year, our centre has been the hospital with the best reputation in Spain (according to MRS ranking).
About Cima Universidad de Navarra
Cima is the research center of the Clinica Universidad de Navarra. The scientific objective of its more than 370 professionals is to face current clinical problems and propose the most effective treatment for each patient. To transfer the results of basic research to clinical application, Cima has a Translation and Transfer unit that seeks to establish collaborations with biotechnological and pharmaceutical companies to facilitate the arrival of scientific discoveries to the patient.
Cima is a leading biomedical institution in the field of immunotherapy, gene therapy, and liver diseases. More information: https:/
For more information, request printable infographics or to arrange interviews with the researchers please contact Miriam Salcedo or María Pilar Huarte, Communications Office, Cima, and Clinica Universidad de Navarra. Email: firstname.lastname@example.org or email@example.com. Tel: +34 948194700 (Cima); or +34 948 296 497 (Clínica Universidad de Navarra).
Miriam Salcedo de Prado
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