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Time:2019-06-03

Pre-inhibition of TNF significantly enhanced the efficacy of combined immunotherapy with pd-1 and ctla-4 and reduced side effects

A collaborative experimental study led by researchers from Cima and navarra clinical university has proposed a novel approach to cancer therapy, using combined immunotherapy to address efficacy and toxicity in animal models. The clinical strategy involves blocking a protein involved in immune system regulation (called tumor necrosis factor, TNF), combined with immunotherapy (suppressing other proteins that "slow down" the immune response, such as pd-1 and ctla-4). The study was published recently in the journal Natrue.


"In this study, we found that the immunomodulation of TNF is nonessential and even harmful to some extent to this combined immunotherapy." "Explains Dr Ignacio Melero, a senior researcher at the clinical university of navarra. "We have demonstrated in these animal models that prophylactic blocking of TNF before immunotherapy avoids adverse reactions and enhances the therapeutic response. This allows us to better adjust the dose of the drug to achieve stronger anti-tumor effects." Cima researcher Pedro Berraondo, PhD.


The study's lead author, Dr. Elisabeth Perez Ruiz of Costa del Sol hospital, emphasized the effectiveness of the approach, "because in terms of prevention, it means that we can treat autoimmune adverse reactions using methods that we already use in our daily practice." The next step, experts say, is to move the research into the clinic. "If we get results from this study in patients, it will change the way we treat cancer," said Dr. Melero. However, despite these promising results in animal models, we must be very careful about their interpretation because we are not sure whether they will replicate in patients undergoing clinical trials or in patients about to start treatment."


Cancer research is trying to spread the benefits of immunotherapy to more patients. Recent advances in this area include combining these treatments. Among them, "pd-1 combined with ctla-4 inhibitors has significant efficacy in the most aggressive skin cancers (melanoma), kidney and lung cancers." However, 40% of patients suffer serious side effects. "This is why preventing side effects in this study is so important to the success of this combination immunotherapy," Melero added.


Pd-1 and ctla-4 are immune cell proteins (T lymphocytes) that prevent these cells from destroying other cells, such as cancer cells. As a result, they act as brakes on the immune system. By suppressing these molecules, the brakes are turned on and the body's defense system is activated. Tumor necrosis factor (TNF) mediates inflammation, induces destruction of certain tumor cells, and activates white blood cells in the immune system.


Dr Berraondo said: "the clinical evidence is not sufficient, but our study points to a good safety profile for inhibiting TNF in patients with advanced cancer. Our results in the laboratory and past clinical experience indicate the need for a clinical trial to test the safety and efficacy of this combined immunotherapy. In fact, we are evaluating a potential clinical trial protocol to study the effect of prophylactic blocking of TNF on nivolumab(anti-pd-1) and ipilimumab(anti-ctla-4) in human cancer."


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