Prophylactic anti-TNF Therapy Improves Safety of Immunotherapies, Mouse Study Says

Prophylactic anti-TNF therapy improves the safety and, to some degree, the efficacy of checkpoint blockade combination immunotherapies, a mouse study says.

The findings of the study, “Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy,” were published in Nature.

Previous studies have shown that a combination of the anti-PD-1 monoclonal antibody Opdivo (nivolumab) with the anti-CTLA-4 monoclonal antibody Yervoy (ipilimumab) is effective against a variety of cancers, including melanoma, renal cell carcinoma, and non-small-cell lung cancer.

Opdivo and Yervoy are two types of checkpoint blockade cancer immunotherapies, based on the principle that removing the “brakes” of the immune system increases its power to fight cancer faster and more effectively.

“However, this comes at the cost of frequent, serious immune-related adverse events, necessitating a reduction in the recommended dose of [Yervoy] that is given to patients,” the investigators said.

When lowering or discontinuing treatment with checkpoint blockade immunotherapies and starting a course of steroids fails to alleviate immune-related adverse events, patients are usually recommended anti-TNF therapy.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine — a molecule that mediates and regulates immune and inflammatory response — often found at abnormally high levels in patients with autoimmune disorders.

In this collaboration study, a group of researchers from the Centro de Investigación Médica Aplicada (CIMA) and the Clinica Universidad de Navarra in Spain devised a new strategy to lower the risk of toxicity and adverse events associated with cancer immunotherapies and, at the same time, maintain their efficacy.

The new treatment approach consisted of administering anti-TNF therapy prophylactically (as preventative measure) before the double combination of anti-PD-1 and anti-CTLA-4 immunotherapies, in mice models of melanoma and colorectal cancer.

According to their findings, mice treated with anti-TNF therapy followed by a combination of anti-PD-1 and anti-CTLA-4 were less likely to develop colitis, one of the most common and serious side effects of cancer immunotherapies in humans.

Besides improving treatment safety, the new strategy also led to a strong anti-tumor response in both models, possibly even enhancing the efficacy of the double immunotherapy combination.

“In this study, we have identified that the immunoregulatory function of TNF is dispensable and, to a certain extent, harmful to the anti-tumor activity of this combined immunotherapy,” Ignacio Melero, MD, PhD, a senior researcher at Cima and co-director of the Department of Immunology at Clinica Universidad de Navarra, said in a news release.

Pedro Berraondo, PhD, a researcher at Cima and co-author of the study, said: “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.”

According to researchers, the next step is to bring the new strategy to the clinic. A Phase 1 clinical trial (NCT03293784) assessing the safety of the new treatment approach in patients with advanced melanoma is underway.

“[T]his should be followed by a larger [Phase 2] clinical trial that examines both safety (measured as the percentage of immune-related adverse events that are of grade 2 or higher) and objective activity (measured as the percentage of overall response rate in patients),” the researchers said.