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A new way to reduce the side effects of immunotherapy

Cancer treatments have come a long way from the surgical approaches and chemotherapy that all but knocked you down as much as the cancer did. Nowadays, cancer is often treated with a more subtle and targeted approach, be that key hole surgery or immunotherapy. While these approaches represent great medical advances, they are still work in progress and far from perfect.

Many cancer treatments come with debilitating side effects, which limit how much of a drug can be given to a patient.  One effective treatment for skin, kidney and lung cancer is the combination of nivolumab and ipilimumab, two drugs that support the immune system in killing cancer cells. Unfortunately, treatment with these drugs can cause serious side effects, including colitis, an inflammation of the colon. This means that the prescribed dose needs to be reduced, making the treatment potentially less effective.

Recent research, co-funded thanks to our supporters, found a new way to help reduce the side effects from nivolumab and ipilimumab. This could ensure that patients can receive the most effective treatment dose that gives them the best chance of suriving. Dr Ignacio Melero from the Clinica Universidad de Navarra and CIMA and lead author of the study, said: “Severe immune-related adverse events occur in about 30% of patients at the current doses. We would like to raise doses of ipilimumab in the combination since it is very likely more efficacious but compromised by autoimmune side effects. The goal is to minimize toxicity and preserve or increase efficacy of the treatment.”

Dr Melero and his team found that mice treated with the two drugs often developed an inflammation of the colon. Inflammation causes cells to release certain chemicals, including a molecule called TNF. Administering a drug that blocks TNF improved the side effects of immunotherapy in these mice and reduced the amount of inflammation. Interestingly, the TNF blocker not only reduced side effects, it also increased the power of the combined drug regimen. Dr Melero explained: “TNF is known to be useful to treat autoimmune adverse events once they are established and drugs exist for people that we know are safe. The novelty here is that we are testing it in a prophylactic setting, prior to the patient being treated for cancer”.

While this research has only been done in mice, the researchers did also find that TNF is present at high levels in the colon of patients suffering from colitis after treatment with ipilimumab and nivolumab. This suggests that their findings might pave the way towards prophylactic treatment with drugs that block TNF, allowing for a higher and more effective dose of immunotherapy to be used in humans. Dr Melero said: “A clinical trial testing safety and efficacy of the approach is being prepared and it has the potential to change clinical practice due to its feasibility and relative simplicity.”

Improving the side effects of current therapies is an important task, as anyone who has undergone chemotherapy knows. Reducing adverse reactions to therapies will allow for higher treatment doses and could also pave the way for different and more effective combinations of drugs. Thanks to the generosity of our supporters we are able to fund this kind of essential research and are one step closer to a world where no life is cut short by cancer.

Read the research: Prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy, Nature, 569, 428–432 (2019)

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