A novel strategy to reduce immune-related adverse events from immunotherapy treatment by targeting the cytokine interleukin-6 (IL-6) has been reported by scientists at the University of Texas MD Anderson Cancer Center.

The study, “Interleukin-6 blockade abrogates immunotherapy toxicity and promotes tumor immunity,” was published in the journal Cancer Cell.

“While combination immunotherapy with anti-PD-1 and anti-CTLA-4 agents has revolutionized treatment for multiple cancer types, it also has high toxicity rates, which can affect quality of life and lead to treatment discontinuation,” the researchers wrote. “Often, patients whose cancers respond to combination immunotherapy also experience high-grade side effects. Immune-related enterocolitis (irEC), an inflammatory bowel condition, is the most common serious complication.”

“We need to overcome immune toxicity, first and foremost, to support patients, and reduce their symptom burden,” said senior author Adi Diab, MD, associate professor of melanoma medical oncology. “Secondly, we know that there are multiple, non-overlapping mechanisms of resistance in the tumor microenvironment. In order to build an effective multi-agent immunotherapy regimen, we have to overcome the barrier of immune-related toxicity so that patients can continue receiving the optimum treatment.”

IL-6 has been associated with immunotherapy resistance in preclinical models, but the mechanism was not well understood. The researchers analyzed patient tissue, preclinical models, and retrospective data to determine how the IL-6 T-helper 17-cell (Th17) pathway contributes to toxicity and can be inhibited to separate the inflammatory autoimmune response from the antitumor immune response.

To validate their findings, the researchers performed a retrospective analysis of 31 patients with melanoma who were treated with immune checkpoint blockade between January 2004 and March 2021 and also received an IL-6 blocker to treat inflammatory arthritis and other immune-related adverse events. Patients in the cohort received IL-6 blockade a median of 3.7 months after beginning to experience side effects, and the researchers noted a 74% improvement in symptoms after a median of two months on IL-6 blockade therapy.

Of the 26 patients with evaluable tumor response before (or early in) IL-6 blockade therapy and at follow-up, the best overall response rate to immune checkpoint blockade was 57.7% before IL-6 blockade initiation and 65.4% after therapy. These clinical results supported the preclinical findings, which determined that targeting IL-6 can alleviate immune-related adverse events without compromising the efficacy of immunotherapy.

“Cytokine blockers have been well established to block autoimmunity. The novelty of this study is bringing cytokine targeting to tumor immunity and demonstrating that autoimmunity and antitumor immunity are not necessarily overlapping immune responses but can be decoupled at the cytokine level,” Diab said. “IL-6 is only one cytokine, but this work offers proof of principle for taking the science to the next level by targeting multiple cytokines in a multi-layered approach.”

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