Targeting Interleukin-6 Helps to Mitigate the Side Effects of Immunotherapy

Researchers at The University of Texas MD Anderson Cancer Center have identified a new strategy to reduce immune-related adverse events by targeting immunotherapy with the cytokine interleukin-6 (IL-6). The study, published in Cancer Cell, provides evidence for the concept of combining immune checkpoint blockers and cytokine blockers to selectively inhibit inflammatory autoimmune responses.

While immunotherapy in combination with anti-pd-1 and anti-ctla-4 agents has revolutionized the treatment of multiple cancer types, it also has high toxicity, which may impact quality of life and lead to treatment interruption. Often, cancer patients who respond to combination immunotherapy also experience serious side effects. Immune-related enterocolitis (irEC) is an inflammatory bowel disease that is the most common serious complication.

"We first need to overcome immunotoxicity to support patients and reduce their symptom burden," said senior author Adi Diab, MD, associate professor of medical oncology in melanoma. “Second, we know that there are multiple non-overlapping resistance mechanisms in the tumor microenvironment. In order to establish an effective multidrug immunotherapy regimen, we must overcome the barriers to immune-related toxicity so that patients can continue to receive optimal treatment.”

This translational study analyzed patient tissues, preclinical models and retrospective data to determine how the IL-6 T helper 17-cell (Th17) pathway is involved in toxic responses and can be inhibited to separate inflammatory autoimmune responses and antitumor immunity reaction.

IL-6 has been implicated in resistance to immunotherapy in preclinical models, but the mechanism is unclear. IL-6 is also associated with some autoimmune diseases, and IL-6 blockers are approved for the treatment of rheumatic diseases and other autoimmune diseases.

Comprehensive immunoassays of matched samples of irEC tissue and normal tissue from patients treated with immune checkpoint blockade (12 in the observation group and 11 in the validation group) showed different immune signals in inflamed tissue (IL-6 and Th17 upregulation) compared with normal tissue. In addition, the IL-6 gene signature was upregulated in those tumors that did not respond to immunotherapy, but no elevated levels were seen in responding tumors.

Based on observations, the researchers used several preclinical models to assess the effect of IL-6 blockade on autoimmune and anti-ctla-4 therapeutic responses. The combination of an IL-6 blocker with an immune checkpoint inhibitor reduced experimental autoimmune encephalomyelitis (EAE) symptoms and improved tumor control, suggesting that the combination suppresses inflammatory responses and may enhance antitumor immunity.

To validate the findings, the researchers retrospectively analyzed 31 melanoma patients who underwent immune checkpoint blockade therapy between January 2004 and March 2021 and received IL-6 blockers for inflammatory arthritis and other immune-related adverse events. Patients in this cohort received IL-6 blockade for an average of 3.7 months after side effects began, and the researchers noted a 74% improvement in symptoms after an average of 2 months of IL-6 blockade.

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

"Cytokine blockers have been shown to block autoimmunity. The novelty of this study is the introduction of cytokines into tumor immunity and demonstrates that autoimmunity and antitumor immunity are not necessarily overlapping immune responses, but can decoupling at the factor level." "IL-6 is only one cytokine, but this work provides proof-of-principle to take science to the next level, targeting multiple cytokines through a multi-layered approach."

Based on these results, Diab is leading an investigator-initiated phase II prospective clinical trial (NCT04940299) to evaluate the safety and efficacy of IL-6 blockade in combination with anti-PD-1 and anti-CTLA-4 in several different cancer types.