Researchers at the MD Anderson Cancer Center at the University of Texas have developed a unique technique to reduce the immune side effects associated with immunotherapy by targeting the cytokine interleukin-6 (IL-6). This study, published in cancer cells on may9,2022, established the proof of concept of combining immune checkpoint blocking with cytokine blockers to selectively inhibit inflammatory autoimmune response.
Although the combined immunotherapy of anti-PD-1 and anti-CTLA-4 agents has completely changed the treatment of many types of cancer, its toxic side effects are also high, which will affect the quality of life and lead to the termination of treatment. Generally, cancer patients who respond to combined immunotherapy will also have obvious and destructive side effects. Immune associated enteritis (IREC), an inflammatory bowel disease, is the most common serious complication.
"We need to overcome immunotoxicity. First, we need to support patients and reduce their symptom burden," said ADI diab, senior author, MD, and associate professor of melanoma medical oncology. "Secondly, we know that there are many non overlapping resistance mechanisms in the tumor microenvironment. In order to establish an effective multi drug immunotherapy scheme, we must overcome the obstacles of immune related toxicity so that patients can continue to receive the best treatment."
This transformation study analyzed patient tissues, preclinical models, and retrospective data to determine how the IL-6 T-helper 17 cell (Th17) pathway contributes to toxicity, and can isolate inflammatory autoimmune responses and anti-tumor immune responses through inhibition.
ADI diab, MD, associate professor of melanoma medical oncology, senior author of the study.
In preclinical models, IL-6 is associated with resistance to immunotherapy, although the mechanism is not clear. IL-6 is also associated with some autoimmune diseases. IL-6 blockers are approved for the treatment of rheumatic diseases and other autoimmune diseases.
Comprehensive immunoassay was performed on the matched samples of IREC tissues and normal tissues of patients receiving immune checkpoint blocking treatment (12 patients in the observation cohort and 11 patients in the validation cohort). It was found that the immune characteristics of inflammatory tissues (in which IL-6 and Th17 were up-regulated) were different from those of normal tissues. In addition, IL-6 gene characteristics increased in patients with tumor unresponsive to immunotherapy, but this change did not exist in responders.
Based on this observation, the researchers then used several preclinical models to evaluate the effects of IL-6 blockers on autoimmunity and response to anti CTLA-4 therapy. The combination of IL-6 blockers and immune checkpoint inhibitors reduced the symptoms of experimental autoimmune encephalomyelitis (EAE) and improved tumor control, indicating that this combination can inhibit inflammatory response and may enhance anti-tumor immunity.
To verify these findings, the researchers conducted a retrospective analysis of 31 melanoma patients who received immune checkpoint blocking therapy from january2004 to march2021 and received IL-6 blockers to treat inflammatory arthritis and other immune related side effects. The patients in the study began to receive IL-6 blocking therapy at a median of 3.7 months after the occurrence of adverse reactions. The researchers observed a 74% reduction in symptoms after a median of 2 months after receiving IL-6 blocking therapy.
Among the 26 patients with assessable tumor response before (or early) IL-6 blockade and during follow-up, the best overall response rate to immune checkpoint blockade was 57.7% before IL-6 blockade and 65.4% after treatment. These clinical results support the preclinical findings that targeting IL-6 can reduce immune related adverse events without affecting the efficacy of immunotherapy.
"Cytokine blockers have been fully confirmed in blocking autoimmunity." diab said: "the novelty of this study is to target cytokines into tumor immunity and prove that autoimmunity and anti-tumor immunity are not necessarily overlapping immune responses, but can be decoupled at the cytokine level. IL-6 is only a cytokine, but this work provides proof of principle, that is, by targeting a variety of cytokines in a multi-layer approach, science will be raised to a new level.
Based on these results, diab is leading a phase II prospective clinical trial (nct04940299) initiated by researchers to evaluate the safety and efficacy of IL-6 blockade combined with anti-PD-1 and anti-CTLA-4 treatment in several different cancer types.
This study was supported by Wilkes family cancer autoimmunity research fund, American Society of Clinical Oncology / conker cancer foundation, National Institutes of health / National Cancer Institute (P30 ca016672, p50ca221703) and National Institute of allergy and infectious diseases (k01ai163412). Diab reported on Bristol Myers Squibb's research support and advisory board fees.