MSGID: 1:317/3 6279eaa0   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Targeting interleukin-6 could help relieve immunotherapy side effects   
    Study shows combined IL-6 and immune checkpoint blockade reduces toxicity   
   while preserving anti-tumor immune response    
      
     Date:   
         May 9, 2022   
     Source:   
         University of Texas M. D. Anderson Cancer Center   
     Summary:   
         Researchers have identified a novel strategy to reduce   
         immune-related adverse events from immunotherapy treatment by   
         targeting the cytokine interleukin-6 (IL-6).   
      
      
      
   FULL STORY   
   ==========================================================================   
   Researchers at The University of Texas MD Anderson Cancer Center have   
   identified a novel strategy to reduce immune-related adverse events   
   from immunotherapy treatment by targeting the cytokine interleukin-6   
   (IL-6). The study, published today in Cancer Cell, establishes a proof of   
   concept for combining immune checkpoint blockade with cytokine blockers   
   to selectively inhibit inflammatory autoimmune responses.   
      
      
   ==========================================================================   
   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.   
      
   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,   
   M.D., 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."   
   The translational study 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.   
      
   Preclinical studies reveal immunobiology of immune-related adverse events   
   IL-6 has been associated with immunotherapy resistance in preclinical   
   models, but the mechanism was not well understood. IL-6 also is associated   
   with several autoimmune diseases, and IL-6 blockers are approved to   
   treat rheumatologic disorders and other autoimmune conditions.   
      
      
      
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   Comprehensive immune profiling of matched samples of irEC tissue and   
   normal tissue from patients treated with immune checkpoint blockade   
   (12 patients in the observation cohort and 11 in the validation cohort)   
   revealed distinct immune signatures in the inflamed tissue (where IL-6   
   and Th17 were upregulated) compared to normal tissue. Furthermore, the   
   IL-6 gene signature was upregulated in those whose tumors did not respond   
   to immunotherapy, but the increased levels were not seen in responders.   
      
   Based on this observation, the researchers then used several preclinical   
   models to evaluate the effect of an IL-6 blockade on autoimmunity and   
   on response to anti-CTLA-4 therapy. The combination of an IL-6 blocker   
   with immune checkpoint inhibitor decreased experimental autoimmune   
   encephalomyelitis (EAE) symptoms and improved tumor control, indicating   
   that the combination could suppress inflammatory response and potentially   
   enhance antitumor immunity.   
      
   Observational cohort validates IL-6 strategy, prospective clinical   
   trial in progress To validate the 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."  Based on these results, Diab is   
   leading an investigator-initiated Phase II prospective clinical trial   
   (NCT04940299) to assess the safety and efficacy of IL-6 blockade in   
   combination with anti-PD-1 and anti-CTLA-4 therapy in several different   
   cancer types.   
      
   This study was supported by Wilkes Family Cancer Autoimmune Research   
   Fund, with additional research support from the American Society of   
   Clinical Oncology/ Conquer Cancer Foundation, National Institutes of   
   Health/National Cancer Institute (P30 CA016672, P50CA221703) and National   
   Institute of Allergy and Infectious Diseases (K01AI163412). Diab reports   
   research support and advisory board fees from Bristol Myers Squibb.   
      
      
   ==========================================================================   
   Story Source: Materials provided by   
   University_of_Texas_M._D._Anderson_Cancer_Center. Note: Content may be   
   edited for style and length.   
      
      
   ==========================================================================   
   Journal Reference:   
      1. Yared Hailemichael, Daniel H. Johnson, Noha Abdel-Wahab, Wai   
      Chin Foo,   
         Salah-Eddine Bentebibel, May Daher, Cara Haymaker, Khalida Wani,   
         Chantal Saberian, Dai Ogata, Sang T. Kim, Roza Nurieva, Alexander   
         J. Lazar, Hamzah Abu-Sbeih, Faisal Fa'ak, Antony Mathew, Yinghong   
         Wang, Adewunmi Falohun, Van Trinh, Chrystia Zobniw, Christine   
         Spillson, Jared K. Burks, Muhammad Awiwi, Khaled Elsayes, Luisa   
         Solis Soto, Brenda D. Melendez, Michael A. Davies, Jennifer Wargo,   
         Jonathan Curry, Cassian Yee, Gregory Lizee, Shalini Singh, Padmanee   
         Sharma, James P. Allison, Patrick Hwu, Suhendan Ekmekcioglu,   
         Adi Diab. Interleukin-6 blockade abrogates immunotherapy toxicity   
         and promotes tumor immunity. Cancer Cell, 2022; 40 (5): 509 DOI:   
         10.1016/j.ccell.2022.04.004   
   ==========================================================================   
      
   Link to news story:   
   https://www.sciencedaily.com/releases/2022/05/220509112023.htm   
      
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