靶向白介素6可以帮助缓解免疫疗法副作用
研究表明，IL-6和免疫检查点的总和可降低毒性，同时保留抗肿瘤免疫反应
MD AndersonNews Release May 09, 2022
188bet体育网址德克萨斯大学医学博士安德森癌症中心的研究人员已经确定了一种新的策略，该策略是通过靶向细胞因子白介素6（IL-6）来减少免疫疗法治疗中与免疫相关的不良事件的新策略。该研究今天发表在Cancer Cell，，，，建立合并的概念证明免疫检查点封锁用细胞因子阻滞剂有选择地抑制炎症自身免疫反应。
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 authorAdi Diab，医学博士，副教授Melanoma Medical Oncology。“其次，我们知道肿瘤微环境中存在多种不重叠的抗性机制。为了建立有效的多药治疗方案，我们必须克服与免疫相关毒性的障碍，以便患者可以继续接受最佳治疗。”
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.
临床前研究揭示了免疫相关不良事件的免疫生物学
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.
来自免疫检查点封锁治疗的患者（观察队列中的12名患者，验证队列中的11例）的患者的匹配样品的全面免疫分析显示，发炎组织中有明显的免疫特征（其中IL-6和TH17上调了IL-6和TH17）与正常组织相比。此外，在肿瘤对免疫疗法没有反应但在反应者中没有看到肿瘤没有反应的人中，IL-6基因的特征被上调。
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
为了验证发现，研究人员对31例患者进行了回顾性分析188bet体育网址黑色素瘤在2004年1月至2021年3月之间接受了免疫检查点封锁治疗，还接受了IL-6阻滞剂，以治疗炎症性关节炎和其他与免疫相关的不良事件。该队列中的患者在开始经历副作用后3.7个月的中位数受到IL-6封锁，研究人员注意到，在IL-6封锁治疗的两个月后，症状提高了74％。188bet体育网址
在IL-6阻滞治疗之前（或早期）具有可评估肿瘤反应的26例患者中，在IL-6阻滞开始之前，对免疫检查点封锁的最佳总体反应率为57.7％，治疗后65.4％。这些临床结果支持临床前发现，该发现确定靶向IL-6可以减轻与免疫相关的不良事件，而不会损害免疫疗法的疗效。
“细胞因子阻滞剂已得到充分建立，可以阻止自身免疫性。这项研究的新颖性是将细胞因子的靶向靶向肿瘤免疫，并证明自身免疫性和抗肿瘤免疫不一定是重叠的免疫反应，但可以在细胞因子水平上解耦。”“ IL-6只是一种细胞因子，但是这项工作提供了原理证明，可以通过以多层方法靶向多种细胞因子将科学提升到一个新的水平。”
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. A full list of co-authors and disclosures is available in the纸。