Bioactive Metabolites Modulate Immune-Related Adverse Events in Cancer Immunotherapy

项目摘要 免疫检查点阻断(ICB)疗法在晚期患者中显示出显著的临床益处。 患有黑色素瘤、肾细胞癌、头颈部癌、霍奇金淋巴瘤、膀胱癌、非小细胞癌 细胞肺癌，胃癌，肝癌，宫颈癌，默克尔细胞癌，以及所有的微卫星- 不稳定的肿瘤。针对CTLA4或PD1免疫检查点的ICB疗法的一个主要限制是 很大一部分患者将经历免疫相关的不良事件(IrAE)，这可能导致 永久性甚至致命的毒性和停止挽救生命的免疫疗法。使这个问题复杂化 目前还没有针对ICB驱动的irAEs的分子调节剂。此R01应用程序 通过研究人检测循环LPC 18：2一种新的小分子调节剂和治疗irAEs 癌症患者和相关的ICB驱动的irAEs的临床前模型和肿瘤消退。建议的目标 将在多个人类癌症队列中系统地检查LPC 18：2和irAEs之间的关联 (例如黑色素瘤、非小肺癌、头颈部鳞状细胞癌)和ICB疗法(例如 CTLA4 ipilimumab、抗PD1 pembrolizumab和联合治疗)；ii)检查 血浆LPC 18：2水平与ICB驱动的肿瘤消退或自然自身免疫性疾病；iii)研究 LPC 18：2抑制ICB诱导的irAEs和自身免疫性结肠炎的免疫学机制 从机制上探讨LPC 18：2和LPC-G2a信号在胚胎发育和功能中的新作用 炎性中性粒细胞。这项研究使用了一种高度创新的方法，利用癌症患者的生物采样 在多个独立的临床试验中，使用最先进的快速质谱学分析技术 分子代谢物和机理研究。这是一项由癌症免疫学家与 拉霍亚免疫学研究所和加州大学圣迭戈分校摩尔斯癌症中心的基础科学家，分析 加州大学圣迭戈分校的化学家，锡达斯-西奈医学中心的统计流行病学家，临床免疫肿瘤学 基础免疫学和中性粒细胞方面的合作者和专家。验证LPC 18：2是一种治疗方法 IRAE毒性的分子解决了临床层面上的迫切需要，即开发出第一种治疗方法 可以将风险降至最低，最大限度地提高收益，并更准确地为以下患者个性化ICB治疗 将从癌症免疫治疗中受益。

Project Summary Immune checkpoint blockade (ICB) therapy has demonstrated significant clinical benefit in late-stage patients with melanoma, renal cell carcinoma, head and neck cancer, Hodgkin lymphoma, bladder cancer, non-small cell lung cancer, gastric cancer, liver cancer, cervical cancer, Merkel cell carcinoma, and for all microsatellite- unstable tumors. A major limitation of ICB therapies targeting the CTLA4 or PD1 immune checkpoints is that a significant portion of patients will experience immune-related adverse events (irAEs), which can result in permanent or even fatal toxicity and discontinuation of life-saving immunotherapy. Compounding this problem is the fact that there currently exist no molecular modulators for ICB-driven irAEs. This R01 application examines circulating LPC 18:2 a novel small molecule modulator and therapeutic for irAEs by studying human cancer patients and relevant preclinical models of ICB-driven irAEs and tumor regression. The proposed aims will systematically i) examine association between LPC 18:2 and irAEs across multiple human cancer cohorts (e.g. melanoma, non small lung cancer, head and neck squamous cell carcinoma) and ICB therapies (e.g. anti- CTLA4 ipilimumab, anti-PD1 pembrolizumab and combination therapies); ii) examine relationship between plasma LPC 18:2 levels and ICB-driven tumor regression or natural autoimmune disease; iii) study the immunological mechanisms by which LPC 18:2 restrains ICB-driven irAEs and autoimmune colitis; iv) mechanistically probe novel effects of LPC 18:2 and LPC-G2A signaling on development and function of inflammatory neutrophils. This study uses a highly innovative approach leveraging cancer patient bio-sampling across multiple independent clinical trials with state-of-the-art rapid mass spectrometry profiling of small molecule metabolites and mechanistic studies. This is a collaborative study between a cancer immunologist and basic scientist at La Jolla Institute for Immunology and UCSD Moores Cancer Center, an analytical chemist at UCSD, a statistical epidemiologist at Cedars-Sinai Medical Center, clinical immune-oncology collaborators and experts on fundamental immunology and neutrophils. Validating LPC 18:2 as a therapeutic molecule for irAE toxicities addresses an urgent need at the clinical level to develop the very first therapies that can minimize risk, maximize benefit, and more accurately personalize ICB therapies for those patients who stand to benefit from cancer immunotherapy.