Bioactive Metabolites Modulate Immune-Related Adverse Events in Cancer Immunotherapy

项目摘要 免疫检查点阻断（ICB）治疗已在晚期患者中显示出显著的临床获益 黑色素瘤、肾细胞癌、头颈部癌、霍奇金淋巴瘤、膀胱癌、非小细胞肺癌 细胞肺癌，胃癌，肝癌，宫颈癌，默克尔细胞癌，以及所有微卫星- 不稳定的肿瘤靶向CTLA 4或PD 1免疫检查点的ICB疗法的主要限制是， 很大一部分患者将经历免疫相关不良事件（irAE），这可能导致 永久甚至致命的毒性和停止挽救生命的免疫治疗。使这个问题更加复杂的是 目前还没有ICB驱动的irAE的分子调节剂。R 01应用程序 通过研究人类，检查循环LPC 18：2，一种新型小分子调节剂和irAE治疗剂 癌症患者和ICB驱动的irAE和肿瘤消退的相关临床前模型。拟议目标 将系统地i）检查多个人类癌症队列中LPC 18：2与irAE之间的关联 (e.g.黑色素瘤、非小细胞肺癌、头颈部鳞状细胞癌）和ICB疗法（例如抗- CTLA 4易普利姆玛、抗PD 1派姆单抗和联合疗法）; ii）检查CTLA 4易普利姆玛、抗PD 1派姆单抗和联合疗法之间的关系; 血浆LPC 18：2水平和ICB驱动的肿瘤消退或天然自身免疫性疾病; iii）研究 LPC 18：2抑制ICB驱动的irAE和自身免疫性结肠炎的免疫机制; iv） 机械地探测LPC 18：2和LPC-G2 A信号传导对发育和功能的新作用， 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，采用最先进的快速质谱分析技术， 分子代谢物和机制研究。这是一项癌症免疫学家和 他是拉霍亚免疫学研究所和加州大学圣地亚哥分校摩尔癌症中心的基础科学家， 加州大学圣地亚哥分校的化学家，雪松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作为治疗剂 针对irAE毒性的分子解决了临床水平上的迫切需要，以开发第一种治疗方法， 可以最大限度地降低风险，最大限度地提高收益，并更准确地为那些 从癌症免疫疗法中受益。

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.