Bioactive Metabolites Modulate Immune-Related Adverse Events in Cancer Immunotherapy

生物活性代谢物调节癌症免疫治疗中与免疫相关的不良事件

基本信息

批准号：
10447679
负责人：
Mohit Jain
金额：
$ 70.64万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-08 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10447679
关键词：
Ablation Address Affect Aftercare Anti-Inflammatory Agents Applications Grants Autoimmune Autoimmune Diseases Autoimmunity Biological Assay Biology Bone Marrow CTLA4 gene Cancer Center Cancer Patient Cells Clinical Clinical Trials Colitis Combined Modality Therapy Development Disease Progression Epidemiologist G2A receptor Genetic Genetic Transcription Genomic Instability Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Hodgkin Disease Human Immune Immunity Immunological Models Immunologics Immunologist Immunology Immunomodulators Immunooncology Immunotherapeutic agent Immunotherapy Individual Inflammation Inflammatory Institutes Life Lysophosphatidylcholines Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of liver Malignant neoplasm of lung Malignant neoplasm of urinary bladder Mass Spectrum Analysis Measures Medical center Merkel cell carcinoma Metabolism Microsatellite Repeats Modeling Molecular Mus Non-Small-Cell Lung Carcinoma Oncogenic Participant Patients Phenotype Plasma Play Population Pre-Clinical Model Renal Cell Carcinoma Research Design Role Sampling Savings Scientist Serum Signal Transduction Solid Neoplasm Supplementation System Therapeutic Tissues Toxic effect Tumor-infiltrating immune cells anti-CTLA4 anti-PD-1 autoimmune toxicity base cancer immunotherapy cancer therapy cohort experience human model immune checkpoint immune checkpoint blockade immune-related adverse events improved in vivo in vivo Model innovation ipilimumab liquid chromatography mass spectrometry malignant stomach neoplasm melanoma metabolomics mouse model murine colitis neutrophil novel pembrolizumab progenitor programmed cell death protein 1 prophylactic prospective reduce symptoms restoration risk minimization small molecule small molecule therapeutics success systemic inflammatory response targeted treatment tumor tumor immunology

项目摘要

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.

项目概要免疫检查点阻断（ICB）疗法已证明对晚期患者具有显着的临床益处黑色素瘤、肾细胞癌、头颈癌、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会经历免疫相关不良事件 (irAE)，这可能导致永久性甚至致命的毒性以及挽救生命的免疫治疗的停止。使这个问题变得更加复杂事实上，目前不存在针对 ICB 驱动的 irAE 的分子调节剂。这个R01应用程序通过研究人类，检查循环 LPC 18:2 是一种新型小分子调节剂和 irAE 治疗方法癌症患者以及 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（例如黑色素瘤、非小细胞肺癌、头颈鳞状细胞癌）和 ICB 疗法（例如抗 CTLA4 易普利姆玛 (ipilimumab)、抗 PD1 派姆单抗 (pembrolizumab) 和联合疗法)； ii）检查之间的关系血浆 LPC 18:2 水平和 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 驱动的 irAE 和自身免疫性结肠炎的免疫机制；四）从机制上探讨 LPC 18:2 和 LPC-G2A 信号对发育和功能的新影响炎症性中性粒细胞。这项研究采用高度创新的方法，利用癌症患者生物采样跨越多个独立的临床试验，采用最先进的快速质谱分析法对小分子进行分析。分子代谢物和机制研究。这是癌症免疫学家之间的合作研究拉霍亚免疫学研究所和加州大学圣地亚哥分校摩尔斯癌症中心的基础科学家，分析加州大学圣地亚哥分校化学家、雪松西奈医疗中心统计流行病学家、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 的治疗作用 irAE 毒性分子解决了临床水平的迫切需要，以开发第一种疗法可以最大限度地降低风险，最大限度地提高效益，并为那些患有以下疾病的患者更准确地个性化 ICB 治疗：有望从癌症免疫疗法中受益。