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Project 3

项目3

基本信息

批准号：
10200703
负责人：
MICHELLE KROGSGAARD
金额：
$ 28.95万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-19 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10200703
关键词：
Adjuvant Adjuvant Study American Antibodies Autoantibodies Autoimmune Autoimmune Diseases B-Lymphocytes Biological Assay Biological Markers Bladder Cancer Patient Clinical Clinical Laboratory Improvement Amendments Clinical Trials Colitis Data Dermatologic Development Diarrhea Endocrine Exposure to Goals Hepatic Human Immune Immune checkpoint inhibitor Immunoglobulin G Immunologic Adjuvants Immunologic Markers Immunosuppression Inflammatory Bowel Diseases Kidney Laboratories Length Lung Malignant Neoplasms Morbidity - disease rate Nivolumab Oncologist Organ Pathogenicity Pathologist Patients Phase Phase II Clinical Trials Placebos Preclinical Testing Predisposition Prevention Prevention strategy Proteins Proteome Proteomics Publishing Randomized Recurrence Regimen Renal Cell Carcinoma Resected Role Selection for Treatments Serum T-Lymphocyte TNF gene Testing Therapeutic Thyroiditis Toxic effect Ulcerative Colitis Validation Work anti-CTLA4 anti-PD-1 base biomarker signature biomarker-driven cancer type checkpoint inhibition cohort college experience experimental study gastrointestinal high risk humanized mouse immune-related adverse events infliximab interest ipilimumab melanoma mouse model pembrolizumab phase 2 study phase II trial predicting response predictive test predictive tools prevent prophylactic response tool treatment optimization treatment strategy tumor

项目摘要

PROJECT 3 SUMMARY Immune checkpoint inhibitors have transformed melanoma treatment, producing durable responses, prolonged survival, and clinical benefit in a significant proportion of patients. Moreover, they delay recurrence and extend survival in the adjuvant melanoma setting, and have also shown efficacy in a range of different cancer types. However, immune checkpoint inhibition (ICI) therapy can also be accompanied by immune-related adverse events (irAEs) that impact multiple organs, cause significant morbidity, and require immunosuppression or discontinuation of ICI treatment. There is an urgent need to identify patients who will develop severe irAEs from ICI. This would enable us to optimize treatment selection and sequencing, justify preventive strategies to mitigate toxicity, and better manage toxicities. While there is intense interest in identifying markers to predict response to ICI, no pre-treatment biomarker tool can predict irAEs associated with ICI for any cancer type. The goal of our project is to develop a predictive tool that enables clinicians to minimize exposure of patients to severe toxicity, while maximizing clinical benefit from ICI. We hypothesize that a subset of melanoma patients has a baseline, sub-clinical autoimmune susceptibility, characterized by specific pre-existing autoantibodies (autoAbs) that can predict and exacerbate the development of toxicity from ICI therapy. We have identified autoAb signatures in baseline (pre-treatment) sera that predict severe immune toxicity in melanoma patients treated with ICI (AUC >0.95). Using a humanized mouse model, we found that autoAbs from baseline sera of melanoma patients can exacerbate irAEs from ICI. In this project, we propose to refine and validate baseline autoAb biomarker signatures of ICI toxicity using sera (n=600) from two large adjuvant ICI clinical trials for resected stage-III/IV melanoma (Aim 1). To understand the relevance of specific autoAbs to common irAEs (e.g., colitis) and to investigate an autoimmune predisposition in some patients, we will compare irAE-associated autoAbs with those from inflammatory bowel disease patients and from normal donors. We will use our humanized FcR mouse model to determine the cause-effect relationship between autoAbs and irAEs, with a focus on colitis, and for preclinical testing of prophylactic anti-TNF- as a strategy to mitigate gastrointestinal (GI) toxicity from ICI (Aim 2). These findings will inform a biomarker-driven phase-II trial of prophylactic anti-TNF- (infliximab) in patients receiving ICI therapy who are at high risk for developing severe diarrhea and colitis (Aim 3). Our work will inform personalized melanoma treatment strategies by validating a robust pre-treatment biomarker to enable clinicians to optimize ICI regimens and minimize patient exposure to severe irAEs. We will both identify an autoimmune susceptibility to irAE development and establish whether prophylactic TNF- blockade mitigates development of GI toxicity from ICI in patients identified as being at high risk of these irAEs.

项目3总结