Core 1: Mouse Model and Tissue Biobank Core

核心 1：小鼠模型和组织生物库核心

基本信息

批准号：
10526106
负责人：
ROGER S LO
金额：
$ 32.29万
依托单位：
INSTITUTE FOR SYSTEMS BIOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-22 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10526106
关键词：
Adoptive Cell Transfers Antigen Presentation Biopsy CD8-Positive T-Lymphocytes Cell Line Child Clinical Clinical Data Combination immunotherapy Combined Modality Therapy Cutaneous Melanoma Data Data Analyses Immune Immune Evasion Immune checkpoint inhibitor Immunocompetent Immunologic Factors Lead MAP Kinase Gene MEKs Melanoma Cell Metastatic Melanoma Mitogen-Activated Protein Kinase Inhibitor Modeling Mus Mutation Pathway interactions Patients Protocols documentation Recurrence Regimen Resistance Services Standardization Therapeutic Tissues Treatment Protocols Triplet Multiple Birth Tumor Immunity Up-Regulation Validation anti-CTLA4 anti-PD-1 anti-PD-L1 base biobank clinical development clinical heterogeneity combat combinatorial immune checkpoint blockade immunogenic cell death in vivo inhibitor inhibitor therapy melanoma mouse model neoplastic cell novel posters predictive test prevent programmed cell death ligand 1 resistance mechanism response spatiotemporal subcutaneous success targeted treatment tumor tumor-immune system interactions

项目摘要

Murine and Clinical Tumors (MCT) Core services. Project Summary The simultaneous combination of anti-PD-L1 with BRAFV600MUT and MEK inhibitors (so-called “triplet” therapy), in early clinical data, appears beneficial and has recently been approved for patients with BRAFV600MUT melanoma (13). This is first mutation-immune co-targeted therapy to be approved, but the data on this triplet appear mixed, with other trials not meeting key endpoints (14), suggesting that simultaneous combination is not optimal. Importantly, retrospective clinical data analysis and in vivo therapeutic modeling using syngeneic models of murine melanoma showed that a regimen of anti-PD-1/L1 (± anti-CTLA-4) lead-in before MAPKi combination augments the efficacy of triplet therapy by enhancing MAPKi durability (and overcoming innate resistance to immune checkpoint blockade) (12). Thus, the realization that immune factors drive resistance to MAPKi therapy opens the door to immune-based strategies, such as adoptive cell therapy (ACT) (Project 1, Aim 3), as combinatorial agents to prevent MAPKi resistance. Building on this recent progress, this Murine and Clinical Tumors (MCT) Core will offer Projects 1 and 2 model and clinical tumors to obtain multi-scale (spatiotemporal) profiles of the tumor immune microenvironment (TIME) early and late on single-agent (MAPKi or anti-PD-1/L1) therapy (Project 1, Aim 1). These “early” data will provide inputs to the agent-based models (ABMs) being developed in Project 1, Aim 2, and “late” data will help validate predictions. Profiles from more successful combination strategies will be compared against less successful combination strategies to teach the ABM on optimized TMEs. This core will also offer clinical tissues for translational validation (Project 1, Aim 4) and tumor models to test predicted novel combination therapies (Project 2, Aim 3).

小鼠和临床肿瘤 (MCT) 核心服务项目摘要。抗PD-L1与BRAFV600MUT和MEK抑制剂同时组合（所谓的“三联”疗法），在早期临床数据中，出现了有益效果，并且最近已被批准用于 BRAFV600MUT 黑色素瘤患者 (13).这是第一个被批准的突变免疫联合靶向治疗，但关于这三联体的数据似乎好坏参半，其他试验未达到关键终点 (14)，表明同时联合治疗并非最佳。重要的是，使用同基因模型进行回顾性临床数据分析和体内治疗模型小鼠黑色素瘤显示，在 MAPKi 组合之前，采用抗 PD-1/L1（± 抗 CTLA-4）治疗方案通过增强 MAPKi 持久性（并克服对免疫检查点阻断）（12）因此，认识到免疫因素会导致对 MAPKi 疗法的抵抗。打开了基于免疫的策略的大门，例如过继细胞疗法 (ACT)（项目 1，目标 3），预防 MAPKi 耐药性的组合药物。基于这一最新进展，该小鼠和临床肿瘤 (MCT) 核心将提供项目 1 和 2 模型和临床肿瘤以获得肿瘤免疫微环境的多尺度（时空）概况（TIME）单药（MAPKi 或抗 PD-1/L1）治疗的早期和晚期（项目 1，目标 1）将提供这些“早期”数据。项目 1、目标 2 中开发的基于代理的模型 (ABM) 的输入和“后期”数据将有助于验证比较成功的组合策略的预测将与不太成功的组合策略进行比较。该核心还将为 ABM 提供有关优化 TME 的组合策略。转化验证（项目 1，目标 4）和肿瘤模型来测试预测的新型联合疗法（项目 2，目标 3）。