Core 1: Mouse Model and Tissue Biobank Core

核心 1：小鼠模型和组织生物库核心

• 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
• 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

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BRAFV 600 MUT和MEK抑制剂的同时组合（所谓的“三联”疗法）， 在早期的临床数据中，似乎是有益的，最近已被批准用于BRAFV 600 MUT黑色素瘤患者 （十三）、这是第一个被批准的突变免疫共靶向治疗，但关于这个三联体的数据似乎是混合的， 其他试验不符合关键终点（14），表明同时联合用药不是最佳选择。 重要的是，回顾性临床数据分析和体内治疗建模使用同源模型， 鼠黑色素瘤显示在MAPKi组合之前抗PD-1/L1（±抗CTLA-4）导入的方案 通过增强MAPKi的持久性（和克服对MAPKi的先天抗性）来增强三联疗法的功效。 免疫检查点阻断）（12）。因此，认识到免疫因素驱动对MAPKi疗法的抗性， 为基于免疫的策略打开了大门，例如过继细胞疗法（ACT）（项目1，目标3）， 预防MAPKi抗性的组合药剂。 在这一最新进展的基础上，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（TIME）的多尺度（时空）谱 早期和晚期单药（MAPKi或抗PD-1/L1）治疗（项目1，目标1）。这些“早期”数据将提供 对正在项目1、目标2中开发的基于主体的模型（ABM）的输入和“后期”数据将有助于验证 预测。将比较成功的组合策略与不太成功的组合策略的配置文件 在优化的TME上教授ABM的组合策略。该核心还将提供临床组织， 翻译验证（项目1，目标4）和肿瘤模型，以测试预测的新型联合疗法 （项目2，目标3）。