Abbreviated targeted therapy to improve anti-PD-1 inhibitor efficacy in melanoma

简化靶向治疗可提高抗 PD-1 抑制剂对黑色素瘤的疗效

• 批准号: 9576657
• 负责人: Arlene H. Sharpe
• 金额: $ 39.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-17 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9576657
• 关键词: Affect; Aftercare; Antibody Therapy; Antigens; BRAF gene; Biological Markers; Biopsy; CD8-Positive T-Lymphocytes; CRISPR screen; Cells; Clinical; Clinical Trials; Clonal Evolution; Clonality; Development; Effectiveness; Enrollment; Fc Receptor; Flow Cytometry; Generations; Genome; Genotype; Goals; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunohistochemistry; Immunologic Memory; Immunologics; Immunosuppressive Agents; In complete remission; Lead; Ligands; Long-Term Survivors; Lymphocyte Count; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Melanoma Cell; Memory; Metastatic Melanoma; Mitogen-Activated Protein Kinases; Modeling; Mus; Mutation; Oncogenic; PDCD1LG1 gene; Pathway interactions; Patients; Phase; Population; Regimen; Relapse; Research Personnel; Resistance; SLEB2 gene; Sampling; Site; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tumor-Infiltrating Lymphocytes; Up-Regulation; anti-PD1 therapy; anti-tumor immune response; base; cancer immunotherapy; cancer type; cytokine; exhaust; exhaustion; exome sequencing; improved; improved outcome; in vivo; inhibitor/antagonist; insight; loss of function mutation; melanoma; mouse model; novel; peripheral blood; receptor; responders and non-responders; response; single-cell RNA sequencing; targeted treatment; trafficking; translational study; treatment response; tumor; tumor microenvironment

Project Summary/Abstract Mitogen activated protein kinase (MAPK)-targeted therapy (MTT) currently is approved for treating metastatic melanoma patients with tumors harboring an oncogenic mutation in BRAF. Anti-PD-1 antibodies are the standard front-line approach for patients with metastatic melanoma, regardless of genotype, but responses only are seen in 40-45% of patients. To improve outcomes with MTT and anti-PD1, more effective approaches are needed. We recently demonstrated that MTT leads to increased tumor infiltrating lymphocyte (TIL) number, clonality, and effector function, as well as increased immune exhaustion markers such as PD-1, its ligand PD- L1, and TIM3. We hypothesize that these MTT-associated tumor microenvironment changes enhance immune responses in the tumor microenvironment and have the potential to convert an immunologically non-responsive tumor microenvironment into one more responsive to subsequent anti-PD1 therapy. To test our hypothesis, we have opened a trial (NCT031429029) that incorporates a lead-in phase of MTT, a brief period of concomitant MTT and anti-PD-1 therapy with pembrolizumab (pembro), followed by single-agent pembro (Aim 1). We will investigate the clinical benefit rate (CBR) of abbreviated MTT in combination with pembro and determine if MTT-associated effects on the tumor-immune microenvironment are associated with improved CBR at 24 weeks. As part of the trial, serial biopsies (pretreatment, post-MTT lead-in, and on-MTT plus pembro) and peripheral blood will be collected, and our team of clinical, translational, and basic investigators will use these samples to identify biomarkers associated with response and to develop a mechanistic understanding of the effects of MTT alone and in combination with anti-PD-1 antibody therapy on the tumor microenvironment. We also will evaluate the effects of anti-PD-1 and MTT on T cell responses in a GEMM melanoma model and in patients (Aim 2). We will analyze T cell subsets in the mouse melanoma model, assessing the generation of memory T cells in mice that control tumors using tumor rechallenge studies. We will characterize T cell responses in the patients enrolled in the clinical trial in Aim 1, focusing on features of effector, memory, and exhausted T cell subsets. Lastly, we will examine memory populations in melanoma patients who are long- term survivors after treatment with immune checkpoint inhibitors or MTT. Finally, we will pair these translational studies with a complementary mouse melanoma model to determine how this therapy affects the generation, function and maintenance of T cell subsets, and identify new potential therapeutic strategies using in vivo CRISPR screens of mouse melanoma cells. (Aim 3)

项目概要/摘要 丝裂原激活蛋白激酶（MAPK）靶向治疗（MTT）目前被批准用于治疗转移性癌症 患有 BRAF 致癌突变的黑色素瘤患者。抗 PD-1 抗体是 转移性黑色素瘤患者的标准一线方法，无论基因型如何，但反应 仅见于 40-45% 的患者。为了改善 MTT 和抗 PD1 治疗的结果，更有效的方法 需要。我们最近证明 MTT 会导致肿瘤浸润淋巴细胞 (TIL) 数量增加， 克隆性和效应子功能，以及增加的免疫耗竭标志物，例如 PD-1、其配体 PD- L1 和 TIM3。我们假设这些 MTT 相关的肿瘤微环境变化增强了免疫 肿瘤微环境中的反应，并有可能转化免疫无反应 肿瘤微环境进入一种对后续抗 PD1 治疗更加敏感的环境。为了检验我们的假设，我们 已经开展了一项试验（NCT031429029），其中包含 MTT 的导入阶段，即短暂的伴随时间 使用 Pembrolizumab (pembro) 进行 MTT 和抗 PD-1 治疗，然后使用单药 pembro（目标 1）。我们将 研究缩写 MTT 与 pembro 组合的临床获益率 (CBR)，并确定是否 MTT 对肿瘤免疫微环境的相关影响与 24 时 CBR 的改善有关 几周。作为试验的一部分，连续活检（预处理、MTT 后导入、MTT 加 pembro）和 将收集外周血，我们的临床、转化和基础研究人员团队将使用这些 样本来识别与反应相关的生物标志物并发展对反应的机制理解 单独使用 MTT 以及与抗 PD-1 抗体联合治疗对肿瘤微环境的影响。我们 还将评估抗 PD-1 和 MTT 对 GEMM 黑色素瘤模型和 T 细胞反应的影响 患者（目标 2）。我们将分析小鼠黑色素瘤模型中的 T 细胞亚群，评估 使用肿瘤再攻击研究控制小鼠体内的记忆 T 细胞。我们将表征 T 细胞 参加目标 1 临床试验的患者的反应，重点关注效应器、记忆和反应的特征 T细胞亚群耗尽。最后，我们将检查长期黑色素瘤患者的记忆群体。 使用免疫检查点抑制剂或 MTT 治疗后的足月幸存者。最后，我们将这些配对 使用互补小鼠黑色素瘤模型进行转化研究，以确定该疗法如何影响 T 细胞亚群的生成、功能和维持，并使用以下方法确定新的潜在治疗策略 小鼠黑色素瘤细胞的体内 CRISPR 筛选。 （目标 3）