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

基本信息

  • 批准号:
    10153453
  • 负责人:
  • 金额:
    $ 38.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-05-17 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

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)

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?
What, if Any, Role Is There for BRAF-Targeted Therapy in BRAF-Mutant Melanoma?
BRAF 靶向治疗在 BRAF 突变黑色素瘤中有何作用(如果有的话)?
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Arlene H. Sharpe其他文献

The complexity of the B7-CD28/CTLA-4 costimulatory pathway.
B7-CD28/CTLA-4 共刺激途径的复杂性。
Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8sup+/sup T cells
肿瘤细胞通过改变 CD8+T 细胞中的丙酮酸利用和琥珀酸盐信号来决定抗肿瘤免疫反应
  • DOI:
    10.1016/j.cmet.2022.06.008
  • 发表时间:
    2022-08-02
  • 期刊:
  • 影响因子:
    30.900
  • 作者:
    Ilaria Elia;Jared H. Rowe;Sheila Johnson;Shakchhi Joshi;Giulia Notarangelo;Kiran Kurmi;Sarah Weiss;Gordon J. Freeman;Arlene H. Sharpe;Marcia C. Haigis
  • 通讯作者:
    Marcia C. Haigis
Age-associated remodeling of T cell immunity and metabolism
T 细胞免疫和代谢的年龄相关重塑
  • DOI:
    10.1016/j.cmet.2022.11.005
  • 发表时间:
    2023-01-03
  • 期刊:
  • 影响因子:
    30.900
  • 作者:
    SeongJun Han;Peter Georgiev;Alison E. Ringel;Arlene H. Sharpe;Marcia C. Haigis
  • 通讯作者:
    Marcia C. Haigis
The B7:CD28 family and friends: Unraveling coinhibitory interactions
B7:CD28 家族及朋友:解开共抑制相互作用
  • DOI:
    10.1016/j.immuni.2024.01.013
  • 发表时间:
    2024-02-13
  • 期刊:
  • 影响因子:
    26.300
  • 作者:
    Kelly P. Burke;Apoorvi Chaudhri;Gordon J. Freeman;Arlene H. Sharpe
  • 通讯作者:
    Arlene H. Sharpe
PD-L2 is a second ligand for PD-1 and inhibits T cell activation
PD-L2 是 PD-1 的第二种配体,可抑制 T 细胞活化
  • DOI:
    10.1038/85330
  • 发表时间:
    2001-03-01
  • 期刊:
  • 影响因子:
    27.600
  • 作者:
    Yvette Latchman;Clive R. Wood;Tatyana Chernova;Divya Chaudhary;Madhuri Borde;Irene Chernova;Yoshiko Iwai;Andrew J. Long;Julia A. Brown;Raquel Nunes;Edward A. Greenfield;Karen Bourque;Vassiliki A. Boussiotis;Laura L. Carter;Beatriz M. Carreno;Nelly Malenkovich;Hiroyuki Nishimura;Taku Okazaki;Tasuku Honjo;Arlene H. Sharpe;Gordon J. Freeman
  • 通讯作者:
    Gordon J. Freeman

Arlene H. Sharpe的其他文献

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{{ truncateString('Arlene H. Sharpe', 18)}}的其他基金

Defining regulators of immunity to acute infection using CRISPR screens
使用 CRISPR 筛选定义急性感染免疫调节因子
  • 批准号:
    10210502
  • 财政年份:
    2020
  • 资助金额:
    $ 38.06万
  • 项目类别:
Project 2: Measuring and modeling the tumor and immune microenvironment before and during therapy and at the time of drug resistance
项目2:治疗前、治疗期间以及耐药时的肿瘤和免疫微环境的测量和建模
  • 批准号:
    10343840
  • 财政年份:
    2018
  • 资助金额:
    $ 38.06万
  • 项目类别:
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:
    9906872
  • 财政年份:
    2018
  • 资助金额:
    $ 38.06万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 38.06万
  • 项目类别:
Defining regulators of immunity to acute infection using CRISPR screens
使用 CRISPR 筛选定义急性感染免疫调节因子
  • 批准号:
    10207344
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:
Project 1: CRISPR screens to discover regulators of CD8 and CD4 cell fates and function
项目 1:通过 CRISPR 筛选发现 CD8 和 CD4 细胞命运和功能的调节因子
  • 批准号:
    10207349
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:
Defining regulators of immunity to acute infection using CRISPR screens
使用 CRISPR 筛选定义急性感染免疫调节因子
  • 批准号:
    9380804
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:
Core D: Mouse Perturbation Core
核心 D:鼠标扰动核心
  • 批准号:
    10207348
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10207345
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:
Defining regulators of immunity to acute infection using CRISPR screens
使用 CRISPR 筛选定义急性感染免疫调节因子
  • 批准号:
    10266219
  • 财政年份:
    2017
  • 资助金额:
    $ 38.06万
  • 项目类别:

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