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
- 来源:
- 关键词:AffectAftercareAntibody TherapyAntigensBRAF geneBiological MarkersBiopsyCD8-Positive T-LymphocytesCRISPR screenClinicalClinical TrialsClonal EvolutionClonalityDevelopmentEffectivenessEnrollmentFc ReceptorFlow CytometryGenerationsGenomeGenotypeGoalsHumanImmuneImmune checkpoint inhibitorImmune responseImmunohistochemistryImmunologic MemoryImmunologicsIn complete remissionLeadLigandsLong-Term SurvivorsLymphocyte CountMAP Kinase GeneMaintenanceMalignant NeoplasmsMelanoma CellMemoryMetastatic MelanomaMitogen-Activated Protein KinasesModelingMusMutationOncogenicPathway interactionsPatientsPhasePopulationRegimenRelapseResearch PersonnelResistanceSamplingSiteT cell clonalityT cell responseT memory cellT-Lymphocyte SubsetsTestingTherapeuticTumor-Infiltrating LymphocytesTumor-infiltrating immune cellsUp-Regulationanti-PD-1anti-PD1 therapyanti-tumor immune responsebasecancer immunotherapycancer typecytokineeffectiveness evaluationexhaustexhaustionexome sequencingimprovedimproved outcomein vivoinhibitor/antagonistinsightloss of function mutationmelanomamouse modelnovelpembrolizumabperipheral bloodprogrammed cell death ligand 1programmed cell death protein 1receptorresponders and non-respondersresponsesingle-cell RNA sequencingtargeted treatmenttraffickingtranslational studytreatment responsetumortumor microenvironmenttumor-immune system interactions
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)
项目总结/摘要
丝裂原活化蛋白激酶(MAPK)靶向治疗(MTT)目前已被批准用于治疗转移性肝癌。
患有在BRAF中携带致癌突变的肿瘤的黑色素瘤患者。抗PD-1抗体是
转移性黑色素瘤患者的标准一线治疗方法,不考虑基因型,但缓解
仅见于40 - 45%的患者。为了改善MTT和抗PD1的结果,更有效的方法
是必要的。我们最近证明MTT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,如PD-1,其配体PD-1,
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功能,
肿瘤微环境中的免疫应答,并有可能将免疫非应答性肿瘤转化为免疫应答性肿瘤。
将肿瘤微环境转化为对后续抗PD1治疗更敏感的环境。为了验证我们的假设,我们
我已经开始了一项试验(NCT 031429029),该试验包括MTT的导入期,短暂的伴随治疗期,
MTT和pembrolizumab(pembro)抗PD-1治疗,然后是单药pembro(Aim 1)。我们将
研究简化MTT联合pembro的临床获益率(CBR),并确定
MTT对肿瘤免疫微环境的相关作用与24小时CBR的改善相关
周作为试验的一部分,连续活检(治疗前、MTT导入后和MTT + pembro)和
将收集外周血,我们的临床、翻译和基础研究团队将使用这些血液。
样本,以确定与反应相关的生物标志物,并建立对
单独的MTT和与抗PD-1抗体疗法组合对肿瘤微环境的影响。我们
还将评估抗PD-1和MTT对GEMM黑色素瘤模型中T细胞应答的影响,
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T细胞亚群的产生。
记忆T细胞在小鼠中使用肿瘤再激发研究控制肿瘤。我们将描述T细胞
目标1中临床试验中招募的患者的反应,重点关注效应器,记忆和
耗尽的T细胞亚群。最后,我们将检查黑色素瘤患者的记忆人群,他们长-
免疫检查点抑制剂或MTT治疗后的长期存活者。最后,我们将这些
使用互补小鼠黑色素瘤模型的转化研究,以确定这种疗法如何影响
T细胞亚群的产生、功能和维持,并使用
小鼠黑色素瘤细胞的体内CRISPR筛选。(Aim第三章
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?
- DOI:10.1007/s40257-020-00506-2
- 发表时间:2020-02-05
- 期刊:
- 影响因子:7.3
- 作者:Banks, Lauren B.;Sullivan, Ryan J.
- 通讯作者:Sullivan, Ryan J.
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)?
- DOI:10.1200/jco.22.01066
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Sullivan,RyanJ
- 通讯作者:Sullivan,RyanJ
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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。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:0
- 作者:
Schweitzer An;Arlene H. Sharpe - 通讯作者:
Arlene H. Sharpe
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
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
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:
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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