Preclinical investigation of PI3K inhibition and immune checkpoint blockade combination therapy for treatment of Merkel cell carcinoma using humanized mouse models
使用人源化小鼠模型进行 PI3K 抑制和免疫检查点阻断联合疗法治疗默克尔细胞癌的临床前研究
基本信息
- 批准号:10618864
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-01 至 2024-09-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAffectAnimal ModelAttenuatedBiological MarkersBiological ModelsCase StudyCaucasiansCell LineCell ProliferationCell SurvivalCell physiologyCellsClinicalCombination immunotherapyCombined Modality TherapyConsensusDevelopmentDiagnosisDiseaseEventFailureFamily memberFutureGenetic EngineeringGoalsHead and Neck Squamous Cell CarcinomaHealthHealthcare SystemsHeterogeneityHumanImmuneImmune responseImmune systemImmunotherapyIn VitroIncidenceInvestigationKnowledgeLigandsMalignant Epithelial CellMalignant NeoplasmsMediatingMerkel cell carcinomaMethodsModalityMolecularMusMutationNeoplasm MetastasisPD-1 blockadePathway interactionsPatientsPharmaceutical PreparationsPhosphatidylinositide 3-Kinase InhibitorPhosphotransferasesPositioning AttributeProtein IsoformsReportingResearchResistanceSkin CancerSolid NeoplasmSurvival RateTestingTherapeuticTimeTissuesTreatment EfficacyTreatment ProtocolsTumor ImmunityTumor-infiltrating immune cellsUnited States Food and Drug AdministrationVeteransWorkXenograft procedureadvanced diseaseanti-PD-1antitumor effectbiomarker identificationcancer immunotherapyclinical translationclinically relevantcombinatorialdosagefunctional statushigh riskhumanized mouseimmune cell infiltrateimmune checkpoint blockadein vivoindexinginhibitorinnovationmalemelanomamilitary veteranmolecular targeted therapiesmouse modelneoplastic cellneuroendocrine cancernovelnovel therapeutic interventionpembrolizumabpre-clinicalpreclinical studyprogrammed cell death ligand 1programmed cell death protein 1responseresponse biomarkersingle-cell RNA sequencingstandard of caresuccesstargeted treatmenttherapeutic targettherapeutically effectivetranscriptometranscriptome sequencingtreatment responsetumortumor growthtumor heterogeneitytumor progressiontumor xenografttumorigenesis
项目摘要
Merkel cell carcinoma (MCC) is an aggressive skin cancer that has quadrupled in incidence with a dismal five-
year survival rate of less than 18% in advanced diseases. MCC disproportionately and predominantly affects
Caucasian males older than 65 who are well represented in our Veteran population, especially for those who are
deployed to high UV index tropical and subtropical zones and are not well protected due to other survival
priorities. Hence, MCC has a growing impact on the VA healthcare system. Currently, there is no Food and Drug
Administration (FDA)-approved targeted therapy for MCC. Recently, immunotherapies such as pembrolizumab
and avelumab have been FDA-approved for advanced MCC; nevertheless, a significant portion of patients still
succumb to their diseases. Thus, there is an urgent clinical need for novel therapeutic strategies for patients who
fail out of or are unsuitable for immunotherapy. Aberrant amplification and mutations of PI3K pathway have been
detected in up to 80% of MCCs, making it an attractive therapeutic target. This is supported by our clinical
success in treating a Stage IV MCC patient with the 1st FDA approved PI3K- inhibitor idelalisib, which elicited a
complete clinical response. Furthermore, our preliminary studies demonstrate that copanlisib, the 2nd FDA
approved PI3K inhibitor with activity predominantly against PI3K-α/ isoforms, exerts the most potent antitumor
growth effects on MCC. Of relevance to this proposal, PI3K inhibition has been reported to enhance cancer
immunotherapies. Thus, there is a strong rationale to develop new combinatorial immunotherapy with targeted
therapies to boost therapeutic response and efficacy in MCC. Lack of syngeneic/genetically engineered animal
models has hampered preclinical studies in MCC. Notably, in our preliminary studies we have successfully
established a powerful, clinically relevant model system of MCC xenograft tumors in mice with competent human
immune systems. We hypothesize that PI3K inhibition by copanlisib and PD-1 blockade by pembrolizumab will
synergistically attenuate MCC tumor growth by inhibiting MCC cell proliferation and survival and enhancing
tumor-infiltration of immune cells and their antitumor activities. Furthermore, we have optimized innovative
single-cell RNA sequencing (scRNA-seq) methods to examine tumor heterogeneity and transcriptome profile in
human MCC cells. Therefore, we are well positioned to pursue the following specific aims: (Aim 1) examine
therapeutic efficacy and identify underlying mechanisms of copanlisib and pembrolizumab therapies on MCC
xenograft tumor growth in humanized mice, and (Aim 2) identify cellular and molecular mechanisms of MCC
tumor-immune interactions and antitumor immunity in response to copanlisib and pembrolizumab treatments.
Using our novel MCC humanized mouse models, we will be able to examine, for the first time, tumor-immune
response to copanlisib and pembrolizumab under competent human immune system. Importantly, tumor
heterogeneity is a critical determinant of therapeutic failure and tumor progression. Recent advancements in
scRNA-seq enable us to explore dynamics of tumor and immune cell subpopulations in response to treatments.
To achieve our goals, we will utilize state-of-the-art biotechniques to comprehensively analyze the effects of
copanlisib and pembrolizumab treatments on tumors and antitumor immunity at tissue, cellular, and molecular
levels. We expect that successful completion of the proposed work will result in the following advances: (1)
establishment of a novel treatment paradigm for combinatorial therapies in MCC, as well as other cancers that
affect our Veterans and their family members such as melanoma and high-risk head and neck squamous cell
carcinoma, (2) identification of tumor and immune cell subpopulations that mediate drug response, as well as
biomarkers for sensitivity/resistance to copanlisib and/or pembrolizumab treatment, which can lead to future
discovery of effective therapeutic strategies. Knowledge gained from the proposed studies will validate and
accelerate clinical translation, which will help Veterans who suffer from MCC and cancers for which current
immunotherapies are insufficient.
默克尔细胞癌(MCC)是一种侵袭性皮肤癌,其发病率增加了四倍,令人沮丧的是
晚期疾病的一年生存率不到18%。MCC不成比例地主要影响
65岁以上的高加索男性,在我们的退伍军人群体中有很好的代表性,特别是对于那些
被部署到高紫外线指数的热带和亚热带地区,由于其他生存而没有得到很好的保护
优先事项。因此,MCC对退伍军人管理局的医疗保健系统的影响越来越大。目前,没有食品和药物
美国食品和药物管理局(FDA)批准的MCC靶向治疗。最近,培溴利珠单抗等免疫疗法
和Avelumab已经被FDA批准用于晚期MCC;然而,相当一部分患者仍然
屈服于他们的疾病。因此,临床上迫切需要对以下患者采取新的治疗策略
免疫治疗失败或不适合免疫治疗。PI3K通路的异常扩增和突变
在高达80%的微囊癌中检测到,使其成为一个有吸引力的治疗靶点。这是由我们的临床支持的
FDA批准的第一个PI3K-抑制剂idelalisib成功治疗了一例IV期微囊癌患者,该药物引起了
完全临床反应。此外,我们的初步研究表明,FDA第二号药物科帕利西布
批准的PI3K抑制剂,主要针对PI3K-α/亚型,发挥最强的抗肿瘤作用
生长对MCC的影响。与这一提议相关的是,据报道,抑制PI3K可以增强癌症
免疫疗法。因此,有很强的理由开发新的靶向联合免疫疗法。
提高微囊癌治疗反应和疗效的治疗方法。缺乏同基因/基因工程动物
模型阻碍了MCC的临床前研究。值得注意的是,在我们的初步研究中,我们成功地
在有能力的人的小鼠体内建立了一个强大的、临床相关的MCC移植瘤模型系统
免疫系统。我们推测,Copanlisib抑制PI3K和Pembrolizumab阻断PD-1将
协同抑制MCC细胞增殖和存活增强MCC肿瘤生长
肿瘤侵袭免疫细胞及其抗肿瘤活性。此外,我们还优化了创新
单细胞RNA测序(scRNA-seq)方法检测肿瘤异质性和转录组图谱
人MCC细胞。因此,我们有能力实现以下具体目标:(目标1)审查
科帕利西布和培溴利珠单抗治疗MCC的疗效及机制探讨
人源化小鼠移植瘤的生长,以及(目的2)鉴定MCC的细胞和分子机制
Copanlisib和Pembrolizumab治疗反应中的肿瘤免疫相互作用和抗肿瘤免疫。
使用我们的新型MCC人源化小鼠模型,我们将能够第一次检查肿瘤免疫
在有能力的人体免疫系统下对科帕利西布和培溴利珠单抗的反应。重要的是,肿瘤
异质性是治疗失败和肿瘤进展的关键决定因素。最新进展
ScRNA-seq使我们能够探索肿瘤和免疫细胞亚群对治疗的反应动态。
为了达到我们的目标,我们将利用最先进的生物技术来全面分析
Copanlisib和Pembrolizumab对肿瘤的治疗和组织、细胞和分子的抗肿瘤免疫
级别。我们预期拟议工作的圆满完成将带来以下进展:(1)
建立一种新的治疗模式,用于MCC以及其他癌症的联合治疗
影响我们的退伍军人及其家庭成员,如黑色素瘤和高危头颈部鳞状细胞
癌症,(2)识别介导药物反应的肿瘤和免疫细胞亚群,以及
对Copanlisib和/或Pembrolizumab治疗的敏感性/耐药性的生物标志物,这可能导致未来
发现有效的治疗策略。从拟议研究中获得的知识将验证和
加速临床翻译,这将帮助患有微囊癌和目前癌症的退伍军人
免疫疗法是不够的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Ling Gao其他文献
Ling Gao的其他文献
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{{ truncateString('Ling Gao', 18)}}的其他基金
Unravel the role of CD276 and determine efficacy of CD276-targeted therapy on Merkel cell carcinoma progression and metastasis
揭示 CD276 的作用并确定 CD276 靶向治疗对默克尔细胞癌进展和转移的疗效
- 批准号:
10584403 - 财政年份:2023
- 资助金额:
-- - 项目类别:
Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment
确定针对默克尔细胞癌和肿瘤微环境的新疗法
- 批准号:
10665544 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Identifying novel therapies targeting Merkel cell carcinoma and tumor microenvironment
确定针对默克尔细胞癌和肿瘤微环境的新疗法
- 批准号:
10341321 - 财政年份:2022
- 资助金额:
-- - 项目类别:
Preclinical investigation of PI3K inhibition and immune checkpoint blockade combination therapy for treatment of Merkel cell carcinoma using humanized mouse models
使用人源化小鼠模型进行 PI3K 抑制和免疫检查点阻断联合疗法治疗默克尔细胞癌的临床前研究
- 批准号:
10454765 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Preclinical investigation of PI3K inhibition and immune checkpoint blockade combination therapy for treatment of Merkel cell carcinoma using humanized mouse models
使用人源化小鼠模型进行 PI3K 抑制和免疫检查点阻断联合疗法治疗默克尔细胞癌的临床前研究
- 批准号:
10015843 - 财政年份:2020
- 资助金额:
-- - 项目类别:
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