An immunocompetent platform for the characterization and discovery of novel therapeutics for hepatocellular carcinoma
用于表征和发现肝细胞癌新疗法的免疫活性平台
基本信息
- 批准号:10507168
- 负责人:
- 金额:$ 17.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAnimal ModelAntigensAutologousBAY 54-9085BackBiologicalBiological ProductsBiopsyCRISPR screenCRISPR/Cas technologyCTNNB1 geneCancer BiologyCancer EtiologyCell CommunicationCell Culture TechniquesCell modelCessation of lifeChemicalsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCombination immunotherapyCombined Modality TherapyCuesDataDissectionDrug CombinationsDrug ScreeningDrug TargetingDrug usageEZH2 geneEnsureEpigenetic ProcessFDA approvedFailureFundingGoalsHeterogeneityImmunocompetentImmunocompromised HostImmunologicsImmunotherapyIn VitroInvestigationKnock-outLaboratoriesLibrariesMalignant neoplasm of liverMediatingMentorsModalityModelingMusMutateMutationNatureOVA-8OrganoidsOvalbuminPatientsPharmaceutical PreparationsPhasePhysiciansPhysiologicalPrimary carcinoma of the liver cellsProtocols documentationRefractoryReportingResearchResearch PersonnelResistanceSignal TransductionT-LymphocyteTestingTherapeuticTransplantationTumor-DerivedTumor-Infiltrating LymphocytesValidationWorkanti-PD-1beta cateninbevacizumabcancer typechemotherapyclinically translatabledrug candidatedrug developmentdrug use screeninggene discoverygenome-wideimmune checkpoint blockadeimprovedin vivoindividual patientindividualized medicineinsightkinase inhibitorliver cancer modelmortalitymouse genomeneoplastic cellnovelnovel therapeuticsorganoid transplantationpersonalized carepersonalized medicinepersonalized therapeuticresistance mechanismscreeningskillssmall molecule inhibitorsuccesstherapeutic targettherapy designtooltreatment strategytumortumor immunologytumor microenvironment
项目摘要
Project Summary
Liver cancer is the fourth leading cause of cancer-related death in the world and mortality rates are rising,
which, in part, reflects historical drug development campaigns focused on single agent therapies (multi-
targeted kinase inhibitors and immunotherapy) that have limited efficacy in patients. Additionally, there are a
lack of targeted, personalized therapeutic options for this cancer type. Thus, there is an urgent need to identify
novel tailored therapeutic strategies. Recent advances in the therapeutic targeting of hepatocellular carcinoma
(HCC) have discovered superiority in efficacy for either small molecule inhibitors (for example, lenvatinib) or
biologics (for example, bevacizumab) used in combination with immunotherapy, though less than 30% of
patients respond to these new frontline therapies. A major gap in the field is the lack of appreciation for inter-
patient heterogeneity and a failure to identify drugs that (I) uniquely target driver-specific vulnerabilities, or (II)
improve immunotherapy. This proposal focuses on an unexplored strategy for therapy design in liver cancer,
which leverages the usage of in vivo CRISPR screens and a novel patient-derived ex vivo autologous tumor
organoid-T cell co-culture platform to provide new biological insight to mechanisms of drug potency on two
critical components of the tumor microenvironment (TME), and allow assessment of combination therapies for
the improvement of immunotherapy. I hypothesize that drug advancement in HCC, particularly in
combination with immunotherapy, is dependent on drug-mediated modulation of tumor-T cell
interactions. This hypothesis will be tested in two aims: (1) dissection of the mechanism of action of a novel
candidate drug, WNTinib, in immunologically tractable models of HCC using in vivo CRISPR screens, and (2)
identification of novel immunotherapy combinations for the personalized treatment of HCC. For Aim 1,
WNTinib’s key targets (or mechanism’s contributing to activity or resistance) will be investigated using two
separate genome-scale CRISPR sgRNA screening strategies: (I) transducing genetically-defined murine HCC
organoids transplanted orthotopically into immunocompetent and immunocompromised mice, and (II)
transducing T cells from OT-I;Cas9 and OT-II;Cas9 mice and transplanting them into tumor models expressing
the OVA-derived peptide SIINFEKL. Analyses done in the presence of WNTinib will identify WNTinib’s tumor
cell intrinsic, TME-dependent, and T cell-dependent targets or mechanisms. For Aim 2, I will use HCC patient
tumor biopsies to establish organoids and tumor infiltrating lymphocyte (TIL) cultures. This approach will allow
the study of tumor and T cells as separate components and in co-culture together. I will expand this platform to
include drug screening, alone or in combination with immunotherapy, using a panel of drugs representing
various stages of HCC clinical advancement. Results from this proposal will represent a major step forward for
the multidimensional understanding of drug usage in HCC, and how drugs may be used in combination with
immunotherapy to provide personalized care.
项目概要
肝癌是世界上第四大癌症相关死亡原因,死亡率正在上升,
这在一定程度上反映了历史上专注于单药治疗(多药治疗)的药物开发活动
靶向激酶抑制剂和免疫疗法)对患者的疗效有限。此外,还有一个
对于这种癌症类型缺乏有针对性的、个性化的治疗选择。因此,迫切需要识别
新颖的定制治疗策略。肝细胞癌靶向治疗的最新进展
(HCC)发现小分子抑制剂(例如乐伐替尼)或
生物制剂(例如贝伐珠单抗)与免疫疗法联合使用,但只有不到 30%
患者对这些新的一线疗法有反应。该领域的一个主要差距是缺乏对相互之间的认识。
患者异质性和未能识别 (I) 专门针对驾驶员特定漏洞的药物,或 (II)
改善免疫治疗。该提案重点关注肝癌治疗设计的未探索策略,
它利用体内 CRISPR 筛选和新型患者体外自体肿瘤
类器官-T 细胞共培养平台为两种药物的药效机制提供新的生物学见解
肿瘤微环境(TME)的关键组成部分,并允许评估联合疗法
免疫治疗的改进。我假设 HCC 药物的进步,特别是在
与免疫疗法相结合,依赖于药物介导的肿瘤 T 细胞调节
互动。该假设将在两个目标上进行检验:(1)剖析小说的作用机制
使用体内 CRISPR 筛选在 HCC 免疫学易处理模型中使用候选药物 WNTinib,以及 (2)
鉴定用于 HCC 个性化治疗的新型免疫治疗组合。对于目标 1,
WNTinib 的关键目标(或对活性或耐药性的贡献机制)将使用两种方法进行研究
单独的基因组规模 CRISPR sgRNA 筛选策略:(I) 转导基因定义的小鼠 HCC
将类器官原位移植到免疫功能正常和免疫功能低下的小鼠中,以及(II)
转导来自 OT-I;Cas9 和 OT-II;Cas9 小鼠的 T 细胞并将其移植到表达表达的肿瘤模型中
OVA 衍生肽 SIINFEKL。在 WNTinib 存在的情况下进行的分析将识别 WNTinib 的肿瘤
细胞内在的、TME 依赖性的和 T 细胞依赖性的靶标或机制。对于目标 2,我将使用 HCC 患者
肿瘤活检以建立类器官和肿瘤浸润淋巴细胞(TIL)培养物。这种方法将允许
将肿瘤和 T 细胞作为单独的成分和一起共培养的研究。我会把这个平台拓展到
包括单独或与免疫疗法组合的药物筛选,使用一组代表的药物
HCC 临床进展的各个阶段。该提案的结果将代表着向前迈出的重要一步
对 HCC 药物使用的多维理解,以及药物如何与 HCC 联合使用
免疫疗法提供个性化护理。
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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Alexander Rialdi其他文献
Alexander Rialdi的其他文献
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{{ truncateString('Alexander Rialdi', 18)}}的其他基金
A Pharmacogenomic Approach Using Precision Models of Hepatocellular Carcinoma to Identify Novel Therapeutics
使用肝细胞癌精密模型来识别新疗法的药物基因组学方法
- 批准号:
10179334 - 财政年份:2020
- 资助金额:
$ 17.15万 - 项目类别:
A Pharmacogenomic Approach Using Precision Models of Hepatocellular Carcinoma to Identify Novel Therapeutics
使用肝细胞癌精密模型来识别新疗法的药物基因组学方法
- 批准号:
9910997 - 财政年份:2020
- 资助金额:
$ 17.15万 - 项目类别:
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