Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments
共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型
基本信息
- 批准号:10212018
- 负责人:
- 金额:$ 65.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-17 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAcuteAddressAdoptive Cell TransfersAdoptive TransferAftercareAirAntigensAutologousB-LymphocytesBiopsyBioreactorsCellsCellular immunotherapyClinicalCoculture TechniquesComplexCutaneousDataDetectionDevelopmentEpithelialEquilibriumExhibitsHumanImmuneImmune EvasionImmune checkpoint inhibitorImmune responseImmune systemImmunologic SurveillanceImmunological ModelsImmunotherapeutic agentImmunotherapyIn VitroInterleukin-2InvadedLigandsLiquid substanceMHC antigenMalignant NeoplasmsMethodsModelingMusNatural Killer CellsNatureNodalOrganoidsOutcomePatientsPeptidesPhosphoric Monoester HydrolasesPopulationPrimary NeoplasmProgressive DiseaseProtein DephosphorylationReceptor InhibitionResistanceResolutionSamplingSystemT-Cell ReceptorT-LymphocyteT-Lymphocyte SubsetsT-cell receptor repertoireTNFRSF5 geneTechniquesTestingTherapeuticTherapeutic antibodiesTimeTransgenic MiceTumor AntigensTumor Cell LineTumor-DerivedTumor-Infiltrating LymphocytesTumor-infiltrating immune cellsair treatmentanti-PD-1anti-PD-1/PD-L1anti-PD-L1anti-PD1 therapyanti-tumor immune responsebasecancer immunotherapycell killingcheckpoint inhibitionclinical decision-makingclinical efficacycohesioncohortcytotoxicityexhaustfollow-uphuman modelimmune checkpoint blockadeimprovedin vitro Modelin vitro activityin vivomacrophagemelanomamouse modelneoplastic cellnetwork modelsnext generationnovelpatient responsepatient subsetsperipheral bloodpredictive markerpreservationprogrammed cell death ligand 1programmed cell death protein 1prospectivereceptorreconstitutionrecruitresponserestraintsingle-cell RNA sequencingskin squamous cell carcinomasuccesstreatment trialtrial comparingtumortumor immunologytumor progressiontumor specificitytumorigenesis
项目摘要
PROJECT SUMMARY
The immune system remarkably distinguishes between self and non-self/self-aberrant antigens, affording
exquisite anti-tumor specificity and inhibition of tumorigenesis. However, tumor immunosurveillance is
unfortunately opposed by tumor cell evasion of the immune response. Immune checkpoint blockade (ICB)
targeting PD-1, PD-L1, CD40 and others, as well as adoptive cell transfer (CAR-T, bulk TILs) favorably modulate
this equilibrium for therapeutic benefit. However, response rates are often incomplete, progressive disease is
common, and predictive biomarkers are suboptimal.
The development of next-generation immunotherapies has been hindered by a lack of in vitro models
that functionally recapitulate syngeneic interactions between tumor and infiltrating immune cells. In response,
we have developed organoid methods that culture primary human tumor biopsies together with their infiltrating
immune components as a cohesive unit without reconstitution. These “patient-derived tumor organoids” (PDO)
preserve tumor cells alongside endogenous T, B, NK cells and macrophages, robustly recapitulate the T cell
receptor clonotype repertoire of the original tumor, and crucially, manifest tumor-infiltrating lymphocyte (TIL)
expansion, activation and tumor cell killing in response to anti-PD-1/PD-L1 therapeutic antibodies (Cell, 2018).
The PDO system thus represents a holistic organoid model of human tumor-immune interactions.
Here, we leverage the PDO technique to investigate immunotherapeutic mechanisms and
treatments in PD-1-responsive cutaneous squamous cell carcinoma (cSCC) and melanoma, exploiting
pre- and post-treatment human biopsies and mouse models. Aim 1 hypothesizes that checkpoint inhibition
induces a complex and sequential network response involving immune-tumor and immune-immune crosstalk.
Thus, Aim 1 employs the ability to perform serial time-course sampling of PDOs to define a single cell RNA-seq
network cellular crosstalk model of the early anti-PD-1-stimulated anti-tumor immune response over multiple
acute time points typically inaccessible to clinical biopsies performed after months. Importantly, comparison of
this immune propagation in responding versus non-responding mouse and human organoids will define nodal
points conferring resistance. Aim 2 improves bulk TIL adoptive transfer immunotherapy by using PDOs as living
bioreactors to enrich tumor-reactive mouse and human melanoma TILs by anti-PD-1 checkpoint inhibition,
followed by testing of enhanced anti-tumor activity in vitro and in vivo. Lastly, Aim 3 performs a co-treatment
trial comparing anti-PD-1 responses of pre-treatment biopsy cSCC PDOs to clinical outcomes. Further, post-
treatment biopsy PDOs are re-challenged with anti-PD-1 and a novel agent inactivating PD-1 by
dephosphorylation. We thus utilize the holistic PDO model preserving endogenous tumor epithelial and immune
components en bloc to investigate and improve cancer immunotherapy via our team of Calvin Kuo (organoids),
Mark Davis and Chris Garcia (tumor immunology) and Anne Chang and Dimitri Colevas (cSCC clinicians).
项目总结
项目成果
期刊论文数量(0)
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CALVIN J KUO其他文献
CALVIN J KUO的其他文献
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{{ truncateString('CALVIN J KUO', 18)}}的其他基金
Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
- 批准号:
10319858 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Core 2: Stanford Breast Metastasis Center Organoid Core
核心 2:斯坦福乳腺转移中心类器官核心
- 批准号:
10704695 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Core 2: Stanford Breast Metastasis Center Organoid Core
核心 2:斯坦福乳腺转移中心类器官核心
- 批准号:
10272393 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
- 批准号:
10654752 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments
共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型
- 批准号:
10374163 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Immunotherapy Modeling in Organoids Co-preserving Tumor and Infiltrating Immune Compartments
共保存肿瘤和浸润免疫区室的类器官的免疫治疗模型
- 批准号:
10586140 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
Intestinal organoid modeling of SARS-CoV-2-stimulated innate and adaptive immunity
SARS-CoV-2 刺激的先天性和适应性免疫的肠道类器官模型
- 批准号:
10450851 - 财政年份:2021
- 资助金额:
$ 65.79万 - 项目类别:
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