Advancing immunotherapy through cross species studies of immune cell responses and immune checkpoint inhibitor effects in dogs and humans with invasive urinary bladder cancer
通过对患有侵袭性膀胱癌的狗和人类的免疫细胞反应和免疫检查点抑制剂作用的跨物种研究来推进免疫治疗
基本信息
- 批准号:10651879
- 负责人:
- 金额:$ 55.25万
- 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 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdvanced Malignant NeoplasmAdverse eventAffectAnimal Cancer ModelAnimal ModelBehaviorBioinformaticsCancer ModelCanis familiarisCellsCellular Indexing of Transcriptomes and Epitopes by SequencingClinicClinicalClinical DataClinical TrialsComplementDataData CommonsData SetDepositionDiseaseDisease remissionDrug KineticsExperimental ModelsFDA approvedFailureGenomicsGoalsHealthHealth Care CostsHumanImmuneImmune checkpoint inhibitorImmune responseImmunobiologyImmunologyImmunotherapyInvadedLiteratureMalignant NeoplasmsMalignant neoplasm of urinary bladderMedical OncologyMicroRNAsMinorityMissionModelingMolecularNCI Center for Cancer ResearchNatureNeoplasm MetastasisOutcomePathologicPathologyPatientsPersonsPrediction of Response to TherapyPublic HealthPublishingRNA analysisReportingResearchSafetySamplingTYRO3 geneTransitional Cell CarcinomaUnited StatesUnited States National Institutes of HealthUniversitiesWorkanti-PD-L1 antibodiescancer heterogeneitycancer immunotherapycanine modelcheckpoint therapycomparativeimprovedmicrobiome researchmolecular subtypesneoplastic celloutcome predictionpre-clinicalpreventprogrammed cell death protein 1responsesingle-cell RNA sequencingsuccesstranscriptome sequencingtreatment responsetumortumor microenvironment
项目摘要
Project Summary / Abstract
Invasive urinary bladder cancer (invasive urothelial carcinoma, InvUC) is lethal in 50% of patients. Immune
checkpoint inhibitors (ICIs) can cause dramatic remission of advanced InvUC, but only ~20% of patients have
this level of benefit. Pre-clinical animal models are critical for research to improve ICI outcomes, but
experimental models lack many of the hallmark features of human cancer and are poor predictors of outcomes
in humans. To address the gap in relevant animal cancer models for immunotherapy research, we will study
dogs with naturally-occurring InvUC as canine InvUC closely mimics the human condition in pathology,
molecular features including luminal and basal subtypes, clinical presentation, local invasion, and frequent
metastasis. The proposed work will strengthen the canine InvUC model by defining immune cell
responsiveness and ICI outcomes, with comparison to human studies. Our long range goal is to improve the
outlook for people with InvUC. The objective of this proposal is to address the gap by determining the suitability
of canine InvUC to serve as a model to improve ICI therapy in humans. The central hypothesis is marked
similarities will exist between dogs and humans in the immune cell responses in InvUC, and ICI therapy effects
including immune adverse events, antitumor activity, immunological responses, and predictors of treatment
success and failure. Some differences between dogs and humans are expected, with these also being
informative. The hypothesis is formulated and based on strong evidence in the literature and preliminary data.
The rationale is that demonstrating the shared immune cell responses and ICI effects between dogs and
humans with InvUC will allow the canine model to be fully employed to improve ICI therapy for humans. The
objective will be accomplished through two specific aims: (1) determine similarities and differences between
dogs and humans in the immune cell responsiveness to InvUC, and (2) determine the safety and antitumor
activity of a canine PD-L1 antibody and predictors of success and failure in dogs with InvUC with comparison
to findings in humans. The approach will be to: (1) perform dog-human comparison of InvUC through analyses
of RNA-seq, scRNA-seq, WGS, and CITE-seq data, and (2) conduct a clinical trial of an ICI, our canine PD-L1
antibody, in dogs with InvUC to assess antitumor activity, pharmacokinetics, adverse event profile, and
correlative sequencing and clinical data to predict outcomes, and to compare results to those from human PD-
L1 antibody trials. The expected results will define shared immune cell responses and ICI effects in dogs and
humans, expand the understanding of predictors of ICI therapy, and justify use of the canine model to improve
ICI and other immunotherapies in humans. Samples from dogs in the ICI trial will also be made available for
other immune, microRNA, and microbiome research by our collaborators and beyond. We look forward to
contributing to the Canine Cancer Immunotherapy Network and depositing our study data in the NCI's
Integrated Canine Data Commons, to complement two InvUC data sets that we have previously deposited.
项目摘要/摘要
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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DEBORAH W KNAPP其他文献
DEBORAH W KNAPP的其他文献
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{{ truncateString('DEBORAH W KNAPP', 18)}}的其他基金
Targeted Intervention Against EphA2 on Cancer Cells
EphA2对癌细胞的靶向干预
- 批准号:
6522671 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Pilot Study--Cox2 Inhibitor in Invasive Bladder Cancer
试点研究——Cox2 抑制剂治疗侵袭性膀胱癌
- 批准号:
6515249 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Pilot Study--Cox2 Inhibitor in Invasive Bladder Cancer
试点研究——Cox2 抑制剂治疗侵袭性膀胱癌
- 批准号:
6405955 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Targeted Intervention Against EphA2 on Cancer Cells
EphA2对癌细胞的靶向干预
- 批准号:
6643496 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Targeted Intervention Against EphA2 on Cancer Cells
EphA2对癌细胞的靶向干预
- 批准号:
6334354 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Targeted Intervention Against EphA2 on Cancer Cells
EphA2对癌细胞的靶向干预
- 批准号:
6785273 - 财政年份:2001
- 资助金额:
$ 55.25万 - 项目类别:
Medicinal Chemistry Research Program (Project-003)
药物化学研究计划(Project-003)
- 批准号:
8855805 - 财政年份:1997
- 资助金额:
$ 55.25万 - 项目类别:
Medicinal Chemistry Research Program (Project-003)
药物化学研究计划(Project-003)
- 批准号:
9369068 - 财政年份:
- 资助金额:
$ 55.25万 - 项目类别:














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