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

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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