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Project

Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

Funder: National Cancer Institute

Funding period
USD 213 K
Funding amount
Abstract
PROJECT SUMMARY Muscle invasive urothelial bladder cancer is a clinically aggressive disease with poor outcomes despite modern therapies. Recently, antibodies targeting the PD-1/PD-L1 immune checkpoint pathway have shown efficacy and were approved for use for locally advanced or metastatic bladder cancer. In some patients, impressive and durable clinical responses are observed, yet the rate of response remains modest at 20%. Mechanisms of pri- mary immune resistance in bladder cancer are not fully understood. The presence of a T cell-inflamed tumor phenotype has been associated with improved survival and response to immunotherapies. T cell-inflamed tu- mors can be identified by the presence of intratumoral CD8+ T cells or expression of a T cell gene signature. Emerging data have indicated that certain oncogenic pathways, such as FGFR3, are activated exclusively in non-T cell-inflamed bladder cancers. The underlying hypothesis of this proposal is that FGFR3 activation pre- vents spontaneous T cell priming in bladder cancer and may be therapeutically targeted to restore sensitivity to immune checkpoint blockade. A mechanistic investigation into the immunomodulatory effects of FGFR3 will be pursued through (a) a new genetically-engineered mouse model system with tamoxifen-inducible KrasG12D/p53fl/fl carcinomas that also express an activating FGFR3K644E mutation, (b) a syngeneic transplantable mouse model system using the MB49 bladder cancer cell line with model antigen expression, (c) in vitro studies examining differential gene expression in CRISPR-Cac9 derived FGFR3 knockout compared with FGFR active tumor cells, and (d) by an analysis of the immune microenvironment and FGFR3 expression in human bladder specimens using RNA in situ hybridization and multichannel immunofluorescence. The predictive capacity of these param- eters will be assessed in relation to outcomes for patients treated with anti-PD-1/L1 immunotherapy. Dr. Sweis is a physician-scientist from the University of Chicago and is the principle investigator on this study. He has devised a career development plan to obtain training in advanced tumor immunology and laboratory mouse modeling in order to facilitate his development as an independent investigator. He has developed a mentoring committee with broad expertise that is led by Dr. Thomas Gajewski, an internationally renowned expert in cancer immunology. Dr. Sweis has dedicated his efforts to the investigation of immunotherapy resistance mechanisms to improve outcomes for patients.

 
395
Projects
USD 188.3 M
Aggregated funding amount
USD 522 K
Average funding amount
Project list item
Investigating underlying molecular mechanisms of epigenetic therapies in muscle-invasive bladder cancer

Bladder Cancer Advocacy Network to Swathi Ramakrishnan

USD 1,700
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Recombinant CCL2 as a novel treatment strategy for bladder cancer

Bladder Cancer Advocacy Network to Neelam Mukherjee, Robert Scott Svatek

USD 50,000
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Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

American Association For Cancer Research to Joshua James Meeks

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Refined phenotyping and personalized targeting of muscle-invasive bladder cancer

Swiss National Science Foundation to Roland Seiler, Vera Genitsch, Franziska Singer, Kiu Yan Charlotte Ng, Marianna Kruithof-de Julio

USD 597,404
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Combatting Bladder Cancer by Inducing Epithelial Turnover

National Cancer Institute to SOMAN N ABRAHAM

USD 203,510
2019 - 2021
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Chromatin Modifier Gene Mutation and Enhancer Dysfunction in Bladder Cancer

National Cancer Institute to BYRON H LEE

USD 243,205
2019 - 2024
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Phase 1/2 Study of Modern Immunotherapy in BCG-Relapsing Urothelial Carcinoma of the Bladder - (ADAPT-BLADDER)

National Cancer Institute to NOAH M HAHN

USD 656,816
2019 - 2024
Project list item
Defining the impact of intra-tumoral morphologic, immune and mutational heterogeneity in urothelial carcinoma

National Cancer Institute to HIKMAT AL-AHMADIE

USD 410,835
2019 - 2024
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The role of a new molecular driver in bladder cancer

National Cancer Institute to DALEY MORERA

USD 45,016
2018 - 2021
Project list item
Modulation of regulatory T cells in the bladder tumor environment by anti-PD-L1 immunotherapy

Bladder Cancer Advocacy Network to David Yoonsuk Oh, Lawrence Fong

USD 50,000
2018 - 2019
Project list item
Modeling bladder cancer pathogenesis and tumor evolution

National Cancer Institute to CORY ABATE-SHEN, DAVID B SOLIT, HIKMAT AL-AHMADIE, MICHAEL M. SHEN

USD 1,765,498
2018 - 2023
Project list item
Novel recombinant BCG for immunotherapy of bladder cancer

National Cancer Institute to BORIS SHOR

USD 290,014
2018 - 2019
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DT-EGF Toxic Fusion Protein for the Treatment of Bladder Cancer

National Cancer Institute to MIKE GLODE, SHAWN PATRICK ZINNEN

USD 299,937
2018 - 2019
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Elucidating Mechanisms of Bladder Cancer Metastasis

European Commission to Prasanna IYENGAR

USD 204,256
2018 - 2020
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SPORE in Bladder Cancer

National Cancer Institute to DEAN F. BAJORIN, TIMOTHY AN-THY CHAN, IRINA OSTROVNAYA, HIKMAT AL-AHMADIE, MICHAEL STEPHEN GLICKMAN, DAVID B SOLIT

USD 2,299,837
2018 - 2023
Project list item
Modeling bladder cancer metastasis using human patient-derived tumor organoids

Bladder Cancer Advocacy Network to Michael M Shen

USD 300,000
2018 - 2020
Project list item
Targeting TAM (Tyro3-Axl-Mer) family of transmembrane receptor tyrosine kinases in bladder cancer.

Bladder Cancer Advocacy Network to Arpita Roy

USD 1,700
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