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Similar Projects for

Project

Novel recombinant BCG for immunotherapy of bladder cancer

Funder: National Cancer Institute

Funding period
USD 290 K
Funding amount
Abstract
PROJECT SUMMARY Bladder cancer is the sixth most common form of cancer and one of the most deadly. In 2017 alone, approximately 79,000 people will be diagnosed with bladder cancer in the U.S. and 17,000 died of the disease. Patients with advanced or metastatic disease have a dismal prognosis and few treatment options after first-line chemotherapy. More recently, therapy with immune checkpoint inhibitor antibodies has shown durable responses in advanced and metastatic bladder cancer, but the reported response rates warrant improvement. Vaccination against mutant tumor neoepitopes is progressively recognized as a strategy to potentiate the immune response of cells activated through immunological checkpoint blockade. Large-scale sequencing efforts have characterized the mutational landscape in bladder cancer and have already identified commonly mutated genes that could be specifically targeted for cancer therapy. The overall goal of this SBIR phase I proposal is to construct and develop proprietary immunotherapy agents for the treatment of advanced and metastatic bladder cancer based on live Mycobacterium bovis BCG genetically engineered to target mutated forms of FGFR3, an oncogenic driver protein with recurrent alterations in cancer. BCG is a non- pathogenic attenuated intracellular bacterium that stimulates diverse innate and anti-bacterial adaptive immune responses and is well-known for its long safety track record as a tuberculosis vaccine and as a non-specific immune stimulant with modest activity in early-stage bladder cancer. Our hypothesis is that BCG can be successfully modified to express neoantigen protein fragments containing tumor-associated mutations, leading to specific antitumor activity against bladder cancer in vivo. Our first Specific Aim is to construct and validate recombinant BCG strains (rBCG-NEO) that stably express and efficiently secrete proposed tumor neoantigen protein fragments of FGFR3 (FGFR3MUT). Candidate strains with highest secretion and expression levels of human proteins will be selected following the integration of the polyepitope expression plasmids into the BCG genome and prioritized based on their biological properties and functional effects in in vitro immunological assays. The second Specific Aim is to evaluate anti-tumor efficacy of rBCG-FGFR3MUT candidates in a therapeutic vaccination setting. To achieve this, we will employ syngeneic mouse models of bladder cancer in immunocompetent wild-type mice. The most efficacious lead strains will be selected for further preclinical development. In Phase II we plan to test the activity of rBCG-FGFR3MUT in humanized mouse models and evaluate its immunogenicity, safety and additional administration routes. Novel immunotherapy products discovered in this study may be used to treat patients with advanced / metastatic, muscle-invasive bladder cancer or developed for other tumor types such as head-and-neck or lung cancers.

 
422
Projects
USD 239.1 M
Aggregated funding amount
USD 624 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
2019 - 2019
Project list item
Recombinant CCL2 as a novel treatment strategy for bladder cancer

Bladder Cancer Advocacy Network to Neelam Mukherjee, Robert Scott Svatek

USD 50,000
2019 - 2020
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Targeting FGF in Bladder cancer after Neoadjuvant Immunotherapy and Surgery

American Association For Cancer Research to Joshua James Meeks

USD 25,000
2019 - 2020
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Biomarker-Based Tools for Treatment Response Decision Support of Bladder Cancer

National Cancer Institute to LUBOMIR M HADJIYSKI, AJJAI SHIVARAM ALVA

USD 653,319
2019 - 2024
Project list item
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
2019 - 2023
Project list item
Combatting Bladder Cancer by Inducing Epithelial Turnover

National Cancer Institute to SOMAN N ABRAHAM

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

National Cancer Institute to BYRON H LEE

USD 243,205
2019 - 2024
Project list item
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
Project list item
The role of a new molecular driver in bladder cancer

National Cancer Institute to DALEY MORERA

USD 45,016
2018 - 2021
Project list item
Identifying DNA Biomarkers of Bacillus Calmette-Guerin (BCG) Resistance in Non-Muscle-Invasive Bladder Cancer

Canadian Institutes of Health Research to Jack Victor Warren Bacon, Alexander William Wyatt

USD 847
2018 - 2019
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
Novel 3D personalized bladder cancer model on demand: A new era for personalized medicine.

Canadian Institutes of Health Research to Alan I So, Claudia Itze Chavez-munoz

USD 141,091
2018 - 2020
Project list item
Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

National Cancer Institute to RANDY F. SWEIS

USD 212,669
2018 - 2022
Project list item
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
Project list item
Elucidating Mechanisms of Bladder Cancer Metastasis

European Commission to Prasanna IYENGAR

USD 204,256
2018 - 2020
Project list item
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
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