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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.

 
214
Projects
USD 109.8 M
Aggregated funding amount
USD 566 K
Average funding amount
Project list item
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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Combatting Bladder Cancer by Inducing Epithelial Turnover

National Cancer Institute to SOMAN N ABRAHAM

USD 203,510
2019 - 2021
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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
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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
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Elucidating immunotherapy resistance mechanisms in non-T cell-inflamed bladder cancer

National Cancer Institute to RANDY F. SWEIS

USD 212,669
2018 - 2022
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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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SPORE in Bladder Cancer

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

USD 2,299,837
2018 - 2023
Project list item
Unraveling disparate roles of Notch-1 and Notch-2 signaling in bladder cancer.

Michael Smith Foundation for Health Research to Peter C Black

USD 338,302
2018 - 2023
Project list item
Role of B-arrestins in bladder cancer progression and response to chemotherapy

United States Department of Veterans Affairs to BAL L LOKESHWAR

 
2018 - 2022
Project list item
Potentiation of Immunotherapy with targeted nanoporphyrin in bladder cancer

United States Department of Veterans Affairs to CHONG-XIAN PAN

 
2018 - 2022
Project list item
Deciphering the neoantigen landscape in bladder cancer patients

Swiss National Science Foundation to Laurent Derré

USD 639,521
2018 - 2022
Project list item
Ty21a immunotherapy of non-muscle-invasive bladder cancer

Swiss National Science Foundation to Denise Nardelli Haefliger

USD 436,670
2018 - 2021
Project list item
CISTO: Comparison of Intravesical Therapy and Surgery as Treatment Options for Bladder Cancer

Patient-Centered Outcomes Research Institute to John Gore

USD 8,500,000
2018 - 2022
Project list item
Circulating tumour DNA as a precision oncology tool for metastatic bladder cancer

Canadian Institutes of Health Research to Alexander William Wyatt

USD 50,152
2017 - 2020
Project list item
INTRAVESICAL ONCOLYTIC THERAPY FOR BLADDER CANCER

National Cancer Institute to ROSA MARIA DIAZ, LUKKANA SUKSANPAISAN, BRADLEY C. LEIBOVICH

USD 1,081,593
2017 - 2020
Project list item
Multi-Antigen Vaccines for the Primary and Secondary Prevention of Bladder CancerTO POP: 9/15/2017 - 3/14/2019

National Cancer Institute to CLINTON GRUBBS

USD 636,313
2017 - 2019
Project list item
(PQ3) Immune epigenetic biomarkers of bladder cancer outcomes

National Cancer Institute to BROCK CLARKE CHRISTENSEN

USD 1,235,254
2017 - 2022
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