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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.

 
418
Projects
USD 223.5 M
Aggregated funding amount
USD 677 K
Average funding amount
Project list item
Intravesical delivery of an Fc-enhanced CD40 agonist antibody for the treatment of bladder cancer

Bladder Cancer Advocacy Network to Jeffrey Ravetch, David Knorr

USD 300,000
2020 - 2022
Project list item
Epigenetic regulators of subtype plasticity in bladder cancer

Bladder Cancer Advocacy Network to John Robert Christin

USD 1,700
2020 - 2020
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
2020 - 2021
Project list item
Defining NRF2 induced tumor invasion in bladder cancer

Bladder Cancer Advocacy Network to Yuki Kita, William Youngkwan Kim, Bernard Weissman

USD 50,000
2020 - 2021
Project list item
Targeting regulatory B cells (Bregs) to improve anti-bladder cancer immunity

Bladder Cancer Advocacy Network to Burles Avner Johnson, David McConkey

USD 50,000
2020 - 2021
Project list item
Alpha1H: A Unique Bladder Cancer Therapeutic, Acting with Great Precision

European Commission

USD 2,452,885
2020 - 2022
Project list item
Dissecting myeloid cell-mediated resistance to immune checkpoint blockade in bladder cancer

National Cancer Institute to NINA BHARDWAJ, JUN ZHU, MATTHEW GALSKY

USD 703,400
2020 - 2025
Project list item
Implication of neutrophil extracellular traps in the efficacy of bladder-sparing therapy in muscle invasive bladder cancer

Canadian Institutes of Health Research to Wassim Kassouf, Ciriaco A. Piccirillo, Jonathan David Spicer

USD 138,878
2020 - 2025
Project list item
Chimeric RNAs and their implication in lymphatic metastasis of bladder cancer

National Cancer Institute to HUI LI

USD 205,913
2020 - 2025
Project list item
CD40 agonism for the treatment of bladder cancer

National Cancer Institute to CHRISTOPHER STUART GARRIS

USD 64,554
2020 - 2023
Project list item
Effect of APOBEC3 on Bladder Cancer Biology and Response to Immunotherapy

National Cancer Institute to ANDREW TRUONG

USD 45,016
2020 - 2023
Project list item
A new bladder cancer model based on tissue reprogramming and gene targeting

National Cancer Institute to FLAMINIA TALOS, DAIFENG WANG

USD 203,843
2020 - 2021
Project list item
Roles of epigenetic regulators in bladder cancer progression

University of California - Cancer Research Coordinating Committee to Zhu Wang

USD 74,960
2020 - 2020
Project list item
Chemotherapy plus PD-1 blockade as bladder-sparing treatment for muscle-invasive bladder cancer

V Foundation for Cancer Research to Matthew D Galsky

USD 600,000
2019 - 2022
Project list item
Unravelling Mechanisms of Resistance to Checkpoint Inhibition in Canine Urothelial Carcinoma

V Foundation for Cancer Research to Nicola J. Mason

USD 500,000
2019 - 2021
Project list item
Bladder cancer chemotherapy potentiation with a multiprong arachidonic acid pathway modulator

National Cancer Institute to PAUL THOMAS HENDERSON

USD 300,000
2019 - 2020
Project list item
[The association between SORL1 and advanced bladder cancer] - Original in Japanese

Japan Society for the Promotion of Science to Takanobu UTSUMI

USD 26,335
2019 - 2021
Project list item
Developing a SMART scaffold for bladder augmentation

National Institute of Biomedical Imaging and Bioengineering to GUILLERMO ANTONIO AMEER, JOHN ROGERS, ARUN SHARMA

USD 1,399,891
2019 - 2023
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