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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.
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System

Categories
  • FOR (ANZSRC)

    1107 Immunology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Lung Cancer

  • RCDC

    Biotechnology

  • RCDC

    Lung

  • RCDC

    Cancer

  • RCDC

    Genetics

  • RCDC

    Immunization

  • RCDC

    Rare Diseases

  • RCDC

    Urologic Diseases

  • RCDC

    Vaccine Related

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science