MANHATTAN BIOSOLUTIONS, LLC — Department of Health and Human Services SBIR Phase I: 102

Description

PROJECT SUMMARY Bladder cancer is the sixth most common form of cancer and one of the most deadlyInaloneapproximatelypeople will be diagnosed with bladder cancer in the U Sanddied of the diseasePatients with advanced or metastatic disease have a dismal prognosis and few treatment options after first line chemotherapyMore recentlytherapy with immune checkpoint inhibitor antibodies has shown durable responses in advanced and metastatic bladder cancerbut the reported response rates warrant improvementVaccination against mutant tumor neoepitopes is progressively recognized as a strategy to potentiate the immune response of cells activated through immunological checkpoint blockadeLarge 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 therapyThe 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 FGFRan oncogenic driver protein with recurrent alterations in cancerBCG is a nonpathogenic 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 cancerOur hypothesis is that BCG can be successfully modified to express neoantigen protein fragments containing tumor associated mutationsleading to specific antitumor activity against bladder cancer in vivoOur first Specific Aim is to construct and validate recombinant BCG strainsrBCG NEOthat stably express and efficiently secrete proposed tumor neoantigen protein fragments of FGFRFGFR MUTCandidate 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 assaysThe second Specific Aim is to evaluate anti tumor efficacy of rBCG FGFR MUT candidates in a therapeutic vaccination settingTo achieve thiswe will employ syngeneic mouse models of bladder cancer in immunocompetent wild type miceThe most efficacious lead strains will be selected for further preclinical developmentIn Phase II we plan to test the activity of rBCG FGFR MUT in humanized mouse models and evaluate its immunogenicitysafety and additional administration routesNovel immunotherapy products discovered in this study may be used to treat patients with advancedmetastaticmuscle invasive bladder cancer or developed for other tumor types such as head and neck or lung cancers PROJECT NARRATIVE Bladder cancer is one of the most common cancers worldwide and is associated with substantial morbiditymortality and costBacteria Bacillus Calmette Gu rinBCGis a non specific immunotherapywhich use is restricted to patients with early stage bladder cancer onlyWe propose to engineer novel recombinant BCGrBCG NEOto induce both innate and tumor specific immune responseswith the potential to improve survival of patients with advancedmetastatic or muscle invasive forms of bladder cancer