More than 80,000 Americans are diagnosed with bladder cancer each year, and more than 17,000 die from the disease. Approximately 75% of new bladder cancer patients present with non-muscle invasive bladder cancer (NMIBC). Not only is NMIBC associated with high recurrence rates (>50%) and risk of progression, but 30% of patients are unresponsive to the standard of care treatment: transurethral resection with intravesical Bacillus Calmette-Guérin (BCG) instillation, the only approved microbial therapeutic for cancer. These individuals are left with limited therapeutic options. While there have been efforts to generate improved recombinant BCG (rBCG) strains, such efforts have not yet yielded demonstrable improvement over traditional BCG. With very few advances in treatment over the past two decades for early stage disease and a limited pipeline of therapeutics in development, there is a major unmet need for improved treatments for NMIBC. To address this need, OncoSTING is developing OS-101, a breakthrough rBCG immunotherapy that overexpresses a potent Stimulator of IFN Genes (STING) agonist. STING agonists potentiate anti-tumor responses through the innate immune STING-IRF3-NF-κB pathway. While other companies are developing small molecule STING agonists as novel anti-cancer immunotherapies, OncoSTING is the only company developing STING agonist delivery by a live bacterial vaccine-BCG-that itself is a well-known immunotherapy already in use for the treatment of bladder cancer, thus offering the benefits of both. Because it is a live bacteria, OS-101 allows for continuous and prolonged delivery of the STING agonist to the tumor microenvironment. Compared with wild type BCG, OS-101 demonstrates superior antitumor efficacy in models of NMIBC; more potent pro-inflammatory cytokine responses; greater myeloid cell reprogramming, producing an M1 shift with enhanced phagocytosis/autophagy; more pronounced epigenetic changes in key cytokine promoter regions; and metabolomic changes favoring antitumor immunity. In Phase I of this Fast Track project, OncoSTING will create a next-generation, antibiotic resistance-free version of 0S-101 using a novel, patent-pending method. The current rBCG prototype, OS-101, relies on a bacterial plasmid that is maintained using an antibiotic resistance cassette. However, Phase 3 studies will require the removal of antibiotic resistance genes. The efficacy of the new construct, called OS-151, will then be confirmed in four relevant bioassays. In Phase II, OS-151 will be compared to ADU-S100 (Aduro's small molecule STING agonist which is in current clinical trials) and wild type BCG in relevant models of bladder cancer. Pre-IND, pharmacokinetic and safety studies of OS-151 will also be conducted, and optimization work will ensure production of OS-151 at scale. Finally, tumor repetitive dosing studies and rechallenge studies will be carried out in mouse syngeneic models. Once approved, OS-151 will first be used to treat patients with BCG-unresponsive NMIBC, with potential to expand to other cancer indications.
Public Health Relevance Statement: Narrative Of all cancers, bladder cancer- the fifth most common malignancy in the U.S.-has the highest lifetime treatment costs per patient. New patients with non-muscle invasive bladder cancer (NMIBC), a subtype that has high recurrence rates (>50%) and risk of progression, are treated with live, attenuated vaccine Bacillus Calmette- Guérin (BCG) microorganisms as first-line therapy, but roughly one-third develop BCG-unresponsive disease. This project will support the development of a novel therapeutic solution consisting of a recombinant BCG strain with improved effectiveness at promoting a patient's anti-tumor immune responses.
Project Terms: Animals; Antibiotics; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antiviral Agents; Antiviral Drugs; Antivirals; anti-viral agents; anti-viral drugs; anti-virals; Autophagocytosis; autophagy; Bacteremia; bacteraemia; Bacteria; Bacterial Vaccines; Bacterin; BCG Vaccine; Bacille Calmette Guerin vaccine; Bacillus Calmette Guerin Vaccine; Bacillus Calmette-Guérin vaccine; Biological Assay; Assay; Bioassay; Biologic Assays; Malignant neoplasm of urinary bladder; Bladder Cancer; Malignant Bladder Neoplasm; Malignant Tumor of the Bladder; Urinary Bladder Cancer; Urinary Bladder Malignant Tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Carcinoma in Situ; Intraepithelial Carcinoma; Preinvasive Carcinoma; in situ cancer; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Complement; Complement Proteins; Cessation of life; Death; Diagnosis; Disease; Disorder; Fermentation; Genes; Growth; Generalized Growth; Tissue Growth; ontogeny; Immunity; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; In Vitro; Infection; Interferons; IFN; Light; Photoradiation; macrophage; MÏ; men; men's; Methods; Mucous Membrane; Mucosa; Mucosal Tissue; Mus; Mice; Mice Mammals; Murine; Pantothenic Acid; pantothenate; Legal patent; Patents; Patients; Phagocytosis; Drug Kinetics; Pharmacokinetics; Phenotype; Plasmids; Production; Promoter Regions; Promotor Regions; genetic promoter element; genetic promoter sequence; promoter sequence; Recurrence; Recurrent; Relapse; Resources; Research Resources; Risk; Safety; Standardization; Time; Attenuated Vaccines; Live-attenuated Vaccine; live vaccine; live vaccines; Work; cytokine; Generations; Antibiotic Resistance; Resistance to antibiotics; Resistant to antibiotics; antibiotic drug resistance; antibiotic resistant; Treatment Cost; base; improved; Left; Phase; Ensure; Training; Submucosa; Individual; Agonist; cancer immunotherapy; anti-cancer immunotherapy; anticancer immunotherapy; immune-based cancer therapies; immunotherapy for cancer; immunotherapy of cancer; Therapeutic; fluid; liquid; Liquid substance; Genetic; Immunes; Immune; intravesical; microorganism; American; auxotrophy; success; RT-PCR; RTPCR; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; microbial; novel; Abscission; Extirpation; Removal; Surgical Removal; resection; Excision; Position; Positioning Attribute; Modeling; response; Myeloid Cells; Effectiveness; preventing; prevent; metabolism measurement; metabonomics; metabolomics; small molecule; IFN-regulatory factor 3; IRF-3 protein; IRF3; Interferon Regulatory Factor 3; IRF3 gene; Address; Dose; Data; Cytokines and Inflammatory Response; Inflammatory Response Pathway; Recombinants; Antitumor Response; anti-tumor response; Cancer Patient; Epigenetic Process; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Transurethral Resection; Tumor Immunity; anti-tumor immunity; antitumor immunity; cancer immunity; Preparation; Development; developmental; safety study; Pathway interactions; pathway; tumor microenvironment; cancer microenvironment; next generation; rBCG; recombinant BCG; clinical efficacy; BCG Live; Bacille Calmette-Guérin; Bacillus Calmette Guérin; tumor eradication; Resistance; resistant; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; prototype; tumor; overexpression; overexpress; standard of care; phase 3 study; Phase III study; head-to-head comparison; head-to-head analysis; resistance gene; resistance locus; resistant gene; antitumor effect; anti-tumor effect; DNA cassette; enhancer cassette; expression cassette; gene cassette; genetic cassette; integration cassette; promoter cassette; reporter cassette; resistance cassette; selectable cassette; selection cassette; stop cassette; transcription cassette; transcriptional cassette; transgene cassette; recruit; anti-tumor immune response; antitumor immune response; Bacillus Calmette-Guerin Therapy; BCG immunotherapy; BCG therapy; BCG treatment; Bacillus Calmette Guérin immunotherapy; Bacillus Calmette Guérin therapy; Bacillus Calmette-Guerin Immunotherapy; intravesical BCG; Stimulator of Interferon Genes; cGAMP STING; cGAMP-STING; cGAMP/STING; cGAS/STING; overtreatment; over-treatment; effector T cell; Teff cell; non-muscle invasive bladder cancer; COVID-19; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019
