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      Preclinical evaluation of VAX-IP, a novel bacterial minicell-based biopharmaceutical for nonmuscle invasive bladder cancer

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          Abstract

          The development of new therapies that can prevent recurrence and progression of nonmuscle invasive bladder cancer remains an unmet clinical need. The continued cost of monitoring and treatment of recurrent disease, along with its high prevalence and incidence rate, is a strain on healthcare economics worldwide. The current work describes the characterization and pharmacological evaluation of VAX-IP as a novel bacterial minicell-based biopharmaceutical agent undergoing development for the treatment of nonmuscle invasive bladder cancer and other oncology indications. VAX-IP minicells selectively target two oncology-associated integrin heterodimer subtypes to deliver a unique bacterial cytolysin protein toxin, perfringolysin O, specifically to cancer cells, rapidly killing integrin-expressing murine and human urothelial cell carcinoma cells with a unique tumorlytic mechanism. The in vivo pharmacological evaluation of VAX-IP minicells as a single agent administered intravesically in two clinically relevant variations of a syngeneic orthotopic model of superficial bladder cancer results in a significant survival advantage with 28.6% ( P = 0.001) and 16.7% ( P = 0.003) of animals surviving after early or late treatment initiation, respectively. The results of these preclinical studies warrant further nonclinical and eventual clinical investigation in underserved nonmuscle invasive bladder cancer patient populations where complete cures are achievable.

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          Most cited references43

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          Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update.

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            Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer.

            Intravesical therapy with bacillus Calmette-Guerin (BCG) has proved to be more effective in the prophylaxis and treatment of superficial bladder tumors and carcinoma in situ than most chemotherapeutic agents. Compared to intravesical chemotherapy, instillations with BCG provoke more local and systemic reactions. In addition to the commonly induced granulomatous inflammatory changes in the bladder, which produce irritative symptoms, this therapy may cause systemic side effects varying from mild malaise and fever to, in rare instances, life-threatening or fatal sepsis. We report the incidence and varieties of toxicities in 2,602 patients treated with intravesical BCG. Side effects are classified according to local and systemic toxicity. Treatment options vary according to the severity of toxicity from delaying or withholding instillations to treatment with antituberculous drugs for up to 6 months. In general, 95% of the patients have no serious side effects. Recognition of risk factors, particularly traumatic catheterization or concurrent cystitis, that result in systemic BCG absorption, as well as the prompt and appropriate treatment of early side effects should significantly decrease the incidence of severe toxicity.
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              Multiple β1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells

              Mammalian cell receptors that promote entry of intracellular bacteria into nonphagocytic cells have not been identified. We show here that multiple members of the integrin superfamily of cell adhesion receptors bind the Y. pseudotuberculosis invasin protein prior to bacterial penetration into mammalian cells. Affinity chromatography of crude detergent extracts demonstrated that integrins containing the subunit structures alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1 bound to immobilized invasin. Furthermore, phospholipid vesicles containing isolated integrin proteins were able to attach to invasin. Specificity for invasin binding to the identified integrin receptors was also demonstrated, as immunoprobing and phospholipid reconstitution studies showed that the alpha 2 beta 1 integrin, beta 2 chain integrins, and vitronectin receptor (alpha v beta 3) were not involved in cellular attachment to invasin.
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                Author and article information

                Journal
                Mol Ther Oncolytics
                Mol Ther Oncolytics
                Molecular Therapy Oncolytics
                Nature Publishing Group
                2372-7705
                16 March 2016
                2016
                : 3
                : 16004
                Affiliations
                [1 ]Vaxiion Therapeutics , San Diego, California, USA
                [2 ]Department of Chemical & Biomolecular Engineering, Tulane University , New Orleans, Louisiana, USA
                Author notes
                Article
                mto20164
                10.1038/mto.2016.4
                4824562
                27119118
                df66f4c5-7ae9-43cb-83bc-f5ed470b9cce
                Copyright © 2016 Official journal of the American Society of Gene & Cell Therapy

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

                History
                : 14 August 2015
                : 08 January 2016
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