Oncolytic virus-mediated target delivery of a therapeutic antibody fragment in glioblastoma

PROJECT SUMMARY More thanpatients are diagnosed each year with glioblastomathe most common primary brain tumorCurrent treatments are inadequate and there have been no major therapeutic breakthroughs in decadesHencethere is an urgent need to develop novel strategies to address this devastating diseaseHoweverdevelopment of an effective treatment for glioblastoma is severely hampered bythe blood brain barrierBBBan infiltrative growth patternrapid development of therapeutic resistanceandin many casesdose limiting toxicity due to systemic exposureTo overcome these challengesOncoSynergyIncin collaboration with DrBalveen KaurUniversity of Texas Houstonis developing a novel therapeutic delivery approach to address each of these hurdlesThis approach consists of a herpes simplex virus typebased oncolytic virusHSVthat expresses an anti CDaCDantibody fragment and intracranial administration to the tumor and or tumor infiltrated brainTIBvia convection enhanced deliveryCEDMany HSV vectors have been generated and are currently being tested at different stages in clinical trials for glioblastomaHowevercomplete responses or therapeutic efficacy have rarely been observedindicating significant improvements in HSV therapy are necessaryRemarkablyour recent study showed that CDblockade using OSa humanized anti CDmonoclonal antibodyenhances the efficacy of HSV in an orthotopic xenograft model of glioblastomaSpecificallyOStreatment decreases interferon signaling and proinflammatory cytokine induction in HSV treated tumor cells and inhibits migration of macrophagesresulting in enhanced HSV replication and cytotoxicityIntratumoral OStreatment also significantly enhances HSV replication and HSV mediated anti tumor efficacy in orthotopic xenograft model of glioblastomaImportantlyOSis FDA Orphan Drug designated in the treatment of glioblastoma andin MarchOncoSynergy has received IND clearance of OSby the FDA as a monotherapy in recurrent glioblastomaINDHencelogically extend our studieswe propose to develop a novel HSV mediated delivery systemi eHSV encoding a fragment of OSwhich will be secreted outside viral infected tumor cellsto precisely enhance the synergistic effects of HSV and CDblockadeWe will engineer an HSV encoding a fragment of OSHSV aCDand determine in vitro and in vivo efficacy of HSV aCDThe successful completion of this Phase I STTR project will result in the generation of a multimodal therapeutic approach empowered by a novel HSV mediated drug delivery system for the treatment of glioblastomaBuilding on this milestoneour Phase II STTR project will further optimize this novel treatment regime in preclinical glioblastoma models and pursue IND enabling studies to support IND submission PROJECT NARRATIVE Current treatments of glioblastoma are inadequate and there have been no major therapeutic breakthroughs in decades due to many hurdlesincluding the blood brain barrieran infiltrative tumor growth patternrapid development of therapeutic resistanceandin many casesdose limiting toxicity due to systemic exposureHenceto overcome these challengesOncoSynergyIncis developing a novel therapeutic delivery approach to improve the treatment outcomes of glioblastoma