Design of a micro-RNA attenuated armed oHSV for the treatment of glioblastoma

The most aggressive form of brain malignanciesglioblastoma multiformeGBMrepresents a particularly acute unmet medical needGBM are highly invasive and do not respond to immune checkpoint inhibition due to their suppressive microenvironmentOncolytic viruses engineered to selectively replicate and kill malignant GBM cells and to express transgenes that stimulate antitumor immunity are attractive approaches to improve patient outcomes as monotherapy and in combination with anti PDtherapeuticsPreliminary data achieved with a prototypical oncolytic herpes simplex virusoHSVarmed with ULBPa ligand for KLRKa stimulatory receptor expressed in CDand NK cells and featuring the improvements in oncolytic potencymicro RNA attenuation and payload capacity designed by Oncorus demonstrated a significant survival benefit after a single intratumoral injection in a genetically inducible model of GBM designed to recapitulate the major genetic alterations and pathobiology of GBMMoreoverinjection of oHSV expressing ULBPin one tumor mass resulted in an abscopal anti tumor response in the uninjected tumor massThis result was surprising since the human specific ULBPgene product does not recognize the mouse KLRKreceptor and primarily acts through the recruitment of macrophages and microgliasuggesting a novel receptor for ULBPon these cells both in mouse and humanPreliminary studies identified tissue factora transmembrane receptor with a role in coagulation and signaling in GBM as this new receptorWe aim to investigate the mode of action of ULBPin GBM models and confirm this novel interactionWe propose to further exploit these initial findings for the design of an optimized armed oHSV for the treatment of GBMAs a first stepwe will tailor the unique safety features of Oncorus oHSVthe selection of micro RNA highly expressed in healthy brain tissues and lost in GBM to insert complementary micro RNA target sequences in multiple genes essential to HSV replicationthus restraining viral replication to malignant cellsMicroRNAandthat showed strong differential expression are likely candidatesAdditionallypayloadsincluding ILand PDand CDantagoniststhat have been validated in GBM preclinical modelsand that may complement the activity of ULBPwill be tested stepwise in GBM cell lines and tumor cells for oncolytic activityexpression and in vivo efficacy in syngeneic GBM models and in state of the art inducible genetic modelsFrom these data the optimized combination of payloads will be introduced into our oHSV in order to create the most potent vector and clinical candidate for future human trials!Our goal is to build the next generationarmed oncolytic HSV for the treatment of glioblastoma by optimizing the potencythe safety feature provided by micro RNA attenuation and the combination of immune stimulatory payloads