Overcoming anti-PD-1 resistance by systemic delivery of an oncolytic adenovirus that targets TGF-beta

Project Summary The overall goal of this proposal is to test a novel systemic Adenoviral therapy that targets transforming growth factorTGFand reverses anti PDresistance to treat advanced breast and lung cancersThis STTR grant application illustrates the synergistic relationship between DrPrem Sethinventor of a novel TGFdecoyand MultiVir Inca leader in clinical development of gene based therapeuticsDrSeth has developed novel adenoviral vectors targeting TGFa well recognized but largely undruggable oncology targetIn additionhe has created a platform that can be delivered systemicallyand specifically targets oncolytic adenoviral vectors to tumorsThis oncolytic adenovirus vector has been engineered to reduce toxicity and the vector targets tumor cells via tumor specific peptideDrSeth has recently expanded his studies to examine if oncolytic adenoviruses targeting TGFcan overcome resistance to checkpoint inhibitor therapiesCKIsuch as PDCTLAAlthough clinical studies have demonstrated encouraging response rates and long term survival in some breast cancer patientsit is clear that most patients do not respond or develop resistance to CKIsBecause of the critical role that TGFplays in immunosuppressionangiogenesis and epithelial mesenchymal transitiona novel approach to overcoming CKI resistance would be to block TGFusing a decoy receptorWe will use two well characterized tumor modelsa mammary tumor and a lung cancer model in immunocompetent mice to conduct the following two Specific AimsIn Aimwe will examine if the intravenous administration of our vector results in reduced liver uptakeenhanced tumor uptake and targets TGFpathways in the tumors and tumor microenvironmentAimwill determine if the intravenous delivery of vector can enhance efficacy of anti PDmediated therapyand inhibit tumor growth and spontaneous metastases in an anti PDresistantTmouse mammary and Lewis lung cancer mouse mammary tumor modelWe believe that the pre clinical research described here is critical to bring our therapeutic vector forward to its clinical evaluationThe proposed research aligns with MultiVirandapos s research interestsMultiVir Incis highly supportive of this PhaseSTTR grant proposaland if successfulplans to continue our collaborations with DrSethleading to the conduct of IND enabling studies as part of potential Phaseproposal NARRATIVE This proposal describes the development of a noveltumor targeted TGFinhibitor delivered by adenoviral gene therapy that induces anti tumor immunity and reverses resistance to other immunotherapies termed immune checkpoint inhibitorsanti PDThe approach will initially be developed for the treatment of metastatic breast and lung cancersSuccessful completion of this project will lead to future clinical trials in breast and lung cancer patients with unmet medical needsThis drug candidate may also find future application in the treatment other types of cancers