Development of a T cell-targeted TGF-b antagonist that reverses immune suppression in melanoma patients

PROJECT SUMMARY ABSTRACT SYNTHIS SBIR PH ISynthisLLC is an early stageNew York based biotech company developing a novel immuno oncologyIOtherapeutic to treat metastatic melanoma patientsThe immune checkpoint inhibitorsanti PDPDLare first line therapies for melanomabut the majority of these patientsare not responsiveleaving a large unmet need in this cancer populationTGFis a pro tumorigenic cytokine that drives cancer developmentin partby promoting angiogenesisdriving epithelial to mesenchymal transition and suppressing the immune systemGeneral TGFantagonists have been developed as cancer therapeuticsbut have two serious issuesserious host tissue toxicity due to broad TGFreceptor expression on normal tissues andpotential to increase tumor development due to paradoxical effects on the tumor and surrounding microenvironmentTogetherthis has led to a small therapeutic window for TGFantagonists and limited patient responsesTo bypass these negative consequences associated with broad TGFinhibitionSynthis has generated a T cell targeted TGFantagonistT Ato selectively reverse TGFmediated immune suppression and restore mediated tumor clearanceIn this Phase SBIR grantwe will determine the efficacy of T A in combination with anti PDagainst melanoma tumors in vitro and in vivoIn Specific AimT AantiPDwill be tested for their ability to restore immune mediated tumor cell killing in the presence of TGFwith corresponding effector function analysisi etumor specific T cell expansionTo investigate potential adverse eventsthe levels of several proinflammatory cytokinessuch as TNFILand ILwill be measured following treatmentIn Specific AimT A will be tested in an in vivo human patient derived xenograftPDXmelanoma model for tumor regression and corresponding intratumoral immune infiltratesA successful outcome is afold increase in tumor cell cytotoxicity compared to untreated cells in vitro and afold increase in tumor infiltrating immune cells ortumor regression in vivoThese studies validate the feasibility of developing a T A as an IO therapy and are the prerequisite for pursuing combination in vivo PDX studies with checkpoint inhibitors in Phase IIVirtually every tumor typeincluding melanomahas increased TGFlevelswhich correlates with worse prognosisAdvanced melanoma is our first indication since many patients fail immune checkpoint blockade and new options are required to address this unmet needWith nearlynew melanoma cases annuallythe melanoma market is forecasted to be $billion bywith the immune checkpoint inhibitors accounting for $billionT A will provide new treatment options for melanoma patients in combination with immune checkpoint inhibitors as well as for refractory relapsed patient populations SBIR PHASE I PROJECT NARRATIVE Synthis is an early stage biotech company focused on developing innovative immune oncology therapeutics to treat advanced melanoma patientsIn this Phase I SBIRSynthis is developing a proprietary antibody drug conjugateADCthat reverses immune suppression and restores tumor clearance in melanoma patients