O-Glycan-dependent Immunotherapy for Cancer

Abstract For decadesthe treatment of cancer has relied on surgical resectionchemotherapy and or radiotherapyRecentlya number of immune based therapies have provided promising new approaches for cancer treatmentThe two most potent immunotherapies are monoclonal antibodymABbased bi specific proteinseg Bispecific T cell engagersBiTEand engineered Chimeric Antigen Receptor T cellsCAR TBoth act by inducing T cell mediated killing of cancer cells and have shown remarkable clinical activitywith complete response rates as high asfor B cell malignanciesHoweverapplying these two therapeutic approaches to the vast majority of cancer types is prevented by multiple factorsFirstthere are only a small number of known cell surface proteins that are sufficiently specific to cancer to safely allow targeting by antibodiesThis is particularly true for solid cancerswhere unlike hematopoietic malignanciesloss of healthy cells cannot be readily replenished by stem cell progenitorsSecondas each individual bi specific protein and or CAR T cell can only target a single cancer typedifferent bi specific and or CAR T cells will need to be developed for each cancer typeThis greatly increases development time and costsThirdneither therapy is able to effectively target the most abundant and widely expressed cancer antigens knownnamely Tumor associated cancer antigensTACAandapos sMany cancer specific antigens are not proteinsbut rather complex carbohydrates that have limited or no expression in normal tissuesIndeedaltered glycosylation is a near universal feature of cancerHowevergeneration of monoclonal antibodies specific to complex carbohydrates has proven to be very challenginggreatly limiting their usefulness as targets for cancer immunotherapyHere we propose to address these issues and develop a novel class of immunotherapeutics that target a carbohydrate antigen common to the vast majority of solid and hematopoietic cancers but not expressed in normal cellsWe have termed these molecules as Glycan dependent T cell RecruiterGlyTRtechnologyCriticallyGlyTR technology does not utilize antibodies to target carbohydrate cancer antigensPreliminary data demonstrates that an O linked carbohydrate targeted bi specific GlyTR protein induces T cell dependent killing of human cancer cells in vitro without off target killing of normal cellsTo further develop this technologywe propose the following AimsAimoptimizes an O linked glycan targeted GlyTR bi specific protein for activity and drug developmentAimexplores the efficacy and safety of the optimized O linked glycan targeted GlyTR bi specific proteinIf successfulthis work will lead to IND enabling studies of an entire new class of immunotherapeutic cancer killing therapeutics that can target multiple solid and hematopoietic cancers with minimal toxicity Project NarrativeImmunotherapy using monoclonal antibodies has been recently developed as a promising approach to treat cancerAlterations in the addition of carbohydrates to proteins is a near universal feature of cancerbut is not targeted by current immunotherapiesHere we examine the possibility of a novel technology that directs immune cells to kill cancer cells based on expression of altered carbohydrates