Inhibition of Cancer Immune Suppression with a First-in-CIass Engineered Therapeutic Enzyme

摘要

Tumors inhibit immune responses largely through two mechanisms:(1)Through protein-protein interactions(e.g.PD1:PD~L1)and(2)By cancer-induced accumulation of immunosuppressive metabolites in the tumor microenvironment.The most potent such metabolite is the tryptophan-oxidation product kynurenine(Kyn)that induces tolerance through many mechanisms(e.g.promotes Treg differentiation and inhibits CD8+ T cell function)and promotes tumor survival and motility.Kyn is synthesized in vivo by three different enzymes: IDO1,IDO2,and TDO.Pharmacological blockade of the Kyn pathway is highly sought after,and three small molecule inhibitors of IDO1 are in clinical trials with TDO inhibitors expected to enter the clinic soon.However,because of the redundancy of the Kyn synthesis pathway,inhibition of IDO1 or TDO alone cannot eliminate Kyn accumulation,a fact underscored by the modest effects reported for inhibitors to date.Because Kyn acts in a paracrine fashion to inhibit immune,we saw an opportunity to eliminate the extracellular Kyn pool though a completely different mechanism-the systemic administration of a Kyn-degrading enzyme,kynureninase.