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Despite the sustained clinical benefit demonstrated by immune checkpoint inhibitors, a majority of patients derive minimal or no appreciable benefit, indicating the urgent need to incorporate novel immunomodulatory targets and therapeutic strategies. Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the first and rate-limiting step in the immunosuppressive tryptophan/kynurenine pathway and are both upregulated in a number of tumor types. Although small-molecule IDO1 inhibitors are being clinically evaluated in several tumor types, so far they have not demonstrated significant clinical benefits either as a single agent or in combination with immune checkpoint inhibition. We are developing pegylated kynureninase (Kynase), a kynurenine degrading enzyme, to treat a broader population with IDO1 and/or TDO2 expressing tumors. We believe that a more robust antitumor immune response can be achieved by depleting kynurenine, produced by both IDO1 and TDO2, with Kynase, than by inhibiting only IDO1. The human Kynase (HsKYN) has been successfully engineered to exhibit vastly improved catalytic activity and stability toward kynurenine over the wild-type human enzyme. HsKYN achieved durable and near complete plasma kynurenine depletion in mice, rats and non-human primates. HsKYN demonstrated single agent efficacy in CT26, MC38 and B16-IDO syngeneic mouse models. Tumor gene expression analysis using NanoString revealed that HsKYN treatment upregulated T-cell and NK cell activation signature. More importantly, HsKYN significantly increased the tumor-infiltrating CD8 T-cells and their activation/polyfunctionality, and reduced the Treg population. As a direct comparison, the lead IDO1 inhibitor epacadostat did not impose any meaningful effects on the same immune cell populations. Furthermore, HsKYN showed beneficial combination efficacy with anti-PD-1 that was superior to combined Epacadostat / anti-PD-1. Evidence to date suggest that HsKYN is well tolerated in multiple species. Therefore, immunoprofiling, efficacy and safety results strongly support that Kynase is a more effective therapeutic approach than IDO1 inhibition. HsKYN is moving toward clinical development for treatment of cancers where IDO1 and/or TDO2 pathways play a significant immunosuppressive role. Citation Format: Silvia Coma, Jillian Cavanaugh, James Nolan, Jeremy Tchaicha, Karen McGovern, Everett Stone, John Blazeck, Candice Lamb, George Georgiou, Mark G Manfredi, Michelle Zhang. Treatment of IDO1 and TDO2 positive tumors with a kynurenine-degrading enzyme: A highly differentiated approach from IDO1 inhibition [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B008.