In the TME, tryptophan (Trp) is catabolized by IDO1 and TDO into kynurenine (Kyn) at an increased rate, leading to immune suppression. To determine whether Kyn accumulation was responsible for this effect, Triplett et al. used pegylated bacterial KYNases to break down Kyn into an inert metabolite. In vitro, the PEG-KYNase reversed Kyn-induced cell death of activated T cells. In various murine tumor models, the enzyme led to enhanced CD8+ T cell infiltration, proliferative capacity, polyfunctionality, and cytotoxicity, and improved survival time and complete response rates, especially in combination with anti-PD-1, anti-CTLA-4, or a cancer vaccine.
Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-gamma-inducible indoleamine 2,3-dioxygenase (IDO1) and/or ectopic expression of the predominantly liver-restricted enzyme tryptophan 2,3-dioxygenase (TDO). Whether these effects are due to Trp depletion in the TME or mediated by the accumulation of the IDO1 and/or TDO (hereafter referred to as IDO1/TDO) product kynurenine (Kyn) remains controversial. Here we show that administration of a pharmacologically optimized enzyme (PEGylated kynureninase; hereafter referred to as PEG-KYNase) that degrades Kyn into immunologically inert, nontoxic and readily cleared metabolites inhibits tumor growth. Enzyme treatment was associated with a marked increase in the tumor infiltration and proliferation of polyfunctional CD8(+) lymphocytes. We show that PEG-KYNase administration had substantial therapeutic effects when combined with approved checkpoint inhibitors or with a cancer vaccine for the treatment of large B16-F10 melanoma, 4T1 breast carcinoma or CT26 colon carcinoma tumors. PEG-KYNase mediated prolonged depletion of Kyn in the TME and reversed the modulatory effects of IDO1/TDO upregulation in the TME.
Author Info: (1) Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA. Department of Oncology, University of Texas Dell Medical School, LiveSTRONG
Author Info: (1) Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA. Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, Texas, USA. (2) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (3) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. Merck Research Laboratories, Rahway, New Jersey, USA. (4) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. MedImmune LLC, Gaithersburg, Maryland, USA. (5) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (6) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (7) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (8) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (9) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (10) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (11) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (12) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (13) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (14) Kyn Therapeutics, Cambridge, Massachusetts, USA. (15) Kyn Therapeutics, Cambridge, Massachusetts, USA. (16) Kyn Therapeutics, Cambridge, Massachusetts, USA. (17) Department of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan. (18) Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA. (19) Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA. (20) Heat Biologics Inc., Durham, North Carolina, USA. (21) Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA. (22) Heat Biologics Inc., Durham, North Carolina, USA. (23) Kyn Therapeutics, Cambridge, Massachusetts, USA. (24) Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA. (25) Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA. (26) Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA. Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, Texas, USA. Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
