2. Academic Validation
  3. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme

Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme

  • Nat Biotechnol. 2018 Sep;36(8):758-764. doi: 10.1038/nbt.4180.
Todd A Triplett 1 2,  Kendra C Garrison 3,  Nicholas Marshall 3 4,  Moses Donkor 3 5,  John Blazeck 3,  Candice Lamb 3,  Ahlam Qerqez 3,  Joseph D Dekker 3,  Yuri Tanno 3,  Wei-Cheng Lu 3,  Christos S Karamitros 3,  Kyle Ford 3,  Bing Tan 3,  Xiaoyan M Zhang 6,  Karen McGovern 6,  Silvia Coma 6,  Yoichi Kumada 7,  Mena S Yamany 3,  Enrique Sentandreu 8,  George Fromm 9,  Stefano Tiziani 8,  Taylor H Schreiber 9,  Mark Manfredi 6,  Lauren I R Ehrlich 1,  Everett Stone 1,  George Georgiou 1 2 3
Affiliations

Affiliations

  • 1 Department of Molecular Biosciences, University of Texas at Austin (UT Austin), Austin, Texas, USA.
  • 2 Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, Texas, USA.
  • 3 Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, USA.
  • 4 Merck Research Laboratories, Rahway, New Jersey, USA.
  • 5 MedImmune LLC, Gaithersburg, Maryland, USA.
  • 6 Kyn Therapeutics, Cambridge, Massachusetts, USA.
  • 7 Department of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Kyoto, Japan.
  • 8 Department of Nutritional Sciences, University of Texas at Austin, Austin, Texas, USA.
  • 9 Heat Biologics Inc., Durham, North Carolina, USA.
PMID: 30010674 DOI: 10.1038/nbt.4180
Abstract

Increased tryptophan (Trp) catabolism in the tumor microenvironment (TME) can mediate immune suppression by upregulation of interferon (IFN)-γ-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.

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