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
  • 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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