Journal for ImmunoTherapy of Cancer (Oct 2020)

Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions

  • Peng Yang,
  • Wendy Blumenschein,
  • David Bauché,
  • Smita Mauze,
  • Christina Kochel,
  • Jeff Grein,
  • Anandi Sawant,
  • Yulia Zybina,
  • Lakshmanan Annamalai,
  • Jennifer H Yearley,
  • Juha Punnonen,
  • Edward P Bowman,
  • Alissa Chackerian,
  • Drake Laface

DOI
https://doi.org/10.1136/jitc-2020-001584
Journal volume & issue
Vol. 8, no. 2

Abstract

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Background Programmed cell death protein 1 (PD-1) and CTLA4 combination blockade enhances clinical efficacy in melanoma compared with targeting either checkpoint alone; however, clinical response improvement is coupled with increased risk of developing immune-related adverse events (irAE). Delineating the mechanisms of checkpoint blockade-mediated irAE has been hampered by the lack of animal models that replicate these clinical events.Methods We have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.Results Sustained treatment with Fc-effector, but not Fc-mutant or Fc-null, anti-CTLA4 antagonist for 7 weeks resulted in enterocolitis. Moreover, combining Fc-null or Fc-mutant CTLA4 antagonists with PD-1 blockade results in potent antitumor combination efficacy indicating that Fc-effector function is not required for combination benefit.Conclusion These data suggest that using CTLA4 antagonists with no Fc-effector function can mitigate gut inflammation associated with anti-CTLA4 antibody therapy yet retain potent antitumor activity in combination with PD-1 blockade.