1. Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions
- Author
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Juha Punnonen, Lakshmanan Annamalai, Edward P. Bowman, Peng Yang, Drake LaFace, Jennifer H. Yearley, Anandi Sawant, Alissa A. Chackerian, Smita Mauze, Jeff Grein, Wendy M. Blumenschein, David Bauché, Yulia Zybina, and Christina Kochel
- Subjects
CTLA-4 antigen ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Programmed Cell Death 1 Receptor ,Immunology ,Inflammation ,chemical and pharmacologic phenomena ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Adverse effect ,RC254-282 ,Clinical/Translational Cancer Immunotherapy ,Enterocolitis ,biology ,business.industry ,Melanoma ,Antagonist ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Immunotherapy ,medicine.disease ,Blockade ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,biology.protein ,Molecular Medicine ,immunotherapy ,medicine.symptom ,Antibody ,business - Abstract
BackgroundProgrammed 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.MethodsWe have developed a mouse model of checkpoint blockade-mediated enterocolitis via prolonged administration of an Fc-competent anti-CTLA4 antibody.ResultsSustained 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.ConclusionThese 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.
- Published
- 2020