Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions
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). Delineati...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2020-10-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001584.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846172501153939456 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Peng Yang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1bda0443d10a44cca19b501ab433abcf |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-1bda0443d10a44cca19b501ab433abcf2024-11-10T00:55:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001584Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactionsPeng Yang0Wendy Blumenschein1David Bauché2Smita Mauze3Christina Kochel4Jeff Grein5Anandi Sawant6Yulia Zybina7Lakshmanan Annamalai8Jennifer H Yearley9Juha Punnonen10Edward P Bowman11Alissa Chackerian12Drake Laface13Department of Gastroenterology, The Affiliated Changzhou No. 2 People’s Hospital of Nanjing Medical University, Changzhou, ChinaAff2 grid.417993.10000000122600793Merck Research Laboratories Palo Alto CA USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USADiscovery, Preclinical and Translational Medicine, Merck & Co Inc, South San Francisco, California, USADiscovery Oncology, Merck & Co. Inc, South San Francisco, California, USA2 Molecular Discovery, Merck & Co. Inc, South San Francisco, California, USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA2 Molecular Discovery, Merck & Co. Inc, South San Francisco, California, USA3 Anatomic Pathology, Merck & Co. Inc, South San Francisco, California, USA3 Anatomic Pathology, Merck & Co. Inc, South San Francisco, California, USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USA1 Discovery Oncology, Merck & Co. Inc, South San Francisco, California, USABackground 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.https://jitc.bmj.com/content/8/2/e001584.full |
| spellingShingle | 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 Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions Journal for ImmunoTherapy of Cancer |
| title | Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions |
| title_full | Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions |
| title_fullStr | Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions |
| title_full_unstemmed | Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions |
| title_short | Antitumor efficacy of combined CTLA4/PD-1 blockade without intestinal inflammation is achieved by elimination of FcγR interactions |
| title_sort | antitumor efficacy of combined ctla4 pd 1 blockade without intestinal inflammation is achieved by elimination of fcγr interactions |
| url | https://jitc.bmj.com/content/8/2/e001584.full |
| work_keys_str_mv | AT pengyang antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT wendyblumenschein antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT davidbauche antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT smitamauze antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT christinakochel antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT jeffgrein antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT anandisawant antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT yuliazybina antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT lakshmananannamalai antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT jenniferhyearley antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT juhapunnonen antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT edwardpbowman antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT alissachackerian antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions AT drakelaface antitumorefficacyofcombinedctla4pd1blockadewithoutintestinalinflammationisachievedbyeliminationoffcgrinteractions |