Liu, Wang, and Du et al. focused on preserving the immunotherapeutic efficacy of CTLA-4 immune checkpoint inhibitors while alleviating or preventing immune-related adverse events (irAEs) that can limit dosing regimens and reduce efficacy. They generated a series of variants of CTLA-4 as soluble Ig fusions that retained binding to B7-1 and B7-2, but lost binding to clinically used anti-CTLA-4 mAbs. Unlike abatacept (wild type CTLA-4-Ig), which neutralized the therapeutic effect of anti-CTLA-4 mAbs, CTLA-4 mutants, including clinically approved belatacept, abrogated irAEs without decreasing antitumor efficacy in mice treated with anti-CTLA-4 and/or anti-PD-1.
Contributed by Katherine Turner
ABSTRACT: Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.
Author Info: (1) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. (2) Division of Immunothe
Author Info: (1) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. (2) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. (3) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China. (4) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. OncoC4 Inc., Rockville, MD 20805, USA. (5) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Department of Immunology and Microbiology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China. (6) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing 100045, China. (7) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, China. (8) OncoC4 Inc., Rockville, MD 20805, USA. (9) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. OncoC4 Inc., Rockville, MD 20805, USA. (10) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. (11) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. Laboratory of Viral Pathogenesis and Immunotherapy, Divisions of Virology, Pathogenesis and Cancer and Immunotherapy, Institute of Human Virology and Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, USA. (12) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. OncoC4 Inc., Rockville, MD 20805, USA. (13) Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. OncoC4 Inc., Rockville, MD 20805, USA.
