title: Eradication of Canine Diffuse Large B-Cell Lymphoma in a Murine Xenograft Model with CD47 Blockade and Anti-CD20.
abstract: Cancer immunotherapies hold much promise, but their potential in veterinary settings has not yet been fully appreciated. Canine lymphomas are among the most common tumors of dogs and bear remarkable similarity to human disease. In this study, we examined the combination of CD47 blockade with anti-CD20 passive immunotherapy for canine lymphoma. The CD47/SIRPα axis is an immune checkpoint that regulates macrophage activation. In humans, CD47 is expressed on cancer cells and enables evasion from phagocytosis. CD47-blocking therapies are now under investigation in clinical trials for a variety of human cancers. We found the canine CD47/SIRPα axis to be conserved biochemically and functionally. We identified high-affinity SIRPα variants that antagonize canine CD47 and stimulate phagocytosis of canine cancer cells in vitro When tested as Fc fusion proteins, these therapeutic agents exhibited single-agent efficacy in a mouse xenograft model of canine lymphoma. As robust synergy between CD47 blockade and tumor-specific antibodies has been demonstrated for human cancer, we evaluated the combination of CD47 blockade with 1E4-cIgGB, a canine-specific antibody to CD20. 1E4-cIgGB could elicit a therapeutic response against canine lymphoma in vivo as a single agent. However, augmented responses were observed when combined with CD47-blocking therapies, resulting in synergy in vitro and in vivo and eliciting cures in 100% of mice bearing canine lymphoma. Our findings support further testing of CD47-blocking therapies alone and in combination with CD20 antibodies in the veterinary setting. Cancer Immunol Res; 4(12); 1072-87. ©2016 AACR.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California. modiano@umn.edu kweiskopf@bwh.harvard.edu.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Katie L
authors.initials: KL
authors.lastname: Anderson
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ito
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schnorr
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Tomiyasu
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.|Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.affiliation: Elanco Animal Health US, Inc., Greenfield, Indiana.
authors.forename: Kristin
authors.initials: K
authors.lastname: Bloink
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Jem
authors.initials: J
authors.lastname: Efe
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California.
authors.forename: Sarah
authors.initials: S
authors.lastname: Rue
authors.affiliation: Elanco Animal Health US, Inc., Greensboro, North Carolina.
authors.forename: David
authors.initials: D
authors.lastname: Lowery
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Amira
authors.initials: A
authors.lastname: Barkal
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Susan
authors.initials: S
authors.lastname: Prohaska
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McKenna
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Cornax
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota.|Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: O'Brien
authors.affiliation: Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Department of Veterinary Population Medicine, University of Minnesota, St. Paul, Minnesota.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.|Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California.|Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota, St. Paul, Minnesota. modiano@umn.edu kweiskopf@bwh.harvard.edu.|Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.|Center for Immunology, University of Minnesota, Minneapolis, Minnesota.|Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jaime F
authors.initials: JF
authors.lastname: Modiano
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000276:immunology*; D051928:CD47 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D004285:Dogs; D005260:Female; D007074:Immunoglobulin G / Q000627:therapeutic use; D007167:Immunotherapy; D016403:Lymphoma, Large B-Cell, Diffuse / Q000276:immunology / Q000628:therapy* / Q000662:veterinary; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D010587:Phagocytosis; D023041:Xenograft Model Antitumor Assays
chemical_list: D018951:Antigens, CD20; D051928:CD47 Antigen; D007074:Immunoglobulin G