Eradication of canine diffuse large B-cell lymphoma in a murine xenograft model with CD47 blockade and anti-CD20

Kipp Weiskopf, Katie L. Anderson, Daisuke Ito, Peter J. Schnorr, Hirotaka Tomiyasu, Aaron M. Ring, Kristin Bloink, Jem Efe, Sarah Rue, David Lowery, Amira Barkal, Susan Prohaska, Kelly M. McKenna, Ingrid Cornax, Timothy D. O'Brien, M. Gerard O'Sullivan, Irving L. Weissman, Jaime F. Modiano

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 highaffinity 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 singleagent 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.

Original languageEnglish (US)
Pages (from-to)1072-1087
Number of pages16
JournalCancer Immunology Research
Volume4
Issue number12
DOIs
StatePublished - Dec 2016

Bibliographical note

Funding Information:
Research reported in this article was supported by grants F30 CA168059 (to K. Weiskopf), F30 CA195973 (to K.L. Anderson), P01 CA139490 (to I.L. Weissman), P30 CA077598 (Comprehensive Cancer Center Support Grant to the Masonic Cancer Center, University of Minnesota), and the Stanford Medical Scientist Training Program T32 GM07365 (to K. Weiskopf, A.M. Ring, and A. Barkal) from the NIH, grants D13CA-033 (to J.F. Modiano) and D12CA-302 (to D. Ito) from Morris Animal Foundation, the Stanford University SPARK Program (to K. Weiskopf and A.M. Ring), the Joseph & Laurie Lacob Gynecologic/Ovarian Cancer Fund (to I.L. Weissman), the Virginia and DK Ludwig Fund for Cancer Research (to I.L. Weissman), an Anonymous Donors Fund (to I.L. Weissman), the Siebel Stem Cell Institute (to I.L. Weissman), the Thomas and Stacey Siebel Foundation (to I.L. Weissman), and the Skippy Frank Fund for Life Sciences and Translational Research (to I.L. Weissman and J.F. Modiano). J.F. Modiano is supported by the Alvin and June Perlman Chair in Animal Oncology, University of Minnesota College of Veterinary Medicine.

Publisher Copyright:
© 2016 AACR.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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