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

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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 1 2016

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Lymphoma, Large B-Cell, Diffuse
Heterografts
Canidae
Lymphoma
Neoplasms
Phagocytosis
Neoplasm Antibodies
Therapeutics
Passive Immunization
Macrophage Activation
Antibodies
Immunotherapy
Clinical Trials
Dogs

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Eradication of canine diffuse large B-cell lymphoma in a murine xenograft model with CD47 blockade and anti-CD20. / Weiskopf, Kipp; Anderson, Katie L.; Ito, Daisuke; Schnorr, Peter J.; Tomiyasu, Hirotaka; Ring, Aaron M.; Bloink, Kristin; Efe, Jem; Rue, Sarah; Lowery, David; Barkal, Amira; Prohaska, Susan; McKenna, Kelly M.; Cornax, Ingrid; O'Brien, Timothy D.; O'Sullivan, M. Gerard; Weissman, Irving L.; Modiano, Jaime F.

In: Cancer Immunology Research, Vol. 4, No. 12, 01.12.2016, p. 1072-1087.

Research output: Contribution to journalArticle

Weiskopf, K, Anderson, KL, Ito, D, Schnorr, PJ, Tomiyasu, H, Ring, AM, Bloink, K, Efe, J, Rue, S, Lowery, D, Barkal, A, Prohaska, S, McKenna, KM, Cornax, I, O'Brien, TD, O'Sullivan, MG, Weissman, IL & Modiano, JF 2016, 'Eradication of canine diffuse large B-cell lymphoma in a murine xenograft model with CD47 blockade and anti-CD20', Cancer Immunology Research, vol. 4, no. 12, pp. 1072-1087. https://doi.org/10.1158/2326-6066.CIR-16-0105
Weiskopf, Kipp ; Anderson, Katie L. ; Ito, Daisuke ; Schnorr, Peter J. ; Tomiyasu, Hirotaka ; Ring, Aaron M. ; Bloink, Kristin ; Efe, Jem ; Rue, Sarah ; Lowery, David ; Barkal, Amira ; Prohaska, Susan ; McKenna, Kelly M. ; Cornax, Ingrid ; O'Brien, Timothy D. ; O'Sullivan, M. Gerard ; Weissman, Irving L. ; Modiano, Jaime F. / Eradication of canine diffuse large B-cell lymphoma in a murine xenograft model with CD47 blockade and anti-CD20. In: Cancer Immunology Research. 2016 ; Vol. 4, No. 12. pp. 1072-1087.
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AU - Schnorr, Peter J.

AU - Tomiyasu, Hirotaka

AU - Ring, Aaron M.

AU - Bloink, Kristin

AU - Efe, Jem

AU - Rue, Sarah

AU - Lowery, David

AU - Barkal, Amira

AU - Prohaska, Susan

AU - McKenna, Kelly M.

AU - Cornax, Ingrid

AU - O'Brien, Timothy D.

AU - O'Sullivan, M. Gerard

AU - Weissman, Irving L.

AU - Modiano, Jaime F.

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N2 - 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.

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