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. Since 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.

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…Alternative strategies have been investigated including targeted blocking of SIRPα with engineered high affinity CD47 ectodomain or development of bispecific antibody targeting both CD47 and tumor-associated antigen [102][101]. To minimize possible off-target toxicity, anti-CD47 antibody may be developed using the Fc scaffold of IgG4 to reduce Fc effector functions, or the engineered SIRPα without Fc fusion may be used in combination with Fc-active tumor-targeted antibodies [100][103]. …”

The histone deacetylase inhibitor panobinostat is a potent antitumor agent in canine diffuse large B-cell lymphoma

“…Therefore, efforts towards bringing together veterinary and human medicine for the comparative research of cancer are being pursued [ 6 ]. These initiatives are also motivated by the increasing healthcare standards demanded by pet owners, originating the need for novel cancer therapies in veterinary settings [ 7 – 9 ]. One of the most common neoplasias in both species is non-Hodgkin lymphoma (NHL), an heterogeneous group of cancers characterized by the proliferation of malignant lymphocytes [ 10 , 11 ].…”

Targeting NEDD8‐activating enzyme is a new approach to treat canine diffuse large B‐cell lymphoma

“…Within a 2‐week period, the xenograft tumours reached ~300 mm 3 at all injection sites and mice bearing the xenograft tumour were able to maintain acceptable quality of life without treatment. Consistent with previous canine DLBCL xenograft models, evaluation of the size of xenograft tumours provides an easy way to monitor the tumour growth, regression and regrowth throughout the treatment period. Thus, our study provides a great mouse model for future drug screening or mechanism studies.…”