Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs

Abstract

Background: Rodent cancer models have limitations in predicting efficacy, tolerability and accompanying biomarkers of ICIs in humans. Companion dogs suffering from neoplastic diseases have gained attention as a highly relevant translational disease model. Despite successful reports of PD-1/PD-L1 blockade in dogs, no compounds are available for veterinary medicine. Methods: Here, we assessed suitability of seven FDA-approved human ICIs to target CTLA-4 or PD-1/PD-L1 in dogs. Cross-reactivity and blocking potential was assessed using ELISA and flow cytometry. Functional responses were assessed on peripheral blood mononuclear cells (PBMCs) derived from healthy donors (n = 12) and cancer patient dogs (n = 27) as cytokine production after stimulation. Immune composition and target expression of healthy donors and cancer patients was assessed via flow cytometry. Results: Four candidates showed cross-reactivity and two blocked the interaction of canine PD-1 and PD-L1. Of those, only atezolizumab significantly increased cytokine production of healthy and patient derived PBMCs in vitro. Especially lymphoma patient PBMCs responded with increased cytokine production. In other types of cancer, response to atezolizumab appeared to correlate with a lower frequency of CD8 T cells. Conclusions: Cross-functionality of atezolizumab encourages reverse translational efforts using (combination) immunotherapies in companion dog tumor patients to benefit both veterinary and human medicine.

Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer

“…Most canine tumors express PD-L1 constitutively and both innate and adaptive immune stimuli can further upregulate PD-L1 expression. 47 48 We expect that combining in situ eCPMV immunotherapy with crossfunctional human anti-PD-L1 inhibitors 49 or canine anti-PD-1/PD-L1 inhibitors, as they become available, 48 50 will result in higher efficacy than single agent used as monotherapy. We have demonstrated that in situ eCPMV synergizes with systemic checkpoint immunotherapy in various mouse models.…”

Canine melanoma: A review of diagnostics and comparative mechanisms of disease and immunotolerance in the era of the immunotherapies

“…Furthermore, the expression of these checkpoint molecules has also been reported by our laboratory as increased in melanoma when compared with its benign counterpart melanocytoma and is associated with the density of CD3+ TILs (139). Recently, a group tested the cross-reactivity of different FDA-approved human immune checkpoint inhibitors (ICI) in canine tissue, showing two anti PD-L1 (Atezolizumab and Avelumab) with cross-reactivity, and Atezolizumab with the most robust T-cell cytokine production in vitro (140). A schematic representation of the immunotherapies in canine cancers is shown in Figure 3B.…”

Defucosylated mouse‑dog chimeric anti‑HER2 monoclonal antibody exerts antitumor activities in mouse xenograft models of canine tumors

“…Therefore, H77B-drug conjugate is one more option to treat dHER2-positive CMT. Recently, FDA-approved human immune checkpoint inhibitor against PD-1 and PD-L1 are used in canine tumor treatment (72)(73)(74); the combination of immune checkpoint inhibitors with other antibody-drugs is expected to be more effective. H77Bf could contribute to the development of canine cancer treatment, which can be feedback for human cancer treatment.…”