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Published on: August 15, 2019
Cross-Reactivity and Functionality of Approved Human Immune Checkpoint Blockers in Dogs
Stanislav Pantelyushin1,2, Elisabeth Ranninger3, Diego Guerrera1
1Institute of Laboratory Animal Science, University of Zurich, CH-8952 Schlieren, Switzerland.
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.
Insights
Companion dogs offer a valuable model for human cancer immunotherapies. Atezolizumab, an immune checkpoint inhibitor (ICI), showed promise by increasing cytokine production in canine cells, suggesting potential for veterinary and human cancer treatment.
Area of Science:
- Comparative oncology
- Immunotherapy research
- Translational medicine
Background:
- Rodent cancer models inadequately predict human immunotherapy outcomes.
- Companion dogs with cancer are a relevant translational model for human immunotherapies.
- Existing veterinary treatments lack effective immune checkpoint inhibitors (ICIs).
Purpose of the Study:
- To evaluate FDA-approved human ICIs for targeting canine CTLA-4 or PD-1/PD-L1.
- To assess the cross-reactivity and functional efficacy of these ICIs in canine immune cells.
- To identify potential ICIs for veterinary cancer immunotherapy.
Main Methods:
- Tested seven human ICIs for cross-reactivity and blocking potential against canine PD-1/PD-L1 using ELISA and flow cytometry.
- Assessed functional immune responses by measuring cytokine production from canine peripheral blood mononuclear cells (PBMCs) after stimulation.
- Analyzed immune cell composition and target expression in healthy dogs and cancer patients.
Main Results:
- Four ICIs demonstrated cross-reactivity, and two successfully blocked canine PD-1/PD-L1 interactions.
- Atezolizumab significantly enhanced cytokine production in PBMCs from both healthy dogs and cancer patients in vitro.
- Enhanced cytokine production was particularly notable in lymphoma patients; other cancers showed correlation with lower CD8 T cell frequency.
Conclusions:
- Atezolizumab exhibits cross-functionality, supporting its use in canine cancer patients.
- This finding encourages reverse translational research using atezolizumab and combination immunotherapies.
- Successful canine trials could advance both veterinary and human cancer treatment strategies.
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