Exploring the Landscape of Immunotherapy for Canine Osteosarcoma

The survival rate for dogs with appendicular osteosarcoma – bone cancer of the limbs – has not changed significantly over the past 30 years. The cancer has usually spread to other parts of the body when the primary tumor is diagnosed. Only 20% of dogs are still living two years after diagnosis and amputation of the affected limb. AKC Canine Health Foundation (CHF) funded researchers at the University of California, Davis are working to improve the statistics for dogs with osteosarcoma through the exploration of immunotherapy.

Immunotherapy stimulates or suppresses the body’s own immune system in order to help fight cancer, infection, or other diseases. Evidence that the immune system could combat osteosarcoma was noted when dogs suffering post-operative infections following limb-sparing surgery* fared better than those with no post-op infection. Did the increased activity of the immune system, stimulated by bacterial infection, delay metastasis in these dogs? Several studies examining immunotherapeutic targets for canine osteosarcoma are underway, but we lack information on the immune cells present within the bone tumor microenvironment. Dr. Sita Withers received a CHF Clinician-Scientist Fellowship in 2018 to study the immune microenvironment in canine osteosarcoma and evaluate the possible association between immune cell tumor infiltrates and clinical outcome. Her research was recently published in the journal Veterinary and Comparative Oncology.¹

Dr. Withers and her team conducted a prospective study of the disease-free interval† (DFI) and overall survival time‡ (ST) in 30 dogs with appendicular osteosarcoma treated with amputation and six doses of the chemotherapy drug carboplatin. She used immunohistochemistry (IHC), a special tissue staining technique, to quantify the lymphocyte and macrophage infiltrates (two types of white blood cells) within the primary tumors and then evaluated any associations between these infiltrates and clinical outcomes. Results showed that macrophages were abundant in the canine osteosarcoma tumors studied and a greater infiltration of macrophages was associated with a prolonged DFI. Of note, tumors of the proximal humerus, which are known to carry a worse prognosis, had less pronounced macrophage infiltration. This indicates that macrophage infiltration alone may not determine prognosis, but perhaps differences in the tumor microenvironment between body sites are a factor in the different clinical outcomes seen. Overall, these results show that macrophages may play a role in osteosarcoma progression and pathways involved in their recruitment and activation are viable targets for immunotherapy.

CHF and its donors are committed to improving outcomes for dogs with osteosarcoma. Studies like the one described here will help us understand the canine immune response to cancer and guide the development of immunotherapeutic agents to augment the current standard of care. Since canine osteosarcoma shares many characteristics with human osteosarcoma, seen mostly in people less than 20 years of age, this research has the potential to benefit dogs and humans affected by this disease. CHF’s Canine Cancer Research Initiative provides a renewed focus to advance our understanding of cancer and improve the health of all dogs. Support canine cancer research at www.akcchf.org/cancer.

* Limb-sparing surgery as a treatment for canine osteosarcoma involves removing only the affected portion of bone, instead of amputating the entire limb. Bone plate fixation, bone graft placement, and/or bone distraction techniques stabilize the leg in place of the diseased bone.
† Disease-free interval was defined as time from amputation to documented or suspected metastasis or death from any cause.
‡ Overall survival time was defined as time from amputation to death from any cause.

1. Withers SS, Skorupski KA, York D, et al. Association of macrophage and lymphocyte infiltration with outcome in canine osteosarcoma. Vet Comp Oncol. 2019;17:49–60.
https://doi.org/10.1111/vco.12444

UPDATE:

Dr. Withers and her research team also explored the immune environment in metastatic canine osteosarcoma. They found that metastatic osteosarcoma lesions are infiltrated by the same types of immune cells present in the primary tumor, but in greater quantities. This means that immune cell infiltrates and biomarkers identified in a primary osteosarcoma tumor could be used to determine the most appropriate immunotherapy for that patient’s metastatic disease.

Read more in the new publication:
Withers, SS, York, D, Choi, JW, et al. Metastatic immune infiltrates correlate with those of the primary tumour in canine osteosarcoma. Vet Comp Oncol. 2019; 1– 11.
https://doi.org/10.1111/vco.12459