Immunotherapeutic advances for the treatment of osteosarcoma, driven by studies in pet dogs with spontaneous disease

Abstract

Osteosarcoma is an aggressive bone malignancy that affects approximately 15,000 older, large breed dogs and 800 adolescent and young adult (AYA) humans annually in the US. Pet dogs with osteosarcoma are recognized as a highly relevant, immune-competent patient population which shares clinical, genomic, transcriptomic and immunologic tumor profiles with human osteosarcoma patients. Standard of care has not changed in over five decades and in both species consists of radical surgery and chemotherapy, which in the AYA population causes significant morbidity. Metastases to the lungs occurs in both species and carries a guarded prognosis. There is a clear need for more effective and less toxic treatments. Clinical observations and the survival advantage seen with tumors that are infiltrated with cytotoxic immune cells suggest that the immune system can control osteosarcoma, providing a sound rationale for immunotherapies that boost anti-tumor immunity and generate memory responses, to prevent relapse. The high incidence of osteosarcoma in dogs facilitates collection of tumor tissue for research and performance of clinical trials to advance our understanding of the disease and develop novel therapies, relevant to both species. This review summarizes the exploratory studies that have been performed, often in small cohorts of dogs with osteosarcoma, using tumor vaccines, adoptive cellular therapies, checkpoint inhibitors, and tumor microenvironment modifying strategies. The review also includes the early efforts that are being made to identify correlative biomarkers of response that may inform human clinical trial design.

Keywords

Osteosarcoma / canine model / adoptive cell therapy / natural killer cells / invariant natural killer T cells / tumor microenvironment / losartan / mifamurtide

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