Novel comparative models of canine tumors xenografted into mice to develop effective immunotherapies against osteosarcoma 2302620

Abstract

Abstract Introduction Osteosarcoma (OSA) in dogs and humans is an aggressive form of bone cancer with limited effective treatment options for both species. Given the many aspects shared by this disease in dogs and humans, we generated preclinical models of comparative value by transplantation of canine OSA derived xenografts (CODXs) into immunocompromised mice. After finding tumor autologous canine immune cells infiltrating the CODXs, we used these models to predict anti-OSA clinical efficacy of immunotherapies targeting T cell function. Methods Canine OSA samples implanted into NOD SCID gamma (NSG) mice were tested for sustainable successive transplants. Amplification by polymerase chain reaction (PCR) of targeted canine genes was used to determine canine origin of transplanted tumors. Retention of parental OSA histology along passage of CODXs into NSG mice was studied. Infiltration of canine lymphocytes into CODXs was investigated using flow cytometry and immunohistochemistry. Finally, NSG mice hosting CODXs were treated with anti-canine CTLA-4 mAb to test anti-tumor functionality of potential canine T cells found infiltrating the CODXs. Results Two CODXs were established as consistently transplantable into successive generations of NSG mice. Canine origin of transplanted tissue across successive generations was proven by PCR. CODXs were also shown to retain parental tumor histology. Both CODX models were consistently infiltrated with canine lymphocytes positive for the T cell lineage marker CD3 across successive generations of NSG recipients. Finally, NSG mice recipients of the sixth generation of one of the two CODXs were treated with canine anti-canine CTLA-4 mAb These mice presented reduced tumor burden (p value = 0.0403) and lived longer (p value = 0.0004) than control treated mice. Conclusion CODXs established will allow pre-clinical development and evaluation of candidate drugs targeting T cell functionality for clinical care of dogs and humans suffering from OSA. Funding Source University of Missouri intra-mural funds NIH, NCI, U01 funds Topic Categories Veterinary and Comparative Immunology (VET)