Combined radiation and Listeria immunotherapy induces cytotoxic immunity that correlates with improved outcome in dogs with osteosarcoma.
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Ionizing radiation acts synergistically with immunotherapy by inducing immunogenic cell death and modulating the tumor microenvironment, promoting anti-tumor immune responses. In this pilot study, the safety and effectiveness of palliative radiation with a Listeria expressing HER2 (Lm-LLO-HER2), on delaying primary tumor progression in immunocompetent dogs with osteosarcoma was evaluated and correlative immune response biomarkers explored. Fifteen dogs with treatment naive, appendicular osteosarcoma, without evidence of metastatic disease received palliative radiation followed by Lm-LLO-HER2 immunotherapy every 3 weeks for an initial 8 doses then booster treatments. Treatment was well tolerated and delayed primary tumor progression and prolonged overall survival in 5/15 dogs. Peripheral blood mononuclear cell transcriptomic profiling revealed that baseline immune status and immune response to Lm-LLO-HER2 distinguished long-term from short-term survivors. Genes associated with Hedgehog signaling, senescence, DNA damage repair, and cell cycle were downregulated when compared to baseline in long-term survivors. These findings support further exploration of combination palliative radiation and Listeria-based immunotherapy in osteosarcoma and suggest that baseline immune status may determine clinical and immunological responses to combination therapy. Pet dogs with osteosarcoma represent a parallel population to pediatric osteosarcoma patients. These findings may inform future pediatric osteosarcoma clinical trials and patient stratification.