Malignant melanoma is a serious health issue for Veterans, and metastatic melanoma is usually incurable if it metastasizes to distant sites. Exciting and impressive data with immune checkpoint blockade demonstrate the ability of the immune system to produce durable responses in some metastatic melanoma patients and have changed the standard of care1. Effective treatment with immune checkpoint blockade seems to require activation of anti-melanoma T cells that are specific for a wide variety of melanoma antigens including patient- unique neoantigens. Canine malignant melanoma provides an excellent preclinical model to study melanoma immunotherapy as it is similar to human melanoma occurring spontaneously in the setting of an intact immune system and with metastasis occurring via lymphatics or blood vessels to regional lymph nodes, lungs, liver, brain, and kidney. Germane to this application, the GD2 disialoganglioside (GD2) is expressed in both human and canine melanoma2-4. We therefore propose intratumoral (IT) injection of the GD2-reactive hu14.18-IL2 immunocytokine (IC) (IT-IC) alone, and in combination with other therapies synergistic in preclinical murine models, in companion dogs with melanoma to convert the injected tumor into an effective in situ tumor vaccine5. Our central hypothesis is that IT-IC in combination with local radiation therapy (RT) in canine melanoma can induce a T cell response to melanoma. Further, we hypothesize that this response can be amplified with immune checkpoint blockade, and that this regimen is safe and well tolerated. These hypotheses will be tested by achieving the following: Aim 1) Determine toxicity, immunogenicity, and assess antitumor activity of IT delivery of hu14.18-IL2 alone and with local RT in dogs with locally advanced or metastatic melanoma; Aim 2) Evaluate local and systemic antitumor activity following IT delivery of hu14.18- IL2 combined with RT and immune checkpoint blockade with anti-PD1 in dogs with locally advan