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• W2897400090 abstract "We recently developed a potent cancer immunotherapy protocol that involves tumor-directed irradiation combined with intratumoral injection of adenoviruses encoding human IL-12 and GM-CSF. The combination protocol was safe and effective in multiple murine models. In this research, we conducted a phase I trial to determine its safety profile in pet dogs. This study was approved by institutional animal care and use committee of National Taiwan University. The protocol followed traditional 3 + 3 dose escalation design to enroll 3 canine subjects with refractory solid tumors per dose level of adenovirus cocktail. The initial dose was set to 0.5 x 109 cfu for both IL-12 and GM-CSF, which is the total dose used in murine experiments. For combination therapy, 10 gray of radiation was delivered via a 6 MV beam with an linear accelerator. After irradiation, adenoviruses were immediately injected into the treated tumor. Clinical manifestation, blood samples, and CT scans were obtained along the course. The primary endpoints were safety profiles. A total of 3 pet dog subjects were enrolled. These subjects have metastatic orbital fibrosarcoma, recurrent malignant peripheral nerve sheath sarcoma of the forelimb, and metastatic buccal melanoma respectively. After treatment, thrombocytopenia was found in all subjects. 2 out of 3 subjects developed severe adverse effects, including 2 grade 5 hematological toxicities and 1 grade 3 cardiac toxicity. Immunophenotyping excluded pathogenic roles of adenovirally encoded human cytokines and suggested IL-6 is a major cytokine induced by the combination therapy. Furthermore, cytokine release syndrome induced by the combination therapy was successfully controlled with tocilizumab. In one subject with malignant peripheral nerve sheath sarcoma, significant partial response was noted 6 months after the procedure. The protocol was prematurely terminated due to high mortality rate. We found significant immune-related systemic toxicity in a locally delivered radiation-immunotherapy for refractory solid tumors in pet dogs. The discordant safety profiles between murine models and canine subjects highlight the risk of translating potent radiation-immunotherapy combination into clinical settings. Further research is warranted to develop early toxicity biomarkers in species of interest that guide timely immunosuppression in translational immuno-oncology platforms." @default.
• W2897400090 created "2018-10-26" @default.
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• W2897400090 date "2018-11-01" @default.
• W2897400090 modified "2023-09-26" @default.
• W2897400090 title "Combination of Radiation Therapy and Intratumoral IL-12/GM-CSF Leads to Systemic Toxicity in Pet Dog Subjects with Refractory Solid Tumors" @default.
• W2897400090 doi "https://doi.org/10.1016/j.ijrobp.2018.07.111" @default.
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