Generating and grading the abscopal effect: Proposal for comprehensive evaluation of combination immunoradiotherapy in mouse models

Numerous published case reports and forthcoming clinical trials combine immunotherapy and radiotherapy with the goal of demonstrating an abscopal effect reaction. However, reports and results are varied, and a comprehensive animal study combining radiotherapy modalities and immunotherapy agents has yet to be performed. Further, clinical reports are mixed, with inconsistent generation of the effect as well as abscopal effects seen ranging from widespread disease elimination to growth stagnation of local lymph node metastasis. We propose a grading system for use in differentiating abscopal effects seen in animal and clinical trials. Further, we will conduct a comprehensive study in mice, evaluating three radiotherapeutic modalities (photon, proton, and carbon-ion) combined with five immunotherapeutic agents with differing actions. Comprehensive cell analysis will be conducted with the aim of improving upon draft models of abscopal effect generation, as well as differentiating between locoregional and systemic methods of action. Further, evaluation of radiation fractionation, as well as combination with ex vivo activated dendritic cell (DC) inoculation, will be performed. Though the abscopal effect has been reported for nearly 70 years, only recently has delineation of its mechanism seemed possible. Comprehensive evaluation of available modalities may shed light on the precise requirements for generating the effect, potentially enabling its regular usage in the treatment of disease.