Abstract Introduction and Objectives: Radiation-induced abscopal effects are characterized by regression of tumor nodules outside the local radiation treatment field. Abscopal effects have been reported in metastatic lymphoma, melanoma, lung and breast cancer as well as renal cell carcinoma amongst others. Radiotherapy causes a perturbation to the local immune profile that is propagated throughout the lymphatic system, shifting systemic immune surveillance towards tumor eradication in distant, non-irradiated sites as well as circulating micrometastases. We hypothesize that abscopal effects could be triggered by targeting combined radiation and immunotherapy to immunogenic hubs in the patient-specific interconnected metastatic-lymphatic network. Materials and Methods: We develop a mathematical model of the systemic response to local radio-immunotherapy. Patient-specific positron emission tomography (PET) scans provide the size and location of each tumor nodule. Metastatic geography is mapped onto the lymphatic network and connections between metastatic sites and lymphatic nodes are calculated. We quantify immune signal flow through the lymphatic network and amplifications through metastatic sites. A local model describes the temporal coevolution of tumor size with effector and regulatory T cells. The local and global models are coupled to quantify systemic responses to local treatment of each tumor site. Results: The ‘virtual patient’ framework successfully simulates the abscopal effect reported for 2 patients with widely metastatic melanoma and non-small cell lung cancer. Model simulations suggest that only one or two tumor nodules in each patient serve as immunogenic hubs that could trigger an abscopal response. Radio-immunotherapy of any other lesion would result in local tumor control but systemic disease progression. Conclusions: Careful selection of immunogenic ‘hub’ nodules holds the key to successful abscopal disease control. The presented mathematical framework may help to identify the immunogenicity of each tumor nodule. Before serving as a novel decision support tool, rigorous calibration and validation remains to be pursued as more clinical abscopal data becomes available. Citation Format: Jan Poleszczuk, Sotiris Prokopiou, Mark Robertson-Tessi, Kimberly Luddy, Eduardo Moros, Mayer Fishman, Julie Djeu, Heiko Enderling. A systems biology approach to predict immunotherapy augmented abscopal effects. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A18.