Takashima, M. E.; Kwon, O.; Ells, Z.; Li, V. R.; Sawicki, C.; Welch Schwartz, R.; Ahn, S. H.; Hyun, M.; Idrissou, M. B.; Berg, T. J.; Clark, P. A.; Lawless, M.; Besemer, A.; Bradshaw, T.; Perlman, S.; Jin, W.; Antonelli, M.; Adeniyi, A. O.; Donnelly Haasch, C.; Chen, T.; Wang, Y.; Kumari, R.; Hernandez, R. T.; Weichert, J.; Belanger, A. P.; Ong, I.; Floberg, J.; Meyer, C.; Kishan, A. U.; Calais, J.; Bednarz, B.; Morris, Z. S.

Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering <2.5 Gy to >20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8+ T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.