Optimized dosing of spatially heterogeneous radiopharmaceutical therapy reprograms poorly immunogenic tumors to enhance response to immune checkpoint blockade

Immune checkpoint inhibitors (ICIs) are ineffective in patients with poorly immunogenic tumors due to exclusion or exhaustion of effector T cells in the tumor microenvironment (TME) and/or inadequate priming of tumor-specific T cells. Preclinical and clinical studies suggest that radiopharmaceutical therapy (RPT) may overcome such challenges, but an optimal approach to RPT dosing has not been clarified in combination with ICIs. Conventional RPT dosimetry emphasizes mean absorbed radiation doses in tumors and normal tissues, neglecting the spatial distribution of this dose in the TME. We hypothesize that RPT dose heterogeneity in tumors may be leveraged to initiate spatially restricted immuno-radiobiological effects in TME that potentiate antitumor immunity when injecting an activity that delivers high dose (V10%>20 Gy) while also preserving low dose regions (V90%<2.5 Gy) in the TME and not inducing systemic lymphopenia. In studies using lutetium-177 RPT in combination with ICIs, administered activities that met these dosimetric optimization metrics occurred at different mean tumor doses for different RPT agents and different models, yet each achieved therapeutic efficacy in poorly immunogenic murine tumors. Spatial transcriptomics at day 7 after RPT revealed heterogeneous distribution of tumor cell markers with distinct dose-response profiles and localization of dendritic cell (DC) migratory markers in regions of moderate/high dose response marker expression. Combination therapy sustained conventional type 1 DC (cDC1) activation in tumor draining lymph nodes and promoted systemic expansion of antigen-specific CD8 T cells, while serial biopsies revealed effector T cell recruitment and inflammatory cytokine expression in the TME. Optimized intratumoral dose heterogeneity may enable and predict response to ICIs when combined with RPT in tumors not responding adequately to ICIs alone.