Ultra-high dose-rate proton FLASH improves tumor control.

Abstract

Proton radiotherapy (PRT) offers potential benefits over other radiation modalities, including photon and electron radiotherapy. Increasing the rate at which proton radiation is delivered may provide a therapeutic advantage. Here, we compared the efficacy of conventional proton therapy (CONV^pr) to ultrahigh dose-rate proton therapy, FLASH^pr, in a mouse model of non-small cell lung cancers (NSCLC). Mice bearing orthotopic lung tumors received thoracic radiation therapy using CONV^pr (<0.05 Gy/s) and FLASH^pr (>60 Gy/s) dose rates. Compared to CONV^pr, FLASH^pr was more effective in reducing tumor burden and decreasing tumor cell proliferation. Furthermore, FLASH^pr was more efficient in increasing the infiltration of cytotoxic CD8⁺ T-lymphocytes inside the tumor while simultaneously reducing the percentage of immunosuppressive regulatory T-cells (Tregs) among T-lymphocytes. Also, compared to CONV^pr, FLASH^pr was more effective in decreasing pro-tumorigenic M2-like macrophages in lung tumors, while increasing infiltration of anti-tumor M1-like macrophages. Finally, FLASH^pr treatment reduced expression of checkpoint inhibitors in lung tumors, indicating reduced immune tolerance. Our results suggest that FLASH dose-rate proton delivery modulates the immune system to improve tumor control and might thus be a promising new alternative to conventional dose rates for NSCLC treatment.