Ultra-high dose-rate proton FLASH improves tumor control

Background and purpose: Proton radiotherapy (PRT) offers potential benefits over other radiation modal-ities, including photon and electron radiotherapy. Increasing the rate at which proton radiation is deliv-ered may provide a therapeutic advantage. Here, we compared the efficacy of conventional proton therapy (CONVpr) to ultrahigh dose-rate proton therapy, FLASHpr, in a mouse model of non-small cell lung cancers (NSCLC).Materials and methods: Mice bearing orthotopic lung tumors received thoracic radiation therapy using CONVpr (<0.05 Gy/s) and FLASHpr (>60 Gy/s) dose rates.Results: Compared to CONVpr, FLASHpr was more effective in reducing tumor burden and decreasing tumor cell proliferation. Furthermore, FLASHpr was more efficient in increasing the infiltration of cyto-toxic CD8+ T-lymphocytes inside the tumor while simultaneously reducing the percentage of immuno-suppressive regulatory T-cells (Tregs) among T-lymphocytes. Also, compared to CONVpr, FLASHpr was more effective in decreasing pro-tumorigenic M2-like macrophages in lung tumors, while increasing infiltration of anti-tumor M1-like macrophages. Finally, FLASHpr treatment reduced expression of check-point inhibitors in lung tumors, indicating reduced immune tolerance.Conclusions: 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.& COPY; 2023 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 186 (2023) 1-11