Ultra-high Dose-rate Proton FLASH Improves Tumor Control

Background And Purpose: 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) to ultrahigh dose-rate proton therapy, FLASH, in a mouse model of non-small cell lung cancers (NSCLC).

Materials And Methods: Mice bearing orthotopic lung tumors received thoracic radiation therapy using CONV (<0.05 Gy/s) and FLASH (>60 Gy/s) dose rates.

Results: Compared to CONV, FLASH was more effective in reducing tumor burden and decreasing tumor cell proliferation. Furthermore, FLASH 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, FLASH was more effective in decreasing pro-tumorigenic M2-like macrophages in lung tumors, while increasing infiltration of anti-tumor M1-like macrophages. Finally, FLASH treatment reduced expression of checkpoint 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.