Abstract Body

Irradiation at ultra-high dose rates (FLASH) has already shown promising potential for improving therapeutic window using electrons and protons, where multiple facilities worldwide have made efforts to modify accelerator settings to achieve FLASH relevant dose rates. At the Heidelberg Ion-Beam Therapy Center, the world’s first dedicated research and pre-clinical platform for FLASH irradiations with protons, helium and carbon ions has been established. With the aim of a future clinical translation of FLASH therapy with multiple radiation qualities, we describe the biological rationale of the FLASH effect in vitro 2D and 3D cultures and in vivo. Our team at HIT provided the first in vitro study using FLASH dose-rate helium beams, indicated decrease DNA damage signal and cell killing potential for normal and tumor lung cells exclusively in hypoxic conditions (1% O₂) and at doses starting from 8 Gy. Moreover, we have demonstrated neuroprotective effect of proton FLASH radiotherapy for the spread-out Bragg peak region on healthy mouse brain in vivo. Similarly, decreased DNA damage signal was observed in human pluripotent stem cell derived brain organoids after carbon ion FLASH radiotherapy. Currently, preclinical in vivo studies using carbon ion FLASH beams on healthy and tumor tissue are ongoing. These studies altogether indicate a promising potential for higher LET particles in FLASH radiotherapy. However, more in-depth in vitro and especially in vivo investigations are necessary to further understand FLASH effect of particle radiotherapy. In order to tackle FLASH mechanistic questions, biological experiments with high LET beams such as oxygen beams are foreseen.