Abstract LB-280: FLASH: A novel paradigm changing tumor irradiation platform that enhances therapeutic ratio by reducing normal tissue toxicity and activating immune pathways

Summary: A novel irradiation platform using a proton beam leads to an improved therapeutic window through sparing of normal tissue toxicity. Preliminary experiments suggest involvement of immune pathways in mediating this effect. Abstract: Radiation therapy is administered to nearly half of all the cancer patients. The beneficial effect of this treatment is limited by the radio resistance of the cancer cells and by the adverse effects of radiation on the surrounding normal tissues. Strategies that would reduce normal tissue toxicity while maintaining potent tumor cell killing would enhance the therapeutic ratio and make radiotherapy more effective. Recent publications have shown that delivering radiation at an ultra-high dose rate ≥40Gy/s (ie. FLASH) vs conventional dose rate of 0.03-0.05Gy/s (CONV), significantly reduces the normal tissue toxicity in lung and skin while still being as effective in killing tumor cells (Favaudon et al Sci Trans Med 2014). These studies were done using experimental radiotherapy equipment able to deliver electrons in that dose rate range in preclinical models. However, translation of this approach into the clinic using electron beams may be challenging. In this work, we show for the first time, reduced normal tissue toxicity in pre-clinical mouse models using proton FLASH on a clinical device capable of translation to humans. The study divided C57BL/6 mice into groups (n=6 to 20) which were sham-irradiated or exposed to a single-dose of 15, 17.5 and 20 Gy Conventional (1Gy/sec protons) or FLASH (40 Gy/sec) protons through whole thorax irradiation, and then sampled at 8, 16, 24, and 34 weeks post-irradiation for evaluation of complications and histopathological analysis of lung fibrosis. We observed up to a 30% reduction in lung fibrosis, as well as reduced incidence of skin dermatitis and improved overall survival in FLASH- vs conventionally-treated mice. Evaluation of the molecular mechanism underlying the FLASH effect was performed through genome wide microarray analysis. This revealed that the major pathways differentially regulated between the two treatments included DNA damage and repair, inflammation and immune modulation. Dendritic cell maturation, PKC signaling in lymphocytes, TH1 pathway modulation and calcium-induced T lymphocyte apoptosis were elevated after CONV radiation and decreased after FLASH treatment. Further analysis of these pathways is ongoing. Together these results suggest that FLASH treatment using clinical proton beams might allow for sparing of both early and late tissue toxicity after radiation and this phenomenon involves pathways related to differential DNA damage response and immune modulation. Citation Format: Swati Girdhani, Eric Abel, Alexander Katsis, Andrew Rodriquez, Shilpa Senapati, Angel KuVillanueva, Isabel L. Jackson, John Eley, Zeljko Vujaskovic, Renate Parry. FLASH: A novel paradigm changing tumor irradiation platform that enhances therapeutic ratio by reducing normal tissue toxicity and activating immune pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-280.