Abdominopelvic FLASH Irradiation Improves PD-1 Immune Checkpoint Inhibition in Preclinical Models of Ovarian Cancer

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise; however, current clinical trials are limited by modest response rates. Radiotherapy has been shown to synergize with PD-1/PD-L1 blockade in some cancers but has not been utilized in advanced ovarian cancer due to toxicity associated with conventional abdominopelvic irradiation. Ultrahigh-dose rate (FLASH) irradiation has emerged as a strategy to reduce radiation-induced toxicity, however, the immunomodulatory properties of FLASH irradiation remain unknown. Here, we demonstrate that single high-dose abdominopelvic FLASH irradiation promoted intestinal regeneration and maintained tumor control in a preclinical mouse model of ovarian cancer. Reduced tumor burden in conventional and FLASH-treated mice was asso-ciated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8 thorn T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infil-tration at early timepoints. Moreover, FLASH irradiation main-tained the ability to increase intratumoral CD8 thorn T-cell infiltration and enhance the efficacy of aPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhi-bition in the treatment of ovarian cancer.

Automated summary

Treatment of advanced ovarian cancer using PD-1/PD-L1 immune checkpoint blockade shows promise. Ultrahigh-dose rate (FLASH) irradiation has the potential to improve therapeutic efficacy and increase intratumoral CD8+ T-cell infiltration.