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

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  • Joshua T. Eggold
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Stephanie Chow
    3Department of Gynecologic Oncology, Stanford University, Stanford, California.
  • Stavros Melemenidis
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Jinghui Wang
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Suchitra Natarajan
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Phoebe E. Loo
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Rakesh Manjappa
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Vignesh Viswanathan
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Elizabeth A. Kidd
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Edgar Engleman
    4Department of Pathology, Stanford University, Stanford, California.
  • Oliver Dorigo
    3Department of Gynecologic Oncology, Stanford University, Stanford, California.
  • Billy W. Loo
    1Department of Radiation Oncology, Stanford University, Stanford, California.
  • Erinn B. Rankin
    1Department of Radiation Oncology, Stanford University, Stanford, California.

説明

<jats:title>Abstract</jats:title> <jats:p>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 associated with an early decrease in intratumoral regulatory T cells and a late increase in cytolytic CD8+ T cells. Compared with conventional irradiation, FLASH irradiation increased intratumoral T-cell infiltration at early timepoints. Moreover, FLASH irradiation maintained the ability to increase intratumoral CD8+ T-cell infiltration and enhance the efficacy of αPD-1 therapy in preclinical models of ovarian cancer. These data highlight the potential for FLASH irradiation to improve the therapeutic efficacy of checkpoint inhibition in the treatment of ovarian cancer.</jats:p>

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