Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2017

Radiation dose-fractionation influences the immune modulatory effects of radiotherapy and anti-cancer activity of checkpoint blockade therapy. (#4)

Joseph Sia 1 , James Hagekyriakou 1 , Boon Chua 2 , Trevor Leong 1 , Ricky W Johnstone 1 3 , Nicole M Haynes 1 3
  1. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  2. Prince of Wales Hospital, Randwick, New South Wales, Australia
  3. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia

Activation of host anti-cancer immune defenses is one mechanism by which radiation therapy can eliminate cancer cells. To promote radiation-induced immune responses to cancer, radiotherapy is now being trialed in combination with immunotherapy, with promising success. In an effort to ensure the full therapeutic potential of radiotherapy can be harnessed with immunotherapy, we have examined the differential impact of radiation dose-fractionation on the immune-modulatory activity of radiotherapy, and its ability to support the anti-cancer effects of antibody-based immunotherapy. We have demonstrated that different fractionated radiation regimens are not equivalent in their ability to support the therapeutic activity of antibody-based checkpoint blockade therapy. A 3x4Gy (consecutive day) or 2x10Gy (10Gy/week) treatment regimen was more effective than a single 12Gy or 20Gy dose, respectively, in promoting T-cell based immune responses and the anti-cancer activity of anti-PD-1 therapy in a C57BL/6 model of triple negative breast cancer. Conversely, a single 20Gy dose of radiotherapy was most effective in supporting the growth inhibitory effects of anti-CTLA-4 therapy. Given that low dose (2Gy) fractionated radiotherapy is routinely used for the treatment of breast cancer we have also demonstrated that such fractionation regimens can enhance the combined curative activity of anti-PD-1 and anti-CTLA-4 therapy. Collectively these findings will help optimize the selection and method of integration of immunotherapeutic agents with radiation therapy and ensure that the burgeoning paradigm of cancer immunotherapy can be best capitalized on for the treatment of breast cancer.