Combination therapy with hydrogen peroxide and irradiation promotes an abscopal effect in mouse models

Hydrogen peroxide (H(2)O(2)) induces oxidative stress and cytotoxicity, and can be used for treating cancers in combination with radiotherapy. A product comprising H(2)O(2) and sodium hyaluronate has been developed as a radiosensitizer. However, the effects of H(2)O(2) on antitumor immunity remain unclear. To investigate the effects of H(2)O(2), especially the abscopal effect when combined with radiotherapy (RT), we implanted murine tumor cells simultaneously in two locations in mouse models: the hind limb and back. H(2)O(2) mixed with sodium hyaluronate was injected intratumorally, followed by irradiation only at the hind limb lesion. No treatment was administered to the back lesion. The H(2)O(2)/RT combination significantly reduced tumor growth at the noninjected/nonirradiated site in the back lesion, whereas H(2)O(2) or RT individually did not reduce tumor growth. Flow cytometric analyses of the tumor‐draining lymph nodes in the injected/irradiated areas showed that the number of dendritic cells increased significantly with maturation in the H(2)O(2)/RT combination group. In addition, analyses of tumor‐infiltrating lymphocytes showed that the number of CD8(+) (cluster of differentiation 8) T cells and the frequency of IFN‐γ(+) (interferon gamma) CD8(+) T cells were higher in the noninjected/nonirradiated tumors in the H(2)O(2)/RT group compared to those in the other groups. PD‐1 (programmed death receptor 1) blockade further increased the antitumor effect against noninjected/nonirradiated tumors in the H(2)O(2)/RT group. Intratumoral injection of H(2)O(2) combined with RT therefore induces an abscopal effect by activating antitumor immunity, which can be further enhanced by PD‐1 blockade. These findings promote the development of H(2)O(2)/RT therapy combined with cancer immunotherapies, even for advanced cancers.