Reduced Number of Lymphocytes by X-ray Irradiation: A Problem in a Combination Therapy Trial that Elicits the Abscopal Effect in Preclinical Studies Using Electron Beam Irradiation

摘要

In preclinical studies with model animals, intravenous administration of a derivative of chemokine CCL3, named eMIP, after local electron-beam irradiation, not only enhanced tumor growth inhibition at a target site but also induced tumor killing beyond the treated site (a phenomenon known as the abscopal effect). eMIP works with alarmins such as high mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70) released from overexpressed tumor cells by irradiation. These alarmins at the irradiated tumor bed trap injected eMIP and, by forming complexes with eMIP, play a key role to recruit and activate tumor inhibitory natural killer (NK) cells and CD4⁺ and CD8⁺ T cells. Tumor type-specific secretion of gamma interferon from splenocytes was also demonstrated, which may also activate NK cells. During Phase 1 clinical studies using X-rays, however, no apparent abscopal effect was observed. Instead, we saw frequent reduction in numbers of lymphocytes in the peripheral blood of irradiated patients. The reduced number of lymphocytes recovered poorly once depleted, in contrast to neutrophils, and persisted for months after the treatment. This might have affected outcome after combination treatment of irradiation and eMIP. To enhance host defense mechanisms during and after photon-beam (X-ray) radiotherapy of a deep-seated tumor, it seems essential to keep lymphocytes undamaged by eliminating reactive oxygen species that are formed in the peripheral blood during irradiation.