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Enhancement of Antitumor Radiation Efficacy and Consistent Induction of the Abscopal Effect in Mice by ECI301, an Active Variant of Macrophage Inflammatory Protein-1

Authors' Affiliations: ¹ Department of Radiology, University of Tokyo Hospital and ² Department of Molecular Preventive Medicine, Graduate School of Medicine, University of Tokyo; ³ Central Laboratory, Effector Cell Institute, Inc., Tokyo, Japan

Requests for reprints: Shiro Kanagasaki, Central Laboratory, Effector Cell Institute, Inc., 4-7-7 Aobadai, Meguro-ku, Tokyo 153-0042, Japan. Phone: 81-5452-2555; Fax: 81-5452-2589; E-mail: shirokan{at}effectorcell.co.jp.

Purpose: We studied whether i.v. administration of a chemokine after local tumor site irradiation could prevent remaining, as well as distant, nonirradiated tumor cell growth by leukocyte recruitment.

Experimental Design: Tumors were implanted s.c. in the right or both flanks. After local irradiation at the right flank, ECI301, a human macrophage inflammatory protein-1 variant was injected i.v. Tumor volumes were measured every 3 days after treatment.

Results: In Colon26 adenocarcinoma-bearing BALB/c mice, repeated daily administration (over 3-5 consecutive days) of 2 µg per mouse ECI301 after local irradiation of 6 Gy prolonged survival without significant toxicity, and in about half of the treated mice, the tumor was completely eradicated. Three weekly administrations of ECI301 after local irradiation also led to significant, although less effective, antitumor radiation efficacy. ECI301 also inhibited growth of other syngenic tumor grafts, including MethA fibrosarcoma (BALB/c) and Lewis lung carcinoma (C57BL/6). Importantly, tumor growth at the nonirradiated site was inhibited, indicating that ECI301 potentiated the abscopal effect of radiation. This abscopal effect observed in BALB/c and C57BL/6 mice was tumor-type independent. Leukocyte depletion studies suggest that CD8+ and CD4+ lymphocytes and NK1.1 cells were involved.

Conclusions: Marked inhibition of tumor growth at the irradiated site, with complete tumor eradication and consistent induction of the abscopal effect, was potentiated by i.v. administration of ECI301. The results of this study may offer a new concept for cancer therapy, namely chemokine administration after local irradiation, leading to development of novel therapeutics for the treatment of advanced metastatic cancer.