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

Abstract

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-1α 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.

Radio-immunothérapie alpha

“…L'effet abscopal est un phénomène très rare en clinique. Toutefois, il a été documenté chez des patients porteurs d'une grande variété de tumeurs [35] et quelques travaux ont montré que cet effet reposait sur le développement d'une immunité antitumorale spécifique [36,37]. D'autres effets antitumoraux indépendants de l'irradiation de la cible ont pu être caractérisés et plusieurs études ont mis en évidence les différents mécanismes par lesquels la radiothérapie stimulait le système immunitaire.…”

Abscopal Effect of Radiation Therapy: Current Concepts and Future Applications

“…Opinion is divided as to the ability of ionizing radiation to generate the signals required for DC maturation; however, the combined approach of inducing cell death by irradiation in combination with the administration of a chemotactic agent that activates DCs can lead to the priming or enhancement of antitumor responses (Shiraishi, et al, 2008).…”

“…Myelosuppressive effect of the active variant (Arango, et al, 1999,Arango, et al, 2001,Gilmore, et al, 1999,Lord, et al, 1995 was investigated in several clinical trials of patients receiving chemotherapy (Bernstein, et al, 1997,Broxmeyer, et al, 1998,Clemons, et al, 1998,Marshall, et al, 1998. We previously showed that the recombinant MIP-1 variant, now called ECI301, strikingly enhanced the antitumor efficacy of subcutaneous tumor irradiation and induced an abscopal effect (Shiraishi, et al, 2008). Our study resulted in tumor-free mice with long-term survival without significant toxicity and complete rejection by surviving mice to a re-challenge with the same tumor cells.…”

Alarmins released during local antitumor treatments play an essential role in enhancing tumor growth inhibition at treated and non-treated sites via a derivative of CCL3

“…In fact, unstable L forms of bacteria can often be isolated from patients with chronic respiratory tract infections who have been treated with cell wall-affecting antibiotics*. 2 Before publishing our first paper on a potential new antitumor treatment, 3 the authors of this article had studied the function of leukocytes and immune-compromised hosts, especially patients with phagocyte disorders. Whether disorders were caused by congenital defects in their function 4,5 or by secondary defects like opsonin deficiency, 6 the patients suffered from recurrent life-threatening infections, and infection control of these patients was difficult using antibiotics.…”

“…The results of the model experiments showed striking inhibition of tumor growth with complete tumor eradication from about half of the mice, as well as consistent induction of the abscopal effect. 3 The limitations in radiation therapy could thus be overcome, and the remaining cells considered eradicated by immune reaction, since depletion of various leukocytes reversed the suppression effect of eMIP. Administration of docetaxel also spoiled the suppressive effect of radiation and eMIP, suggesting that the immune reaction was inhibited by the chemotherapeutic agent.…”