Abstract 450: The impact of the therapy with HF-10 on tumor microenvironment in patients with recurrent breast cancer
Authors: Sahin Tevfik Tolga , Kasuya Hideki , Nomura Naohiro , Nomoto Shuji , Takeda Shin , Sugimoto Hiroyuki , Sugae Takashi , Imai Tsuneo , Kikumori Toyone , Misawa Makoto , Nishikawa Yoko , Nishiyama Yukihiro , Nakao Akimasa 
Published: February 2011

Abstract
Aim: HF10 is a naturally mutated oncolytic virus subtype of Herpesviridae which has a potent antitumor activity. There is no study evaluating the mechanism of action of the virus on the tumor tissue in actual clinical setting. Present study is unique in evaluating the impact of HF-10 treatment on tumor microenvironment from actual clinical setting of patients with recurrent breast cancers.
Patients and Methods: 6 patients with recurrent breast cancer were recruited to clinical part of the study in order to evaluate the efficacy of HF10 therapy. The virus was delivered in various doses: single dose injection of 104 pfu/0.5 ml to patient 1, single dose injection of 105pfu/0.5ml to patient 2, 3 dose injection of 105pfu/0.5ml to patient 3, single dose injection of 5x105pfu/0.5 ml to patient 4 and 5, 3 doses injection of 5x105pfu/0.5 ml to patient 6. In the present study specimens from 5 patients were eligible for evaluation. The patient 6 had a fibrotic tissue remnant therefore was excluded from histopathological analysis. The specimens were divided into 2 groups; saline injected control group and HF10 injected treatment group. Investigated parameters included neovascularization (CD31 antigen) and tumor lymphocyte infiltration (CD8 and CD4 antigen) determined by immunohistochemistry and apoptosis determined by TUNEL assay.
Results: Median apoptotic cell count was 25.6/hpf(x100) in treatment group where as 50.0/hpf(x100) in the control group (p=0.016). On the other hand CD31 traced neovascularization were significantly higher in treatment group when compared to the control group [medians 30.0/hpf(x100) versus 12.0/hpf (x100); p=0.032]. Median CD8 positive lymphocyte count infiltrating the tumors in the treatment and control groups were 75.0/hpf (x100) and 42.0/hpf (x100); respectively (p=0.008). We were unable to detect CD4 positive cells in both groups.
Conclusions: Our results suggest that reduced apoptosis by HF10 results in a prominent oncolytic activity because apoptosis is a host cell defense mechanism that limits viral infection by shutting down the cellular machinery necessary for viral production. Reduced apoptosis causes efficient intratumoral propagation of HF10 and viral cycle leads to enhanced oncolysis. Wild-type herpes simplex virus type 1 virus cause some of its pathology by increasing the vascularity of infected tissue but uptil now we have encountered no data regarding impact HF10 on angiogenesis in human tissue. Most probable explanation would be the inflammatory process enhancing angiogenesis. Nevertheless this must be carefully addressed in following clinical trials to improve safety of the treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 450.