Evaluation of recombinant vaccinia viruses for oncolytic virotherapy

概要

Oncolytic viruses have potential to provide clinical benefits for cancer patients who do not respond to conventional therapies. The mechanisms of action include direct infection, immune-mediated cell death and vascular collapse. Previously, we reported that an miRNA and thymidine kinase doubly regulated vaccinia virus (MDVV) selectively infected multiple myeloma (MM) cells and showed that the intravenous injection of MDVV significantly prolonged the survival of severe combined immunodeficiency (SCID) mice with subcutaneous human RPMI8226 MM tumours. Although highly effective, it remained to be confirmed whether MDVV would be similarly effective in an immunocompetent setting. To address this question, I used immunocompetent C57BL/6 (B6) mouse models in this study.

　First, I generated a mouse MM model by transplanting Vk*MYC tumour cells into syngeneic B6 mice. Contrary to expectations, I observed neither a clearly infected region nor prolongation of survival of these mice, probably due to differences in infectivity between human and murine systems. In an in vitro screening experiment using B6 mouse-derived cancer cells, I found that the murine lung adenocarcinoma cell line 3LL was sensitive to MDVV. Therefore, the B6/3LL subcutaneous tumour model was chosen for further studies, instead of the B6/Vk*MYC model.

　Next, I examined in vivo infection using MDVV and B6/3LL mice. Intravenous injection of MDVV led to tumour regression and survival prolongation. However, the viral signals disappeared within 7 days compared with more than 4 weeks in SCID mice, and the tumour regrew, culminating in death.

　As natural killer (NK) cells are thought to play a role in the clearance of VV in B6 mice, I next attempted to prolong viral retention by depleting NK cells using anti-asialo GM1 antibody. Following NK cell depletion, persistent viral signals were detected in B6/3LL mice, but tumour regression was milder than in control mice.

　These results suggested that the oncolytic activity of MDVV alone or in combination with NK depletion is not sufficient to achieve a robust anti- tumour response. Further modifications to achieve longer viral retention, stronger oncolysis, and enhanced anti-tumour immunity should be considered before clinical application.