Oncolytic Foamy Virus: Generation and Properties of a Nonpathogenic Replicating Retroviral Vector System That Targets Chronically Proliferating Cancer Cells

Abstract

ABSTRACT Nonpathogenic retroviruses of the Spumaretrovirinae subfamily can persist long term in the cytoplasm of infected cells, completing their life cycle only after the nuclear membrane dissolves at the time of cell division. Since the targeting of slowly dividing cancer cells remains an unmet need in oncolytic virotherapy, we constructed a replication-competent foamy virus vector (oFV) from the genomes of two chimpanzee simian foamy viruses (PAN1 and PAN2) and inserted a green fluorescent protein (GFP) transgene in place of the bel-2 open reading frame. oFV-GFP infected and propagated with slow kinetics in multiple human tumor cell lines, inducing a syncytial cytopathic effect. Infection of growth-arrested MRC5 cells was not productive, but oFV genomes persisted in the cytoplasm, and the productive viral life cycle resumed when cell division was later restored. In vivo, the virus propagated extensively in intraperitoneal ovarian cancer xenografts, slowing tumor growth, significantly prolonging survival of the treated mice, and sustaining GFP transgene expression for at least 45 days. Our data indicate that oFV is a promising new replication-competent viral and gene delivery platform for efficient targeting of the most fundamental trait of cancer cells, their ability to sustain chronic proliferation. IMPORTANCE The infectivity of certain retroviruses is limited to dividing cells, which makes them attractive tools for targeting cancer cell proliferation. Previously developed replication-competent gammaretroviral vectors spread efficiently in rapidly dividing cancer cells, but not in cancer cells that divide more slowly. In contrast to rapidly proliferating transplantable mouse tumors, slow proliferation is a hallmark of human cancers and may have contributed to the clinical failure of the preclinically promising murine leukemia virus vector Toca 511, which failed to show efficacy in a phase 3 clinical trial in patients with glioblastoma. The studies presented in our manuscript show that oFV vectors are capable of persisting unintegrated in quiescent cells and resuming their life cycle once the cells start dividing again. This property of oFVs, together with their lack of pathogenicity and their ability to catalyze the fusion of infected cancer cells, makes them an attractive platform for further investigation.