Potential of Alphavirus Vectors in the Treatment of Advanced Solid Tumors

Barbara J. Kelly; Marina N. Fleeton; Gregory J. Atkins

Abstract

Alphaviruses are positive-strand RNA viruses that are being developed as a high level transient expression vectors. Although most work so far has centered on their use as vaccine vectors, they do have potential as tumor therapy agents. The region of the genome coding for non-structural proteins induces rapid apoptosis in most infected cells, leaving the mutiple cloning site (MCS) of the vector free for other purposes. Two types of vector have been developed: recombinant suicide particles capable of only one round of replication and expression, and replication competent vectors which carry an extra viral 26S subgenomic promoter. Sindbis virus vectors may be capable of targeting at least some tumor cells. A new enhanced Semliki Forest virus (SFV) expression vector is now available and this is particularly effective when used in combination with pro-inflammatory cytokines such as IL-12 or anti-angiogenic treatment based on the induction of autoimmunity to tumor endothelial cell antigen (vascular endothelial growth factor receptor 2). Such treatments can result in the inhibition of metastasis formation as well as inhibition of primary tumor growth. It is concluded that the alphavirus vector systems have potential for the treatment of rapidly growing, otherwise untreatable tumors. Patents have been published for the basic vector systems, for targeting vectors to tumor tissue and for the use of replication competent vectors for cancer treatment.

Keywords: Oncolytic tumor therapy, virus vector, Semliki Forest virus, Sindbis virus, Venezuelan equine encephalitis virus, apoptosis, terminal tumors, rapidly growing tumors