Alphavirus vectors for cancer therapy.

Alphaviruses contain a single strand RNA genome that can be easily modified to express heterologous genes at very high levels in a broad variety of cells, including tumor cells. Alphavirus vectors can be used as viral particles containing a packaged vector RNA, or directly as nucleic acids in the form of RNA or DNA. In the latter case alphavirus RNA is cloned within a DNA vector downstream of a eukaryotic promoter. Expression mediated by these vectors is generally transient due to the induction of apoptosis. The high expression levels, induction of apoptosis, and activation of type I IFN response are the key features that have made alphavirus vectors very attractive for cancer treatment and vaccination. Alphavirus vectors have been successfully used as vaccines to induce protective and therapeutic immune responses against many tumor-associated antigens in animal models of mastocytoma, melanoma, mammary, prostate, and virally induced tumors. Alphavirus vectors have also shown a high antitumoral efficacy by expressing antitumoral molecules in tumor cells, which include cytokines, antiangiogenic factors or toxic proteins. In these studies induction of apoptosis in tumor cells contributed to the antitumoral efficacy by the release of tumor antigens that can be uptaken by antigen presenting cells, enhancing immune responses against tumors. The potential use of alphaviruses as oncolytic agents has also been evaluated for avirulent strains of Semliki Forest virus and Sindbis virus. The fact that this latter virus has a natural tropism for tumor cells has led to many studies in which this vector was able to reach metastatic tumors when administered systemically. Other "artificial" strategies to increase the tropism of alphavirus for tumors have also been evaluated and will be discussed.