Aims:
Recently, new therapeutic approaches to treat cancer have been developed in which viruses are trained to specifically attack cancer cells, without harming the normal tissue. Probably the most famous tumor-killing virus is the genetically modified adenovirus called ONYX-015. This virus can replicate only in tumor cells that lack a functional p53 tumor suppressor gene, and promising results have been reported in clinical trials on patients with head and neck cancers. Here, we propose to construct a virus that specifically replicates in human leukemic cells of the lymphocyte or monocyte lineage. For this purpose, we will use the genetic backbone of the human immunodeficiency virus (HIV-1), which naturally targets these two cell types. There is accumulating evidence that HIV-1 needs all 9 virally encoded genes for growth in primary cells, but much less of the viral genome is required for replication in transformed T-cell lines. In fact, it has been shown repeatedly that HIV-1 spontaneously loses some of the accessory genes upon prolonged replication in T-cell lines of leukemic origin, a phenomenon often referred to as 'T-cell line adaptation'. We propose to perform repeated cycles of gene deletion and subsequent spontaneous adaptation of these viruses in prolonged tissue culture infections of tumor cells with the aim to obtain a virus variant with a minimal number of genes that replicates efficiently and selectively in certain leukemic cell types. Our laboratory has optimized the tissue culture infection system to improve the selection of virus variants with novel phenotypes ('forced evolution'). These viral adaptation studies will be performed with established T-cell and monocytic lines, but we will also use patient-derived leukemic cells. Although we expect that these virus variants will be cytolytic, the killing of cancer cells can be enhanced further by manipulation of the viral genome, e.g. the introduction of apoptosis-inducing genes. The safety of such oncolytic viruses will be extensively tested, and will be improved if necessary by several alternative strategies. This research should yield designer virus reagents that specifically target certain types of leukemia and lymphoma. This concept is exceptionally exciting as it raises the possibility of a self-limiting cancer-specific viral infection that would be able to seek and destroy cancer cells throughout the body. Such a new approach is particularly needed for those cases of leukemia that resist traditional radiation or chemotherapy. Finally, the study of these cancer-specific viruses may also tell us something novel about the biology of cancer cells. |
