Engineered synergistic oncolytic viral symbiosis
In one aspect, the invention provides methods for preferentially killing target proliferating cells in a host, such as cancer cells, by infecting host tissues with two or more strains of virus. The strains of virus may be selected to provide a synergistic and symbiotic effect, involving a contemporaneous lytic infection in the target proliferating cells. In selected embodiments, the viruses are selected so that expression of a first virulence factor in proliferating cells infected with the first virus increases the lytic effect of the second virus; and, expression of the second virulence factor in proliferating cells infected with the second virus increases the lytic effect of the first virus. The genomes of the first and second viruses may be selected so that they are incompatible for recombination between the viral genomes in cells of the host.
1. A method of inducing a contemporaneous synergistic oncolytic infection of a cancer cell, said method comprising infecting the cancer cell with
(i) an effective amount of an oncolytic vaccinia virus (VV) expressing a functional vaccinia virus type 1 interferon (IFN) binding protein comprising the amino acid sequence as set forth in SEQ ID NO: 2, wherein the VV does not express functional thymidine kinase and functional vaccinia growth factor; and,
(ii) an effective amount of an IFN-sensitive oncolytic vesicular stomatitis virus (VSV) comprising a mutation in the gene encoding matrix (M) protein rendering the encoded polypeptide unable to block IFN gene expression, wherein the oncolytic VSV has an attenuating deletion of methionine 51 of the matrix protein (VSVdeltaM51);
wherein the cancer cell is infected with the VV before the oncolytic VSV, and wherein the cancer cell is selected from the group consisting of a liver, colon, ovarian, kidney, rectal, endometrial, brain, pancreatic, lung, breast, sarcoma and groin cancer cell,
thereby inducing a contemporaneous synergistic oncolytic infection of cancer cells by the viruses.
2. The method of claim 1 , wherein the cancer cell is in a human subject.
3. The method of claim 1 , wherein the genome of the oncolytic VSV does not encode type 1 interferon (IFN) binding protein.
4. The method of claim 1 , wherein the VV expresses GM-CSF.
5. The method of claim 1 , wherein the oncolytic VSV has a genome encoding a reovirus Fusion Associated Small Transmembrane (FAST) protein, wherein the p14 protein has the amino acid sequence set forth as SEQ ID NO:1.
6. The method of claim 1 wherein the VV lacks a functional E3L gene.