Producer Viruses for Generation of Retroviruses In Situ
This disclosure provides compositions comprising a modified oncolytic virus that can contain modifications in the viral genome and exogenous nucleic acids coding for proteins. The viral compositions and methods provided herein can be utilized for the treatment of cancer.
1 . A virus comprising a retroviral envelope construct, a retroviral packing construct, and a retroviral transfer construct, wherein at least one of the envelope construct, the packaging construct, or the transfer construct comprises a transgene that codes for a non-retroviral protein, and wherein the virus is an oncolytic virus.
2 . The virus of claim 1 , wherein the envelope construct, the packing construct, and the transfer construct are inserted at different locations within a genome of the oncolytic virus.
3 . The virus of claim 1 , wherein the envelope construct comprises a gene that codes for a retroviral envelope protein and the packaging construct comprises a gene that codes for a retroviral structural protein.
4 . The virus of claim 3 , wherein the gene that codes for the retroviral envelope protein is under the control of a first early viral promoter and the gene that codes for the retroviral structural protein is under the control of a second early viral promoter.
5 . The virus of claim 3 , wherein the gene that codes for the retroviral envelope protein is under the control of a first early viral promoter, a first early/late viral promoter or a first late viral promoter; and the gene that codes for a retroviral structural protein is under the control of a second early viral promoter, a second early/late viral promoter, or a second late viral promoter.
6 . The virus of claim 1 , wherein the oncolytic virus is a measles virus, a poliovirus, a poxvirus, a vaccinia virus, an adenovirus, an adeno-associated virus, a herpes simplex virus, a vesicular stomatitis virus, a reovirus, a Newcastle disease virus, a senecavirus, a mengovirus, or a myxomavirus.
7 . The virus of claim 6 , wherein the oncolytic virus is a vaccinia virus.
8 . The virus of claim 7 , wherein the vaccinia virus comprises a mutation or deletion of at least one viral gene.
9 . The virus of claim 8 , wherein the at least one viral gene is selected from the group consisting of: B5R, A52R (VACWR178), F13L, A36R, A34R, A33R, B8R, B18R, SPI-1, SPI-2, B15R, VGF, E3L, K3L, A41L, K7R, NIL, C12L, TK, and any combinations thereof.
10 . The virus of claim 1 , wherein the non-retroviral protein comprises a therapeutic protein or a diagnostic protein.
11 . The virus of claim 10 , wherein the non-retroviral protein comprises the therapeutic protein, and wherein the therapeutic protein comprises an immune checkpoint modulator, an antibody or portion thereof, a Fc fusion protein, an anticoagulant, a blood factor, a bone morphogenetic protein, an immunosuppressive agent, an immunostimulatory agent, an enzyme, a growth factor, a hormone, an interferon, an interleukin, a thrombolytic, an anti-angiogenic, a chemotherapeutic, an antibiotic, an antifungal, an antiviral, and any combination thereof.
12 . The virus of claim 1 , wherein the retroviral envelope construct, the retroviral packing construct, and the retroviral transfer construct are from an Alpharetrovirus, a Betaretrovirus, a Deltaretrovirus, an Epsilonretrovirus, a Gamma retrovirus, a Lentivirus, or any combination thereof.
13 . The virus of claim 12 , wherein the retrovirus is the lentivirus.
14 . The virus of claim 13 , wherein the lentivirus is an HIV.
15 . The virus of claim 12 , wherein the retrovirus is the Gamma retrovirus.
16 . The virus of claim 15 , wherein the Gamma retrovirus is a Moloney murine leukemia virus.
17 . The virus of claim 1 , comprising an exogenous nucleic acid sequence that codes for a nucleic acid polymerase.
18 . The virus of claim 17 , wherein the nucleic acid polymerase is selected from the group consisting of: T7 RNA polymerase, T3 RNA polymerase and SP6 RNA polymerase, a RNA polymerase variant, and a DNA polymerase mutant.
19 . The virus of claim 1 , comprising an exogenous nucleic acid sequence that codes for a bacteriophage polymerase.
20 . The virus of claim 19 , wherein the bacteriophage is selected from the group consisting of a T3 bacteriophage, a T7 bacteriophage, and an SP6 bacteriophage.
21 . The virus of claim 20 , wherein a T3 bacteriophage polymerase is expressed with a T3 bacteriophage promoter, a T7 bacteriophage polymerase is expressed with a T7 bacteriophage promoter, and an SP6 bacteriophage polymerase is expressed with an SP6 bacteriophage promoter.