Recombinant vaccinia virus and methods of use thereof
The present disclosure provides a replication-competent, recombinant oncolytic vaccinia virus, compositions comprising the vaccinia virus, and use of the vaccinia virus or composition for inducing oncolysis in an individual having a tumor.
1. A replication-competent, recombinant oncolytic vaccinia virus comprising: a) a nucleotide sequence encoding a variant herpes simplex virus (HSV) TK polypeptide capable of catalyzing phosphorylation of deoxyguanosine; and b) a modification that results in a lack of endogenous thymidine kinase expression or function, wherein the variant HSV TK polypeptide comprises the amino acid sequence of SEQ ID NO:2, 3, or 4.
2. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the variant HSV TK polypeptide comprises the amino acid sequence of SEQ ID NO:2.
3. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the variant HSV TK polypeptide comprises the amino acid sequence of SEQ ID NO:3.
4. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the variant HSV TK polypeptide comprises the amino acid sequence of SEQ ID NO: 4.
5. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the vaccinia virus is a Copenhagen strain vaccinia virus.
6. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 wherein the vaccinia virus is a WR strain vaccinia virus.
7. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the vaccinia virus comprises an A34R gene that encodes an A34 polypeptide comprising a K151E substitution.
8. A composition comprising:
a) the vaccinia virus of claim 1 ; and
b) a pharmaceutically acceptable excipient.
9. A method of inducing oncolysis in an individual having a tumor, the method comprising administering to the individual an effective amount of the composition of claim 8 .
10. The method of claim 9 , further comprising administering to the individual a second cancer therapy.
11. The method of claim 10 , wherein the second cancer therapy comprises an anti-PD1 agent or an anti-PD-L1 agent.
12. The method of claim 9 , further_comprising administering to the individual an amount of ganciclovir that, in combination with the vaccinia virus, is effective to reduce an adverse side effect of the vaccinia virus.
13. The method of claim 9 , wherein the variant (HSV) HSV TK polypeptide comprises_the amino acid sequence of SEQ ID NO: 4.
14. The method of claim 13 , wherein the vaccinia virus is a Copenhagen strain vaccinia virus and comprises an A34R gene comprising a K151E substitution.
15. The replication-competent, recombinant oncolytic vaccinia virus of claim 1 , wherein the nucleotide sequence encoding the variant HSV TK polypeptide is set forth in SEQ ID NO: 11, 12 or 13.