Exogenous tap inhibitor armed oncolytic viruses and therapeutic uses thereof
The present invention relates to exogenous TAP inhibitor armed oncolytic viruses that replicate selectively in cancer cells, evade CD8+ cytolytic T-cells, and induce the immune system to recognize tumor cells. Preferred viruses of the invention have a heterologous gene that encodes a function that affects antigen presentation by inhibiting TAP. The viruses of the invention also comprise one or more heterologous genes encoding immunomodulatory polypeptides, prodrug converting enzymes, or matrix degrading enzymes. Compositions and therapeutic methods using the oncolytic viruses are also provided, including compositions and therapeutic methods for treating cancers, such as melanoma, head and neck cancer, ovarian cancer, breast cancer, glioblastoma, bladder cancer, prostate cancer, lung cancer, liver cancer, colorectal cancer, pancreatic cancer, and renal cancer.
1. An exogenous TAP inhibitor armed oncolytic virus comprising:
a. a viral backbone that in its wildtype form does not encode a TAP inhibitor, wherein said viral backbone is selected from Vaccinia virus, Adenovirus, Adeno-Associated virus, Myxoma virus, Vesicular Stomatitis virus, New Castle Disease virus, Seneca valley virus and Reovirus; and
b. a polynucleotide sequence encoding a TAP inhibitor polypeptide sequence; and
c. a polynucleotide sequence encoding an immunomodulatory polypeptide, wherein the immunomodulatory polypeptide is selected from:
i. B7-1 (CD80);
ii. B7-2 (CD86);
iii. CD40L;
iv. TNF-α;
v. IL-10;
vi. a PD-1 inhibitor;
vii. a PDL-1 inhibitor;
viii. a CTLA4 inhibitor;
ix. CMV Us2;
x. CMV Us11;
xi. RANTES; or
xii. MIP-3; and
(d) a polynucleotide sequence encoding a prodrug converting enzyme and/or a matrix degrading enzyme.
2. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the TAP inhibitor polypeptide acid sequence is at least 70% identical to the amino acid sequence selected from:
a. HSV-1 ICP47;
b. Bovine herpes virus-1 UL49.5;
c. Bubaline herpes virus-1 UL49.5;
d. Cervid virus-1 UL49.5;
e. Feline herpes virus-1 UL49.5;
f. Equine herpes virus-1 UL49.5;
g. Pseudorabies UL49.5;
h. CMV US6;
i. EBV BNLF2a; or
j. CPXV CPXV12.
3. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the TAP inhibitor polypeptide acid sequence is at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence selected from:
a. HSV-1 ICP47;
b. Bovine herpes virus-1 UL49.5;
c. Bubaline herpes virus-1 UL49.5;
d. Cervid virus-1 UL49.5;
e. Feline herpes virus-1 UL49.5;
f. Equine herpes virus-1 UL49.5;
g. Pseudorabies UL49.5;
h. CMV US6;
i. EBV BINLF2a; or
j. CPXV CPXV12.
4. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the TAP inhibitor polypeptide sequence is selected from:
a. HSV-1 ICP47;
b. Bovine herpes virus-1 UL49.5;
c. Bubaline herpes virus-1 UL49.5;
d. Cervid virus-1 UL49.5;
e. Feline herpes virus-1 UL49.5;
f. Equine herpes virus-1 UL49.5;
g. Pseudorabies UL49.5;
h. CMV US6;
i. EBV BINLF2a; or
j. CPXV CPXV12.
5. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein said prodrug converting enzyme is selected from:
a. Cytosine deaminase;
b. Uracil phosphoribosyltransferase; or
c. Thymidine kinase.
6. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein said matrix degrading enzyme is selected from:
a. Collagenase;
b. Gelatinase;
c. Stromelysins;
d. Relaxin;
e. Bacterial collagenase; or
f. Chondroitinase ABC I.
7. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein said exogenous TAP inhibitor armed oncolytic virus further comprises a promoter selected from:
a. a CMV promoter; or
b. EFlα promoter.
8. A pharmaceutical composition comprising the exogenous TAP inhibitor armed oncolytic virus of claim 1 .
9. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is B7-1 (CD80).
10. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is B7-2 (CD86).
11. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is CD40L.
12. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is TNF-α.
13. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is IL-10.
14. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is a PD-1 inhibitor.
15. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is a PDL-1 inhibitor.
16. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is a CTLA4 inhibitor.
17. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is CMV Us2.
18. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is CMV Us11.
19. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is RANTES.
20. The exogenous TAP inhibitor armed oncolytic virus of claim 1 , wherein the immunomodulatory polypeptide is MIP-3.
21. A method of treating a patient with cancer, wherein said method comprises administering to said patient a therapeutically effective amount of the exogenous TAP inhibitor armed oncolytic virus of claim 1 .
22. The method of claim 21 , wherein the exogenous TAP virus is administered prophylactically.
23. The method of claim 21 , wherein said patient has cancer selected from:
a. melanoma;
b. head and neck cancer;
c. ovarian cancer;
d. breast cancer;
e. glioblastoma;
f. bladder cancer;
g. prostate cancer;
h. lung cancer;
i. liver cancer;
j. colorectal cancer;
k. pancreatic cancer; and
l. renal cancer.