Methods of treating solid or lymphatic tumors by combination therapy
The present invention provides methods for treating an individual having bladder cancer, the methods comprising intravesical administration of an oncolytic virus and intravenously administering an anti-PD-1 antibody.
1. A method of treating bladder cancer in an individual, comprising: a) intravesically administering an effective amount of an oncolytic virus, wherein the oncolytic virus is an oncolytic adenovirus; and b) intravenously administering an effective amount of an immunomodulator, wherein the immunomodulator is an anti-PD-1 antibody, and wherein the oncolytic virus comprises a viral vector comprising a tumor cell-specific promoter operably linked to a viral gene essential for replication of the virus, and a heterologous gene encoding an immune-related molecule.
2. The method of claim 1 , wherein the oncolytic virus is an adenovirus serotype 5, wherein the endogenous Ela promoter of the native adenovirus serotype 5 is replaced by the human E2F-1 promoter, and the endogenous E3 19kD coding region of the native adenovirus serotype 5 is replaced by a nucleic acid encoding human GM-CSF.
3. The method of claim 1 , wherein the oncolytic virus is CG0070.
4. The method of claim 1 , wherein the oncolytic virus is administered weekly.
5. The method of claim 1 , wherein the oncolytic virus is administered for about 1 week to about 6 weeks.
6. The method of claim 1 , further comprising locally administering to the site of the tumor a pretreatment composition prior to the administration of the oncolytic virus.
7. The method of claim 6 , wherein the pretreatment composition comprises a transduction enhancing agent.
8. The method of claim 1 , wherein the individual is subject to a prior therapy prior to the administration of the oncolytic virus and the immunomodulator.
9. The method of claim 8 , wherein the prior therapy comprises administration of a therapeutic agent.
10. The method of claim 8 , wherein the prior therapy is provided at a dose that is insufficient to treat the tumor.
11. The method of claim 1 , wherein the bladder cancer is non-muscle invasive bladder cancer.
12. The method of claim 11 , wherein the non-muscle invasive bladder cancer comprises carcinoma in situ.
13. The method of claim 12 , wherein the non-muscle invasive bladder cancer further comprises Ta, T1, or a combination thereof.
14. The method of claim 7 , wherein the transduction enhancing agent is N-Dodecyl-β-D-maltoside (DDM).
15. The method of claim 8 , wherein the individual is resistant to the prior therapy.
16. The method of claim 8 , wherein the individual has recurrent bladder cancer after the prior therapy.
17. The method of claim 8 , wherein the prior therapy is treatment with Bacillus Calmette-Guerin (BCG).
18. The method of claim 17 , wherein:
a. the individual is resistant to treatment of bladder cancer with BCG;
b. the individual is initially responsive to treatment of bladder cancer with BCG but has progressed after treatment; or
c. the individual has recurrent bladder cancer after treatment with BCG.
19. The method of claim 1 , wherein the immunomodulator is administered once every 6 weeks.
20. The method of claim 1 , wherein the method comprises intravenously administering a single immunomodulator.
21. The method of claim 1 , wherein the anti-PD-1 antibody is nivolumab.