Adenovirus Expressing Immune Cell Stimulatory Receptor Agonist(s)

1 . A replication competent oncolytic virus comprising a heterologous nucleic acid inserted into a nonessential region of the adenovirus genome, said nucleic acid comprising a sequence encoding an OX40 (CD134) agonist operatively linked to a transcriptional control element.

2 . The replication competent oncolytic virus of claim 1 , wherein the replication competent oncolytic virus is a replication competent oncolytic adenovirus.

3 . The replication competent oncolytic adenovirus of claim 2 , wherein the adenovirus comprises a deletion in part or all of the E3 gene region.

4 . The replication competent oncolytic adenovirus of claim 3 , wherein said heterologous nucleic acid is inserted in the E3 deleted gene region of the adenovirus.

5 . The replication competent oncolytic adenovirus of claim 1 , wherein the OX40 agonist is OX40 ligand (OX40L) (gp36).

6 . The replication competent oncolytic adenovirus of claim 5 , wherein the nucleic acid encoding OX40L encodes a polypeptide having the amino acid sequence set forth in GenBank Accession Number NP_003317.1 or a sequence at least 95% identical thereto.

7 . The replication competent oncolytic adenovirus of claim 6 , wherein the nucleic acid encoding OX40L has the nucleic acid sequence of NCBI Reference Sequence: NM_003326.3 or a sequence at least 95% identical thereto.

8 . The replication competent oncolytic adenovirus of claim 1 wherein the adenovirus is a human adenovirus type 5 or a hybrid comprising a human adenovirus type 5 component.

9 . The replication competent oncolytic adenovirus of claim 8 wherein the adenovirus is Delta-24 or Delta-24-RGD.

10 . The replication competent oncolytic adenovirus of claim 1 wherein the adenovirus is selected from ICOVIR-5, ICOVIR-7, ONYX-015, ColoAd1, H101 and AD5/3-D24-GMCSF.

11 . The replication competent oncolytic adenovirus of claim 1 wherein the adenovirus genome comprises one or more heterologous nucleic acid sequences encoding a tumor antigen, whereby the adenovirus expresses the tumor antigen(s) on its surface.

12 . The replication competent oncolytic adenovirus of claim 11 wherein the tumor antigen is selected from the group consisting of: MAGE-1, MAGE-2, MAGE-3, CEA, Tyrosinase, midkin, BAGE, CASP-8, β-catenin, CA-125, CDK-1, ESO-1, gp75, gplOO, MART-1, MUC-1, MUM-1, p53, PAP, PSA, PSMA, ras, trp-1, HER-2, TRP-1, TRP-2, IL13Ralpha, IL13Ralpha2, AIM-2, AIM-3, NY-ESO-1, C9orfl 12, SART1, SART2, SART3, BRAP, RTN4, GLEA2, TNKS2, KIAA0376, ING4, HSPH1, C13orf24, RBPSUH, C6orfl53, NKTR, NSEP1, U2AF1L, CYNL2, TPR, SOX2, GOLGA, BMI1, COX-2, EGFRvIII, EZH2, LICAM, Livin, Livin, MRP-3, Nestin, OLIG2, ART1, ART4, B-cyclin, Glil, Cav-1, cathepsin B, CD74, E-cadherin, EphA2/Eck, Fra-1/Fosl 1, GAGE-1, Ganglioside/GD2, GnT-V, β1,6-N, Ki67, Ku70/80, PROX1, PSCA, SOX10, SOX11, Survivin, UPAR and WT-1 or an immunogenic peptide thereof.

13 . The replication competent oncolytic adenovirus of claim 12 , wherein the heterologous nucleic acid is inserted in hyper-variable region 5 of the hexon gene of the adenovirus or is inserted into the HI loop region of the adenovirus fiber gene.

14 . The replication competent oncolytic adenovirus of claim 12 , wherein the adenovirus comprises a heterologous nucleic acid encoding EGFRvIII or an immunogenic peptide thereof inserted into the HI loop region of the fiber gene of the adenovirus and/or a heterologous nucleic acid encoding NY-ESO-1 or an immunogenic peptide thereof inserted in the hyper-variable region 5 of the hexon gene of the adenovirus.

15 . A pharmaceutical composition comprising a replication competent oncolytic adenovirus according to claim 1 and a pharmaceutically acceptable carrier.

16 . The pharmaceutical composition of claim 15 , further comprising one or more Th1 stimulating agents selected from the group consisting of: IL-12p70, IL-2, IFN-γ, lenalidomide, temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene-9-carboxamide), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide), lomustine (CCNU; N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea), bis-chloroethylnitrosourea (BCNU), melphalan hydrochloride (4 [bis(chloroethyl)amino]phenylalanine), busulfan (butane-1,4-diyl dimethanesulfonate), mechlorethamine (nitrogen mustard), chlorambucil, ifosfamide, streptozocin, dacarbazine (DTIC), thiotepa, altretamine (hexamethylmelamine), cisplatin, carboplatin, oxalaplatin, Ipilimumab, Tremelimumab, MDX-1106, MK-3475, AMP-224, Pidilizumab, and MDX-1105.

17 . The pharmaceutical composition of claim 16 , wherein the Th1 stimulating agent is IFN-γ or temozolomide.

18 . A method for treating cancer in a patient in need thereof, comprising administering to the patient a replication competent oncolytic adenovirus according to claim 1 or a composition according to claim 15 .

19 . The method of claim 18 , wherein the patient has a cancer selected from primary or metastatic brain cancer, melanoma, adenocarcinoma, thyoma, lymphoma, sarcoma, lung cancer, liver cancer, colon cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, leukemia, uterine cancer, breast cancer, prostate cancer, ovarian cancer, cervical cancer, bladder cancer, kidney cancer, and pancreatic cancer.

20 . The method of claim 19 , wherein the patient has a low-level or high-level glioma.

21 . The method of claim 18 , wherein the adenovirus is administered intratumorally, intravascularly, or in a neuronal or mesenchymal stem cell carrier.

22 . The method of claim 21 , wherein the adenovirus is administered intratumorally.

23 . The method of claim 18 , wherein the adenovirus is administered once or multiple times at a dose of 10 8 -10 13 plaque forming units (pfu).

24 . The method of claim 22 , comprising injection of an effective amount of the adenovirus into the tumor mass or vasculature.

25 . The method of claim 24 , whereby tumor growth is reduced in both the injected tumor and at least one non-injected tumor.

26 . The method of claim 18 , wherein the patient exhibits an IL-12 to IL-4 ratio less than 20.

27 . A method for treating cancer in a patient in need thereof, comprising co-administering to the patient an effective combined amount of (i) a replication competent oncolytic adenovirus according to claim 1 or a composition according to claim 15 and (ii) a Th1 stimulating agent.

28 . The method of claim 27 , wherein the Th1 stimulating agent is selected from the group consisting of: IL-12p70, IL-2, IFN-γ, lenalidomide, temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene-9-carboxamide), cyclophosphamide ((RS)—N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide), lomustine (CCNU; N-(2-chloroethyl)-N′-cyclohexyl-N-nitrosourea), bis-chloroethylnitrosourea (BCNU), melphalan hydrochloride (4 [bis(chloroethyl)amino]phenylalanine), busulfan (butane-1,4-diyl dimethanesulfonate), mechlorethamine (nitrogen mustard), chlorambucil, ifosfamide, streptozocin, dacarbazine (DTIC), thiotepa, altretamine (hexamethylmelamine), cisplatin, carboplatin, oxalaplatin, Ipilimumab, Tremelimumab, MDX-1106, MK-3475, AMP-224, Pidilizumab, and MDX-1105.

29 . The method of claim 28 , wherein the Th1 stimulating agent is IFN-γ or temozolomide.

30 . The method of claim 27 , wherein the Th1 stimulating agent is administered prior to the replication-competent oncolytic adenovirus.

31 . The method of claim 27 , wherein adenovirus is Delta-24 or Delta-24-RGD and the OX40 agonist is OX40 ligand (OX40L) (gp36).

32 . The method of claim 18 wherein the patient is a human.