ARMED REPLICATION-COMPETENT ONCOLYTIC ADENOVIRUSES
Disclosed are replication-competent oncolytic adenoviruses, comprising chimeric human/mouse CD40 ligands. The oncolytic adenoviruses may be replication competent. The chimeric human/mouse CD40 ligand may be MEM40. Also disclosed are methods comprising administering a replication competent oncolytic adenovirus armed with at least one chimeric human/mouse CD40 ligand, for example MEM40, to a patient suffering from a cancer.
1 . A composition, comprising;
a replication-competent oncolytic adenovirus containing a heterologous nucleic acid inserted into a nonessential region of the adenovirus genome, said nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element.
2 . The composition of claim 1 , wherein the replication competent oncolytic adenovirus comprises a deletion in part, or all of the E3 gene region.
3 . The composition of claim 2 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the E3 deleted gene region.
4 . The composition of claim 3 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the reverse orientation to the native E3 gene.
5 . The composition of claim 1 , wherein the CD40 agonist is at least one CD40 ligand (CD40L).
6 . The composition of claim 5 , wherein the at least one CD40L is a chimeric human/mouse CD40 ligand.
7 . The composition of claim 6 , wherein the at least one chimeric human/mouse CD40 ligand is selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).
8 . The composition of claim 7 , wherein the at least one chimeric human/mouse CD40 ligand is MEM40.
9 . The composition of claim 6 , wherein the at least one chimeric human/mouse CD40 ligand has at least 90% identity with a ligand selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).
10 . The composition of claim 1 , wherein the transcriptional control element operatively linked to the CD40 agonist is a transcriptional promoter.
11 . The composition of claim 10 , wherein the transcriptional promoter is a cytomegalovirus (CMV) promoter.
12 . The composition of claim 1 , wherein the replication competent oncolytic adenovirus is a human type 5 adenovirus.
13 . The composition of claim 12 , wherein the replication competent oncolytic adenovirus is a Delta 24 adenovirus or Delta-24-RGD adenovirus.
14 . The composition of claim 1 , further comprising a pharmaceutically-acceptable carrier.
15 . A method, comprising:
administering to a patient suffering from a cancer a replication competent oncolytic adenovirus containing a heterologous nucleic acid inserted into a nonessential region of the adenovirus genome, said nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element.
16 . The method of claim 15 , wherein the replication competent oncolytic adenovirus comprises a deletion in part, or all of the E3 gene region.
17 . The method of claim 16 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the E3 deleted gene region.
18 . The method of claim 17 , wherein the nucleic acid comprising a sequence encoding a CD40 agonist operatively linked to a transcriptional control element is inserted in the reverse orientation to the native E3 gene.
19 . The method of claim 15 , wherein the replication competent oncolytic adenovirus is a Delta 24 adenovirus or Delta-24-RGD adenovirus.
20 . The method of claim 15 , wherein the CD40 agonist is at least one CD40 ligand (CD40L).
21 . The method of claim 20 , wherein the at least one CD40L is a chimeric human/mouse CD40 ligand.
22 . The method of claim 21 , wherein the at least one chimeric human/mouse CD40 ligand is selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).
23 . The method of claim 22 , wherein the at least one chimeric human/mouse CD40 ligand is MEM40.
24 . The method of claim 21 , wherein the at least one chimeric human/mouse CD40 ligand has at least 90% identity with a ligand selected from the group consisting of ISF30 (SEQ ID NO:1), ISF31 (SEQ ID NO:2), ISF32 (SEQ ID NO:3), ISF33 (SEQ ID NO:4), ISF34 (SEQ ID NO:5), ISF35 (MEM40) (SEQ ID NO:6), ISF36 (SEQ ID NO:7), ISF37 (SEQ ID NO:8), ISF38 (SEQ ID NO:9), ISF39 (SEQ ID NO:10), ISF40 (SEQ ID NO:11), and ISF41 (SEQ ID NO:12).
25 . The method of claim 15 , wherein the transcriptional control element operatively linked to the CD40 agonist is a transcriptional promoter.
26 . The method of claim 25 , wherein the transcriptional promoter is a cytomegalovirus (CMV) promoter.
27 . The method of claim 15 , wherein the oncolytic adenovirus is administered in a composition comprising a pharmaceutically-acceptable carrier.
28 . The method of claim 15 , wherein the patient has a cancer selected from primary or metastatic cancer.
29 . The method of claim 15 , wherein the patient has brain cancer or bladder cancer.
30 . The method of claim 15 , wherein the oncolytic adenovirus is administered intratumorally, intravenously, intraperitoneally, intratracheally, intramuscularly, intracranially, endoscopically, intralesionally, percutaneously, subcutaneously, regionally, or by direct injection or perfusion.
31 . The method of claim 15 , wherein the oncolytic adenovirus is administered once or multiple times.
32 . The method of claim 31 , wherein the replication competent oncolytic adenovirus is administered at a dose of 10 6 -10 13 plaque forming units (pfu).
33 . The method of claim 15 , further comprising:
administering at least one additional therapeutic agent.
34 . The method of claim 33 , wherein the at least one additional therapeutic agent is chemotherapy, immunotherapy, surgery, radiotherapy, viral therapy, or biotherapy.
35 . The method of claim 34 , wherein the at least one additional therapeutic agent is administered to the patient before administration of the replication competent oncolytic adenovirus.
36 . The method of claim 34 , wherein the at least one additional therapeutic agent is administered to the patient at the same time as administration of the replication competent oncolytic adenovirus.
37 . The method of claim 34 , wherein the at least one additional therapeutic agent is administered to the patient after administration of the replication competent oncolytic adenovirus.
38 . The method of claim 15 , wherein the patient is a human.