Oncolytic adenoviruses for treating cancer
The invention is related to an oncolytic adenovirus that comprises a sequence encoding a hyaluronidase enzyme inserted in its genome. This adenovirus spreads more efficiently in the tumour mass and therefore the oncolytic effect is increased. Injecting the oncolytic adenovirus of the invention endovenously, tumour volume regressions are obtained. Therefore the oncolytic adenovirus of the present invention is useful for the treatment of a cancer or a pre-malignant state of cancer.
1. A method for the treatment of a solid tumor in a subject, comprising administering a human oncolytic adenovirus to the subject, wherein the oncolytic adenovirus comprises a sequence encoding a human hyaluronidase enzyme inserted in the genome of the adenovirus, wherein:
the human hyaluronidase amino acid sequence lacks a membrane binding domain resulting in a soluble enzyme;
the expression of the hyaluronidase is controlled by a promoter;
the adenovirus comprises a modified capsid comprising a replacement of the KKTK heparan sulfate proteoglycan binding sequence (SEQ ID NO: 11) with a RGDK sequence (SEQ ID NO: 12); and
the solid tumor is characterized by selective replication of the adenovirus.
2. The method according to claim 1 , wherein the human oncolytic adenovirus is selected from any of human adenovirus serotypes 1-51.
3. The method according to claim 2 , wherein the human adenovirus is human adenovirus serotype 5.
4. The method according to claim 1 , wherein the human hyaluronidase enzyme is human testicular hyaluronidase.
5. The method according to claim 1 , wherein the hyaluronidase coding sequence is inserted into the genomic sequence of the oncolytic adenovirus downstream of the fibre coding sequence.
6. The method according to claim 1 , wherein the promoter is selected from the group consisting of the cytomegalovirus promoter, the adenovirus major late promoter, the SV40 promoter, the herpes simplex virus thymidine kinase promoter, the RSV promoter, the EF1 alpha promoter, the beta-actin promoter, the human IL-2 promoter, the human IL-4 promoter, the IFN promoter, the E2F promoter, and the human GM-CSF promoter.
7. The method according to claim 1 , wherein the adenovirus comprises a tissue-specific or a tumor-specific promoter, wherein the promoter controls the expression of one or more genes of the group of E1a, E1b, E2, and E4, to obtain selective replication in tumors.
8. The method according to claim 7 , wherein the promoter is selected from the E2F promoter, the telomerase hTERT promoter, the tyrosinase promoter, the prostate-specific antigen promoter, the alphafetoprotein promoter, and the COX-2 promoter.
9. The method according to claim 1 , wherein the adenovirus has mutations in one or more genes selected from E1a, E1b, E4, and VA-RNAs, to obtain selective replication in tumors.
10. The method according to claim 1 , wherein the adenovirus comprises a sequence that optimizes the translation into protein of the sequence that encodes the hyaluronidase.
11. The method according to claim 1 , wherein the adenovirus comprises a sequence selected from a splicing acceptor sequence, an IRES sequence, and a picornavirus 2A sequence.
12. The method according to claim 1 , wherein the adenovirus comprises one or more genes inserted in its genome.
13. The method according to claim 1 , wherein the solid tumor is a pancreatic cancer.
14. The method according to claim 1 , wherein the solid tumor is a melanoma.
15. The method according to claim 1 , wherein the adenovirus is administered directly to the tumor.
16. The method according to claim 1 , wherein the adenovirus is administered systemically.
17. The method according to claim 1 , wherein the solid tumor is a colon cancer.
18. The method according to claim 1 , wherein the solid tumor is a lung cancer.