Recombinant adenoviruses for gene therapy in cancers

Abstract

The invention concerns recombinant viruses comprising a heterologous DNA sequence under the control of expression signals specifically active in tumor cells, and their preparation and use in the treatment and prevention of cancers.

1. A replication defective recombinant adenovirus comprising a heterologous DNA sequence under the control of an expression signal which is inducible by the an Epstein-Barr virus (EBV) antigen, or by a papilloma virus antigen, wherein the EBV antigen is EBNA 1  or EBNA 2 , and wherein the papilloma virus antigen is E 6 . 
     
     
       2. An The adenovirus according to  claim 1 , wherein the expression signal is activated by the EBNA1 antigen, or the EBNA 2  antigen. 
     
     
       3. An The adenovirus according to  claim 2 , wherein the expression signal consists of a chimeric promoter comprising a sequence which is activated by the EBNA1 antigen fused upstream of a viral promoter. 
     
     
       4. An The adenovirus according to claim  1   2 , lacking regions of its genome which are required for replication in a target cell. 
     
     
       5. An The adenovirus according to  claim 4 , wherein said adenovirus is a type Ad5 human adenovirus or a type CAV-2 canine adenovirus. 
     
     
       6. An The adenovirus according to claim  1   2 , wherein the heterologous DNA sequence comprises a gene which encodes a product toxic in a cell infected by said adenovirus. 
     
     
       7. An The adenovirus according to  claim 6 , wherein said product renders said cell sensitive to a therapeutic agent. 
     
     
       8. An The adenovirus according to  claim 7 , wherein the gene is the thymidine kinase gene and the therapeutic agent is ganciclovir or acyclovir. 
     
     
       9. An The adenovirus according to claim  1   2 , wherein the heterologous DNA sequence comprises a gene which encodes a product effective to inhibit cell division. 
     
     
       10. An The adenovirus according to  claim 9 , wherein the gene is selected from the group consisting of tumour suppressor genes, antisense sequences and ribozymes. 
     
     
       11. An The adenovirus according to  claim 6 , wherein the heterologous DNA sequence comprises a gene whose expression product induces apoptosis of a cell infected by said adenovirus. 
     
     
       12. A composition comprising a the replication defective recombinant adenovirus according to claim  1   2  and an acceptable carrier. 
     
     
       13. A The composition according to  claim 12 , in injectable form. 
     
     
       14. The adenovirus of claim  4   3 , wherein the viral promoter is the terminal protein 1 (TP1) gene promoter. 
     
     
       15. An isolated cell comprising the adenovirus of claim  1   2 . 
     
     
       16. The composition of  claim 12  comprising from 10 6  to 10 10  pfu/ml of replication defective recombinant adenoviruses. 
     
     
       17. The adenovirus according to  claim 2 , wherein the expression signal is the EBNA 1  responsive element ( EBNA 1   - RE ). 
     
     
       18. The adenovirus according to  claim 14 , wherein the sequence which is activated by the EBNA 1  antigen is the EBNA 1  responsive element ( EBNA 1   - RE ). 
     
     
       19. The adenovirus according to  claim 17 , wherein said adenovirus is a type Ad 5  human adenovirus or a type CAV-   2  canine adenovirus.   
     
     
       20. The adenovirus of  claim 2 , wherein the expression signal comprises a promoter sequence from an Epstein- Barr virus.   
     
     
       21. The adenovirus according to  claim 20 , wherein said adenovirus is a type Ad 5  human adenovirus or a type CAV-   2  canine adenovirus.   
     
     
       22. The adenovirus according to  claim 20 , wherein the promoter sequence is inducible by the EBNA 1  antigen. 
     
     
       23. The adenovirus according to  claim 1 , wherein the expression signal is inducible by the papilloma virus E 6  antigen. 
     
     
       24. The adenovirus according to  claim 2 , wherein the expression signal comprises a BCR 2  viral promoter.