Influenza virus vector for virotherapy
The present invention provides a recombinant influenza virus vector comprising an NS gene encoding a truncated NS1 protein of at least 73 and up to 122 amino acids of the N-terminus of the respective wild type NS1 protein, wherein the vector replicates in IFN-sensitive tumor cells and does not replicate in normal, non-tumor cells, and expresses a heterologous immunostimulatory polypetide. The invention further provides a pharmaceutical composition containing the influenza virus vector, its use for the treatment of cancer patients and methods for producing the influenza virus vaccine.
1. A recombinant influenza B virus vector comprising an NS gene encoding a truncated NS1 protein consisting of 106 amino acids of the N-terminus of the respective wild type NS1 protein, wherein the vector:
(i) replicates in IFN-sensitive tumor cells and in IFN-resistant tumor cells, and is attenuated in normal cells, and
(ii) expresses a heterologous immunostimulatory polypeptide, wherein the heterologous polypeptide is a tumor associated antigen.
2. The influenza virus vector of claim 1 , wherein the influenza virus vector has an IFN-inducing phenotype.
3. The influenza virus vector of claim 1 , wherein the IFN-sensitive tumor cells are melanoma cells.
4. The influenza virus vector of claim 1 , wherein the NS gene is further modified by mutations in the noncoding region.
5. The influenza virus vector of claim 1 , wherein the vector comprises modifications of the genes encoding the NA and/or HA proteins.
6. The influenza virus vector of claim 1 , wherein the vector comprises modifications of the polymerase genes encoding the PB1, PB2, and/or PA proteins.
7. The influenza virus vector of claim 1 , wherein the vector comprises modifications of the genes encoding the M and/or NP proteins.
8. A composition comprising the influenza virus vector of claim 1 and a physiologically acceptable excipient.
9. The composition of claim 8 , comprising at least two influenza virus vectors, wherein each vector is a vector according to claim 1 , and wherein said vectors are derived from at least two types of influenza viruses selected from the group consisting of type A influenza viruses, type B influenza viruses, and type C influenza viruses.
10. The composition of claim 8 , further comprising an immunomodulatory molecule.
11. The composition of claim 10 , wherein the immunomodulatory molecule is an antibody.
12. The composition of claim 10 , wherein the immunomodulatory molecule is an antagonist of CTLA-4, PD-1 or 4-1BB21.
13. A method of inducing an immune response in a subject, comprising the step of administering an effective amount of the recombinant influenza B virus vector of claim 1 to a subject in need thereof.
14. The method of claim 13 , wherein the influenza virus vector is administered to the subject on a plurality of occasions.