Recombinant influenza viruses expressing tumor-associated antigens as antitumor agents
The present invention relates to the engineering of recombinant influenza viruses that express tumor-associated antigens. Expression of tumor-associated antigens by these viruses can be achieved by engineering specific epitopes into influenza virus proteins, or by engineering viral genes that encode a viral protein and the specific antigen as independent polypeptides. Tumor-bearing patients can be immunized with the recombinant influenza viruses alone, or in combination with another treatment, to induce an immune response that leads to tumor reduction. The recombinant viruses can also be used to vaccinate high risk tumor-free patients to prevent tumor formation in vivo.
1. A method of inducing an immune response against a tumor-associated antigen or an epitope of a tumor-associated antigen in a patient, comprising administering to a patient in need thereof an immunogenic composition consisting essentially of an effective amount of a recombinant influenza virus and a pharmaceutically acceptable carrier, wherein the genome of the virus contains a region encoding the tumor-associated antigen or the epitope of a tumor-associated antigen.
2. The method of claim 1 , wherein the region of the genome of the virus encoding the tumor-associated antigen or epitope of a tumor-associated antigen is inserted into an open reading frame of a genomic segment of the influenza virus.
3. The method of claim 2 , wherein said genomic segment is a structural gene of the influenza virus.
4. The method of claim 3 , wherein said structural gene is hemagglutinin (HA) or neuraminidase (NA).
5. The method of claim 1 , wherein said tumor-associated antigen is a melanoma antigen.
6. The method of claim 1 , wherein said tumor-associated antigen is a nonmelanoma antigen.
7. The method of claim 6 , wherein said nonmelanoma antigen is a breast, ovarian, cervical or pancreatic antigen.
8. The method of claim 1 , wherein said tumor-associated antigen is gp100, MART-1/MelanA, TRP-1 (gp75), tyrosinase, MAGE-1, MAGE-3, BAGE, GAGE-1, GAGE-2, N-acetylglucosaminyltransferase-V, p15, b-catenin, MUM-1, CDK4, Her-2/neu, human papillomavirus-E7 or MUC-1.
9. The method of claim 1 , wherein said recombinant influenza virus is attenuated.
10. The method of claim 1 , wherein a dosage of between 10 6 and 10 7 plaque forming units of the recombinant influenza virus is administered to the patient.
11. The method of claim 1 , wherein said immunogenic composition is administered through a mucosal membrane or surface, or by a non-respiratory route.
12. The method of claim 1 , wherein said immunogenic composition is administered intravenously, intraperitoneally, intramuscularly, subcutaneously, by pulmonary administration, or intranasally.
13. The method of claim 1 , wherein the patient is human.