Combined gene therapy for the treatment of macroscopic gliomas
Described herein are compositions and methods for the treatment of cancer, and particularly brain cancer (e.g., glioma) in a mammal. In various embodiments of the invention, a combined therapeutic approach including TK with systemic ganciclovir administration and Flt3L are used in connection with gene therapeutic techniques or direct peptide injection for the aforementioned indications. Kits useful in practicing the inventive method are also disclosed, as are animal models useful for studying brain cancer.
1. A method of prolonging the survival of a mammal that has a brain tumor, comprising:
providing a quantity of a first viral vector encoding thymidine kinase (TK) operably linked to a first promoter;
providing a quantity of a second viral vector encoding Fms-like tyrosine kinase 3 ligand (Flt3L) operably linked to a second promoter;
co-administering a therapeutically effective amount of the quantity of the first viral vector encoding TK operably linked to the first promoter and the quantity of the second viral vector encoding Flt3L operably linked to the second promoter directly into the brain tumor in the mammal; and
administering a therapeutically effective quantity of systemic ganciclovir to the mammal, wherein the TK and Flt3L are expressed in the brain tumor, wherein the brain tumor is macroscopic at the time of initial treatment, and wherein survival of the mammal is prolonged for at least six months.
2. The method of claim 1 , wherein the first and second viral vectors are independently selected from the group consisting of recombinant adenoviral vectors, recombinant adeno-associated viral vectors, herpes simplex virus type 1 vectors, and lentiviral vectors.
3. The method of claim 1 , wherein the viral vector encoding TK operably linked to the first promoter is a recombinant adenoviral vector.
4. The method of claim 1 , wherein the viral vector encoding Flt3L operably linked to the second promoter is a herpes simplex virus type-1 vector.
5. The method of claim 1 , wherein the brain tumor is a glioma.
6. A method for prolonging the survival of a mammal that has a brain tumor, comprising:
providing a quantity of a viral vector encoding a TK gene operably linked to a promoter;
providing a composition comprising Flt3L protein;
co-administering a therapeutically effective amount of the quantity of the viral vector encoding the TK gene operably linked to the promoter and the composition comprising Flt3L protein directly into the brain tumor in the mammal; and
administering a therapeutically effective quantity of systemic ganciclovir to the mammal, wherein TK is expressed in the brain tumor and Flt3L protein is present in the brain tumor, wherein the brain tumor is macroscopic at the time of initial treatment, and wherein survival of the mammal is prolonged for at least six months.
7. The method of claim 6 , wherein the composition further comprises a pharmaceutically acceptable carrier.
8. The method of claim 6 , wherein the viral vector is selected from the group consisting of recombinant adenoviral vectors, recombinant adeno-associated viral vectors, herpes simplex virus type 1 vectors, and lentiviral vectors.
9. The method of claim 6 , wherein the viral vector is a recombinant adenoviral vector.
10. The method of claim 6 , wherein the brain tumor is a glioma.
11. An animal model for brain cancer, comprising a non-human mammal, wherein the non-human mammal carries in at least a portion of the cells of its brain at least one exogenous TK gene operably linked to a first promoter and at least one exogenous Flt3L gene operably linked to a second promoter, wherein the non-human mammal carries a macroscopic tumor in its brain.
12. The method of claim 1 , wherein the brain tumor is a glioblastoma.
13. The method of claim 6 , wherein the brain tumor is a glioblastoma.