Adenoviral vectors and methods and uses related thereto

Abstract

The present invention relates to the fields of life sciences and medicine. Specifically, the invention relates to cancer therapies. More specifically, the present invention relates to oncolytic adenoviral vectors and cells and pharmaceutical compositions comprising said vectors. The present invention also relates to a use of said vectors in the manufacture of a medicament for treating cancer in a subject and a method of treating cancer in a subject. Furthermore, the present invention relates to methods of producing GM-CSF in a cell and increasing tumor specific immune response in a subject, as well as uses of the oncolytic adenoviral vector of the invention for producing GM-CSF in a cell and increasing tumor specific immune response in a subject.

1 . An oncolytic adenoviral vector or a pharmaceutical composition comprising the oncolytic adenoviral vector, wherein the oncolytic adenoviral vector comprises an adenovirus serotype 5 (Ad5) nucleic acid backbone; a 24 bp deletion (D24) in the Rb binding constant region 2 of E1; a capsid modification wherein the capsid modification is Ad5/3 chimerism; a gp19k/6.7K deletion in the E3 region; and a nucleic acid sequence encoding a human granulocyte-macrophage colony-stimulating factor (GM-CSF) in the place of the deleted gp19k/6.7K in the E3 region, wherein the oncolytic adenoviral vector is capable of selectively replicating in cells having defects in the Rb-p16 pathway, and wherein the effective amount of the oncolytic adenoviral vector contains between 5×10e10-5×10e11 viral particles. 
     
     
         2 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , further comprising one or more regions selected from the group consisting of E2, E4 and late regions. 
     
     
         3 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , further comprising regions including a left inverted terminal repeat (ITR), a partial E1, a pIX, a pIVa2, a E2, a VA1, a VA2, a L1, a L2, a L3, a L4, a partial E3, a L5, a E4, and a right ITR. 
     
     
         4 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein the regions are in a sequential order in a 5′ to 3′ orientation. 
     
     
         5 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , further comprising a wild type region located upstream of the E1. 
     
     
         6 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein the E1 comprises a viral packaging signal. 
     
     
         7 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein the nucleic acid sequence encoding GM-CSF is of a wild type. 
     
     
         8 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein at least one of the one or more regions is E4 and is of a wild type. 
     
     
         9 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein the capsid modification is a RGD-4C modification. 
     
     
         10 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , further comprising at least one expression cassette. 
     
     
         11 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , further comprising only one expression cassette. 
     
     
         12 . The oncolytic adenoviral vector or pharmaceutical composition of  claim 1 , wherein said anticancer effect is selected from the group consisting of an anti-tumor effect, an tumoricidal effect and a cytotoxic effect.