Immunotherapeutic vaccine and antibody combination therapy

Abstract

The present invention relates to a combination product, composition(s) and kit of parts comprising at least (i) a therapeutic vaccine and (ii) one or more immune checkpoint modulator(s). The present invention also concerns a method for treating a proliferative or an infectious disease as well as a method for eliciting or stimulating and/or re-orienting an immune response, wherein said methods comprise administering to a subject in need thereof said combination product or said composition(s).

1 . A combination product comprising at least (i) a therapeutic vaccine and (ii) one or more immune checkpoint modulator(s). 
     
     
         2 . The combination product of  claim 1 , wherein said therapeutic vaccine comprises a recombinant plasmid or a viral vector. 
     
     
         3 . The combination product of  claim 2 , wherein said therapeutic vaccine comprises a poxvirus. 
     
     
         4 . The combination product of  claim 2 , wherein said therapeutic vaccine comprises a human or an animal adenovirus. 
     
     
         5 . The combination product of  claim 4 , wherein said adenovirus is replication-defective. 
     
     
         6 . The combination product of  claim 1 , wherein said therapeutic vaccine comprises or encodes one or more polypeptide(s) selected from the group consisting of suicide gene products, immunostimulatory polypeptides, and antigenic polypeptides. 
     
     
         7 . The combination product of  claim 6 , wherein said therapeutic vaccine comprises or encodes one or more polypeptide(s) selected from the group consisting of the MUC1 antigen, HPV E6 and E7 antigens, the human IL-2, the human GM-CSF, the FCU1 suicide gene, HBV antigens, mycobacteria antigens, and the HCV non structural antigens. 
     
     
         8 . The combination product of  claim 7 , wherein said therapeutic vaccine comprises a MVA virus encoding the MUC-1 antigen and IL-2; a MVA virus encoding a fusion of NS3 and NS4 HCV antigens and NS5b antigen; a MVA virus encoding membrane anchored HPV-16 non-oncogenic E6 and E7 antigens and IL-2; a MVA virus encoding the FCU1 suicide gene; a MVA virus encoding a combination of TB antigens or an Ad vector encoding a combination of HBV antigens. 
     
     
         9 . (canceled) 
     
     
         10 . The combination product of  claim 1 , wherein said one or more immune checkpoint modulator(s) is a human or humanized monoclonal antibody that specifically binds to any of PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA, SLAM, 2B4, CD160, KLRG-1, and CTLA4. 
     
     
         11 . The combination product of  claim 10 , wherein at least one of said one or more immune checkpoint modulator(s) is selected from the group consisting of (a) an antibody that specifically binds to human PD-1; (b) an antibody that specifically binds to human PD-L1; and (c) an antibody that specifically binds to human CTLA-4. 
     
     
         12 . The combination product of  claim 1 , wherein said one or more immune checkpoint modulator(s) is/are expressed by said therapeutic vaccine. 
     
     
         13 . The combination product of  claim 1 , wherein said combination product is a composition comprising a therapeutically effective amount of at least said therapeutic vaccine and said one or more immune checkpoint modulator and a pharmaceutically acceptable vehicle. 
     
     
         14 . The combination product of  claim 1 , comprising from about 0.5 mg/kg to about 25 mg/kg of the immune checkpoint modulator(s). 
     
     
         15 . The combination product of  claim 1 , wherein said combination comprises from approximately 10 8  vp to approximately 5×10 11  vp of an adenoviral vector or from approximately 10 6  pfu to approximately 10 10  pfu of a MVA vector. 
     
     
         16 . The combination product of  claim 15 , wherein the immune checkpoint modulator(s) comprised in said combination is formulated for intravenous or intratumoral administration and wherein the therapeutic vaccine comprised in said combination is formulated for intravenous, intramuscular, subcutaneous or intratumoral administration. 
     
     
         17 . The combination product of  claim 1 , wherein the administrations of said therapeutic vaccine and said one or more immune checkpoint inhibitor is concomitant, sequential, or interspersed. 
     
     
         18 . The combination product of  claim 17 , wherein the administration(s) of said therapeutic vaccine starts before the administration(s) of said immune checkpoint modulator(s). 
     
     
         19 . The combination product according to  claim 1  comprising from 4 to 15 administrations of 10 7  or 10 9  pfu of a MVA-based therapeutic vaccine at approximately 1 to 3 week interval interspersed with 2 to 6 administrations of 3 to 10 mg/kg of anti-immune checkpoint antibody/antibodies every 2 or 3 weeks. 
     
     
         20 . A composition comprising effective amounts of:
 (a) a therapeutic vaccine that comprises a recombinant plasmid or viral vector; and   (b) one or more immune checkpoint modulator(s) that is/are a human or humanized monoclonal antibody/antibodies that specifically bind(s) to any of PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA, SLAM, 2B4, CD160, KLRG-1, and CTLA4.   
     
     
         21 . A method for treating a proliferative or an infectious disease comprising administering:
 (a) a combination product comprising at least (i) a therapeutic vaccine and (ii) one or more immune checkpoint modulator(s); or   (b) a composition comprising effective amounts of: (1) a therapeutic vaccine that comprises a recombinant plasmid or viral vector; and (2) one or more immune checkpoint modulator(s) that is/are a human or humanized monoclonal antibody/antibodies that specifically bind(s) to any of PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA, SLAM, 2B4, CD160, KLRG-1, and CTLA4.   
     
     
         22 . The method of  claim 21 , wherein said proliferative disease is a cancer and wherein said infectious disease results from infection with a virus selected from the group consisting of herpes virus papillomavirus, poxvirus, retrovirus, HCV, HBV, and influenza virus. 
     
     
         23 . A method for eliciting or stimulating and/or re-orienting an immune response comprising administering:
 (a) a combination product comprising at least (i) a therapeutic vaccine and (ii) one or more immune checkpoint modulator(s); or   (b) a composition comprising effective amounts of: (1) a therapeutic vaccine that comprises a recombinant plasmid or viral vector; and (2) one or more immune checkpoint modulator(s) that is/are a human or humanized monoclonal antibody/antibodies that specifically bind(s) to any of PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA, SLAM, 2B4, CD160, KLRG-1, and CTLA4 to a subject in need thereof so as to activate the patient's immunity.   
     
     
         24 . The method of  claim 21  which is used or carried out in association with one or more conventional therapeutic modalities. 
     
     
         25 . A kit comprising:
 (a) a container comprising a therapeutic vaccine that comprises a recombinant plasmid or viral vector; and   (b) a different container comprising one or more immune checkpoint modulator(s) that is/are a human or humanized monoclonal antibody/antibodies that specifically bind(s) to any of PD-1, PD-L1, PD-L2, LAG3, Tim3, BTLA, SLAM, 2B4, CD160, KLRG-1, and CTLA4.   
     
     
         26 . The combination product of  claim 3 , wherein said poxvirus is a vaccinia virus. 
     
     
         27 . The method of  claim 23  which is used or carried out in association with one or more conventional therapeutic modalities