Immunotherapeutic combination for the treatment of tumors that over-express receptors with tyrosine kinase activity

Abstract

The present invention is related to the field of immunology and more specifically to cancer immunotherapy, particularly with immunotherapeutic combinations and treatment methods to prevent tumor cell growth and/or to eliminate those cells. The methods described in the present invention are based on the blockade of receptors with protein kinase activity in tyrosine residues (Receptor Tyrosine Kinases, RTK) and of ligands for those receptors. Immunotherapeutic combinations are described that cause the blockade of RTK receptors and/or their ligands, by means of a combination of passive and active immunotherapy. The referenced procedures can be applied to patients in different clinical stages with tumors of epithelial origin that over-express those receptors. The combination of active and passive immunotherapy can be simultaneous or sequential independent of whether the therapeutic procedure will be used in patients with advanced disease or as adjuvant therapy.

1 . A combination useful for immunotherapy, where this combination has an effect on growth and/or proliferation of cells, whose growth is dependent on the interaction between a receptor and its ligand, in the receptor tyrosine kinase system (RTK), this combination includes: 
 a. —An antibody against a RTK receptor.    b. —A vaccine in which the active principle is the RTK receptor, and that induces antibodies against this receptor.    
     
     
         2 . Immunotherapy combination according to  claim 1  where the RTK is the EGF receptor.  
     
     
         3 . Immunotherapy combination according to  claim 2  where the vaccine is directed against the EGF receptor.  
     
     
         4 . Immunotherapy combination according to  claim 2  where the antibody against the RTK receptor is an antibody against the EGF receptor.  
     
     
         5 . Immunotherapy combination according to  claim 4  where the antibody against the RTK receptor is a humanized antibody against the EGF receptor.  
     
     
         6 . Immunotherapy combination according to  claim 5  where the humanized antibody against the EGF receptor is IOR R3.  
     
     
         7 . A treatment combination useful for immunotherapy, where this combination has an effect on growth and/or proliferation of cells, whose growth is dependent on the interaction between a receptor and its ligand, in the system of receptor tyrosine kinases (RTK), this combination including: 
 a. —An antibody against the ligands of the RTK receptor and    b. —A vaccine whose active principle is (are) the RTK receptor's ligand(s) and that induces antibodies against this (those) ligand(s).    
     
     
         8 . A therapeutic combination according to  claim 7  where the RTK receptor's ligand is EGF.  
     
     
         9 . A therapeutic combination according to  claim 8  where the vaccine is composed of conjugated proteins P64K and EGF.  
     
     
         10 . A therapeutic combination according to  claim 7  where the RTK receptor ligand is TGF-alpha.  
     
     
         11 . A therapeutic combination according to  claim 10  where the vaccine is composed of conjugated proteins P64K and TGF alpha.  
     
     
         12 . A combination useful for immunotherapy, where this combination has an effect on growth and/or proliferation of cells, whose growth is dependent on the interaction between a receptor and its ligand, in the system of receptor protein tyrosine kinases (RTK), this combination includes: 
 a. —A first agent selected from one of the antibodies against the RTK receptor and of a vaccine where the active principle is the RTK receptor that induces antibodies against this receptor, and    b. —A second agent selected from of one of the antibodies against the ligands of the RTK receptor and of a vaccine where the active principle is this ligand, which induces antibodies against said ligand.    
     
     
         13 . An immunotherapy combination according to  claim 12 , where the first agent is an antibody against the RTK receptor.  
     
     
         14 . An immunotherapy combination according to  claim 13  where the antibody against the RTK receptor is an antibody against the EGF receptor.  
     
     
         15 . An immunotherapy combination according to  claim 14  where the antibody against the EGF receptor is a monoclonal antibody.  
     
     
         16 . An immunotherapy combination according to  claim 15  where the antibody against the EGF receptor is a humanized antibody.  
     
     
         17 . An immunotherapy combination according to  claim 16  where the antibody against the EGF receptor is IOR R3.  
     
     
         18 . An immunotherapy combination according to  claim 12 , where the first agent is a vaccine whose active principle is an RTK receptor.  
     
     
         19 . An immunotherapy combination according to  claim 18 , where the first agent is a vaccine whose active principle is the EGF receptor.  
     
     
         20 . An immunotherapy combination according to  claim 12  where the second agent is an antibody against an RTK receptor ligand.  
     
     
         21 . An immunotherapy combination according to  claim 20  where the antibody against the RTK receptor's ligand is an antibody against EGF.  
     
     
         22 . An immunotherapy combination according to  claim 20  where the antibody against the RTK receptor is an antibody against TGF-alpha.  
     
     
         23 . An immunotherapy combination according to  claim 12 , where the second agent is a vaccine whose active principle is an RTK receptor's ligand.  
     
     
         24 . An immunotherapy combination according to  claim 23  where the vaccine contains EGF as active principle.  
     
     
         25 . An immunotherapy combination according claim to  24  where the vaccine contains conjugated proteins p64K and EGF as active principle.  
     
     
         26 . An immunotherapy combination according to  claim 23  where the vaccine contains TGF-alpha as active principle.  
     
     
         27 . An immunotherapy combination according to  claims 1  to  26  inclusive, whose combination consists of a mixture of reagents containing independent doses of effective formulations, either of Mab or vaccines, where the combination of those independent formulations induces decreased growth of tumors that over-express EGF-R.  
     
     
         28 . An immunotherapy combination according to  claim 27 , whose combination consists of a mixture of reagents containing independent doses of effective formulations, either of Mab against the EGF receptor and its ligands or of vaccines with EGF-R and its ligands (EGF, TGF alpha) as active principle, and where the combination of those independent formulations induces decreased growth of tumors that over-express EGF-R.  
     
     
         29 . A method to control growth and/or proliferation of cells whose growth is dependent on the interaction between a receptor and its ligand, in the receptor tyrosine kinase (RTK) system, this method including the treatment with one of the therapeutic combinations defined in any one of the preceding claims.  
     
     
         30 . A method according to  claim 29  that includes the simultaneous treatment with agents against RTK receptors and their ligands.  
     
     
         31 . A method according to  claim 29  that includes the simultaneous treatment with vaccines and antibodies.  
     
     
         32 . A method according to  claim 29  that includes the treatment at the first stage with this antibody and at a second stage with this vaccine.  
     
     
         33 . A method according to  claim 29  that includes the treatment at a first stage with this vaccine and at a second stage with this antibody.