Therapeutical Composition Containing Dentritic Cells And Use Thereof

Abstract

The present invention relates to a method for the preparation of a therapeutical composition, in particular, the present invention relates to a method for treating dendritic cells with a combination of at least one interferon gamma receptor agonist and at least one toll like receptor 2 and/or TLR 6 agonist and using these pretreated dendritic cells for the preparation of a therapeutical composition. Moreover, the present invention relates to a therapeutical composition containing dendritic cells and the use thereof for the treatment of various diseases and disorders.

1 . Method for the preparation of a composition containing dendritic cells and/or lymphocytes, comprising the step of culturing dendritic cells (DC) from any source in the presence of at least one IFNγ receptor agonist and of at least one toll like receptor (TLR)  2  and/or TLR  6  agonist.  
     
     
         2 . The method of  claim 1 , wherein the source of DC includes progenitor derived DC, in particular monocyte derived DC and stem cell derived DC, or in vivo existent DC, in particular blood derived DC, and wherein the DC are preferably derived from autologous monocytes of a person or animal to be treated with said composition.  
     
     
         3 . The method of  claim 1 , wherein the IFNγ receptor agonist is the appropriate species-specific interferon gamma or a variant thereof.  
     
     
         4 . The method according to  claim 1 , wherein the TLR  2 / 6  agonist is a bisacyloxypropyl-5-cystein derivative, in particular a lipopeptide derived from  Mycoplasma fermentans  or a corresponding synthetic lipopeptide capable of stimulating macrophages in vitro or in vivo, preferably Macrophage Activating Lipopeptide 2 kDa (MALP-2) or biologically active derivatives thereof, in particular S-[2,3-bis(palmitoyloxy)-(2S)-propyl]-L-cysteinyl-rboxy-polyethylenglykol oder S-[2,3-bis(palmitoyloxy)-(2R)-propyl]-L-cysteinyl-carboxy-polyethylenglykol.  
     
     
         5 . The method according to  claim 1 , wherein the treated DC are finally washed and preferably resuspended in water, saline or physiological medium.  
     
     
         6 . The method according to  claim 1 , wherein the DC are loaded with antigens.  
     
     
         7 . The method according to  claim 1 , wherein autologous or allogeneic lymphocytes acquired from the peripheral blood of donors are added, whereafter the DC and the lymphocytes and optionally further ingredients are cocultivated for a time period of up to several days, preferably at least 24 hours, more preferred at least 3 days.  
     
     
         8 . The method according to  claim 7 , wherein the lymphocytes are separated from the culture and optionally washed.  
     
     
         9 . The method according to  claim 1 , further comprising the step of processing the composition obtained into a therapeutical composition.  
     
     
         10 . A therapeutical composition containing DC and/or lymphocytes cocultivated with said DC, said DC have acquired the property to drive a T helper cell type I response, obtainable by a method according to  claim 1 .  
     
     
         11 . A use of the therapeutical composition according to  claim 10  as a vaccine for the treatment of malignancies, allergic disorders, infectious disorders including viral, bacterial, fungal and parasite infections, autoimmune disorders and host-versus-graft or graft-versus-host reactions in transplantation.  
     
     
         12 . The use of DC treated in vitro with at least one IFNγ receptor agonist in combination with at least one TLR 2 and/or TLR 6 agonist for the manufacture of a therapeutical composition for medical use, especially for the treatment of malignancies, allergic disorders, infectious disorders including viral, bacterial, fungal and parasite infections, autoimmune disorders and host-versus-graft or graft-versus-host reactions in transplantation.  
     
     
         13 . The use of lymphocytes cocultivated with DC treated with at least one IFNγ receptor agonist in combination with at least one TLR 2 and/or TLR 6 agonist for the manufacture of a therapeutical composition for medical use, especially for the treatment of malignancies, allergic disorders, infectious disorders including viral, bacterial, fungal and parasite infections, autoimmune disorders and host-versus-graft or graft-versus-host reactions in transplantation.  
     
     
         14 . The use according to  claim 12 , where the DC have been treated with a method according to  claim 1 .  
     
     
         15 . A diagnostic method to monitor the immune status of persons or animals characterized in that DC which have been prestimulated with at least one IFNγ receptor agonist and at least one TLR 2 and/or TLR 6 agonist are cocultivated with autologous or allogenic lymphocytes, whereafter proliferation, release of molecules, cytotoxic activity and/or antibody formation are measured, and the data is evaluated.  
     
     
         16 . Pharmaceutical composition comprising effective amounts of at least one IFNγ receptor agonist and at least one TLR 2 and/or TLR 6 agonist and a pharmaceutically acceptable carrier and/or diluent.  
     
     
         17 . A Pharmaceutical composition according to  claim 16  wherein the IFNγ receptor agonist is the appropriate species-specific interferon gamma or a variant thereof.  
     
     
         18 . A pharmaceutical composition according to  claim 16 , wherein the TLR 2/6 agonist is a bisacyloxypropyl-S-cystein derivative, in particular a lipopeptide derived from  Mycoplasma fermentans  or a corresponding synthetic lipopeptide capable of stimulating macrophages in vitro or in vivo, preferably Macrophage Activating Lipopeptide 2 kDa (MALP-2) or biologically active derivatives thereof, in particular S-[2,3-bis(palmitoyloxy)-(2S)-propyl]-L-cysteinyl-rboxy-polyethylenglykol oder S-[2,3-bis(palmitoyloxy)-(2R)-propyl]-L-cysteinyl-carboxy-polyethylenglykol.  
     
     
         19 . A method for treating a subject by immunotherapy comprising the step of administering an effective amount of a therapeutical composition according to  claim 10  to the subject in need thereof.  
     
     
         20 . A method according to  claim 19  for the treatment of malignancies, allergic disorders, infectious disorders including viral, bacterial, fungal and parasite infections, autoimmune disorders and host-versus-graft or graft-versus-host reactions in transplantation.  
     
     
         21 . A method according to  claim 19 , wherein the dendritic cells and the lymphocytes are administered simultaneously, separately or sequentially.  
     
     
         22 . A method according to  claim 19 , wherein the at least one IFNγ receptor agonist and the at least one TLR  2  and/or TLR  6  agonist are administered simultaneously, separately or sequentially.  
     
     
         23 . A method according to  claim 16 , wherein the way of administering the composition is selected from the group consisting of oral, intradermal, subcutaneous, intravenously, inhalatively, intranasal, intranodal or by injection into or near the tumor in the case of cancer.  
     
     
         24 . A method for treating a subject by immunotherapy comprising the step of administering an effective amount of a therapeutical composition according to  claim 16  to the subject in need thereof.