In situ injection of antigen-presenting cells with genetically enhanced cytokine expression

Abstract

The use of professional antigen presenting cells genetically modified to enhance expression of an immunostimulatory cytokine is disclosed for the treatment of individuals having tumors or infections. The genetically modified professional antigen presenting cells are injected directly at or near the site of the tumor or infection. Preferred professional antigen presenting cells include dendritic cells, and preferred immunostimulatory cytokines include interleukins such as IL-12.

What is claimed is:  
     
         1 . A method of treating an individual having an tumor comprising: 
 injecting an individual near a site of said infection or tumor with an effective amount of genetically modified professional antigen presenting cells,    wherein said professional antigen presenting cells have been genetically modified to enhance expression of an immunostimulatory cytokine.    
     
     
         2 . A method as in  claim 1  wherein said professional antigen presenting cells are dendritic cells.  
     
     
         3 . A method as in  claim 2  wherein said dendritic cells have been genetically modified by transduction with a viral vector encoding said cytokine.  
     
     
         4 . A method as in  claim 3  wherein said viral vector is a retroviral vector.  
     
     
         5 . A method as in  claim 3  wherein said viral vector is selected from the group consisting of adenoviral vectors and adeno-associated viral vectors.  
     
     
         6 . A method as in  claim 4  wherein said dendritic cells have been genetically modified by centrifuging said professional antigen presenting cells with the supernatant of producer cells expressing said retroviral vector encoding said cytokine.  
     
     
         7 . A method as in  claim 2  wherein said dendritic cells are selected from the group consisting of CD34+-derived dendritic cells, bone marrow-derived dendritic cells, monocyte-derived dendritic cells, splenocyte derived dendritic cells, skin-derived dendritic cells, follicular dendritic cells, and germinal center dendritic cells.  
     
     
         8 . A method as in  claim 2  wherein said dendritic cells are CD34+-derived dendritic cells cultured in the presence of at least one factor selected from the group consisting of G-CSF, GM-CSF, TNF-α, IL-4, the Flt-3 ligand and the kit ligand.  
     
     
         9 . A method as in  claim 1  wherein said cytokine is selected from the group consisting of the interleukins (e.g., IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-8, IL-9, IL-10, IL-12, IL-18, IL-19, IL-20), the interferons (e.g., IFN-α, IFN-β, IFN-γ), tumor necrosis factor (TNF), transforming growth factor-β (TGF-β), granulocyte colony stimulating factors (G-CSF), macrophage colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), the Flt-3 ligand and the kit ligand.  
     
     
         10 . A method as in  claim 1  wherein said individual has a cancer selected from the group consisting of melanomas, hepatomas, adenocarcinomas, basal cell cancers, oral cancers, nasopharyngeal cancers, laryngeal cancers, bladder cancers, head and neck cancers, renal cell cancers, pancreatic cancers, pulmonary cancers, cervical cancers, ovarian cancers, esophageal cancers, gastric cancers, prostate cancers, testicular cancers, and breast cancers.  
     
     
         11 . A method of treating an individual having an infection comprising: 
 injecting an individual near a site of said infection or tumor with an effective amount of genetically modified professional antigen presenting cells professional antigen presenting cells,    wherein said professional antigen presenting cells have been genetically modified to enhance expression of an immunostimulatory cytokine.    
     
     
         12 . A method as in  claim 11  wherein said professional antigen presenting cells are dendritic cells.  
     
     
         13 . A method as in  claim 12  wherein said dendritic cells have been genetically modified by transduction with a viral vector encoding said cytokine.  
     
     
         14 . A method as in  claim 13  wherein said viral vector is a retroviral vector.  
     
     
         15 . A method as in  claim 13  wherein said viral vector is selected from the group consisting of adenoviral vectors and adeno-associated viral vectors.  
     
     
         16 . A method as in  claim 14  wherein said dendritic cells have been genetically modified by centrifuging said professional antigen presenting cells with the supernatant of producer cells expressing said retroviral vector encoding said cytokine.  
     
     
         17 . A method as in  claim 12  wherein said dendritic cells are selected from the group consisting of CD34+-derived dendritic cells, bone marrow-derived dendritic cells, monocyte-derived dendritic cells, splenocyte derived dendritic cells, skin-derived dendritic cells, follicular dendritic cells, and germinal center dendritic cells.  
     
     
         18 . A method as in  claim 12  wherein said dendritic cells are CD34+-derived dendritic cells cultured in the presence of at least one factor selected from the group consisting of G-CSF, GM-CSF, TNF-α, IL-4, the Flt-3 ligand and the kit ligand.  
     
     
         19 . A method as in  claim 11  wherein said cytokine is selected from the group consisting of the interleukins (e.g., IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-6, IL-8, IL-9, IL-10, IL-12, IL-18, IL-19, IL-20), the interferons (e.g., IFN-α, IFN-β, IFN-γ), tumor necrosis factor (TNF), transforming growth factor-β (TGF-β), granulocyte colony stimulating factors (G-CSF), macrophage colony stimulating factor (M-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), the Flt-3 ligand and the kit ligand.