Treatment for CD5+ B cell lymphoma

Abstract

The present invention provides methods for increasing expression of cell surface molecules of CD5 + B cell lymphoma cells by contacting cells with immune response modifiers. The invention also provides methods for the treatment of CD5 + B cell lymphomas, including chronic lymphocytic leukemia and small lymphocytic lymphoma, by administering immune response modifier compounds to a subject in need of such treatment. Suitable immune response modifier compounds include agonists of TLR7 and/or TLR8.

1 . A method of increasing the expression of at least one cell surface molecule of CD5 +  B cell lymphoma cells, the method comprising contacting the CD5 +  B cell lymphoma cells with at least one IRM compound effective to increase the expression of at least one cell surface molecule of the CD5 +  B cell lymphoma cells.  
     
     
         2 . The method of  claim 1  wherein the CD5 +  B cell lymphoma cells are selected from the group consisting of chronic lymphocytic leukemia (CLL) cells, small lymphocytic lymphoma cells (SLL), mantle cell lymphoma cells, splenic lymphoma with villous lymphocytes, and combinations thereof.  
     
     
         3 . The method of  claim 1  wherein the IRM is a TLR7 agonist.  
     
     
         4 . The method of  claim 1  wherein the IRM is a TLR8 agonist.  
     
     
         5 . The method of  claim 1  wherein the IRM is a tetrahydroimidazoquinoline amine.  
     
     
         6 . The method of  claim 1  wherein the IRM is a sulfonamide substituted imidazoquinoline amine.  
     
     
         7 . The method of  claim 1  wherein the cell surface molecule is a costimulatory molecule.  
     
     
         8 . The method of  claim 7  wherein at least one costimulatory molecule is CD25, CD38, CD40, CD54, CD80, CD83, or CD86.  
     
     
         9 . The method of  claim 1  wherein the cell surface molecule is CD20, CD22, or CD23.  
     
     
         10 . The method of  claim 1  wherein contacting the CD5 +  B cell lymphoma cells with an IRM occurs in vitro.  
     
     
         11 . The method of  claim 1  wherein contacting the CD5 +  B cell lymphoma cells with an IRM occurs in an organ, tissue, or blood.  
     
     
         12 . The method of  claim 1  wherein contacting the CD5 +  B cell lymphoma cells with an IRM occurs in vivo in a subject.  
     
     
         13 . A method of stimulating CD5 +  B cell lymphoma cells to produce a cytokine, the method comprising contacting the CD5 +  B cell lymphoma cells with an IRM effective to produce at least one cytokine above a level produced by the CD5 +  B cell lymphoma cells not contacted by the IRM, wherein the at least one cytokine is IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α, GM-CSF, or a combination thereof.  
     
     
         14 . The method of  claim 13  wherein contacting the CD5 +  B cell lymphoma cells occurs in vitro.  
     
     
         15 . The method of  claim 13  wherein contacting the CD5 +  B cell lymphoma cells occurs in an organ, tissue, or blood.  
     
     
         16 . The method of  claim 13  wherein contacting the CD5 +  B cell lymphoma cells occurs in vivo in a subject.  
     
     
         17 . A method of increasing T cell proliferation, the method comprising: 
 contacting CD5 +  B cell lymphoma cells with an IRM effective to increase the expression of at least one costimulatory molecule on the cell surface of CD5 +  B cell lymphoma cells; and    contacting the CD5 +  B cell lymphoma cells with T cells, thereby activating the T cells;    wherein the activated T cells demonstrate increased proliferation compared to T cells contacted with CD5 +  B cell lymphoma cells that have not been contacted with an IRM.    
     
     
         18 . The method of  claim 17 , further comprising contacting the CD5 +  B cell lymphoma cells with at least one additional immunomodulating agent.  
     
     
         19 . The method of  claim 18  wherein the additional immunomodulating agent comprises IL-2.  
     
     
         20 . The method of  claim 18  wherein the additional immunomodulating agent comprises a protein kinase C agonist.  
     
     
         21 . The method of  claim 18  wherein the T cells and the CD5 +  B cell lymphoma cells are contacted in vivo.  
     
     
         22 . A method of increasing the killing of CD5 +  B cell lymphoma cells by CD5 +  B cell lymphoma cell-specific cytotoxic T cells, the method comprising: 
 contacting CD5 +  B cell lymphoma cells with an IRM effective to increase the expression of at least one costimulatory molecule on the surface of the CD5+ lymphoma cells; and    contacting the CD5+ lymphoma cells with CD8 +  T cells, thereby activating the CD8 +  T cells;    wherein the activated CD8 +  T cells are CD5 +  B cell lymphoma cell-specific cytotoxic T cells that demonstrate increased killing of CD5 +  B cell lymphoma cells compared to CD8 +  T cells contacted with CD5 +  B cell lymphoma cells that have not been contacted with an IRM.    
     
     
         23 . The method of  claim 22 , further comprising contacting the CD5 +  B cell lymphoma cells with at least one additional immunomodulating agent.  
     
     
         24 . The method of  claim 23  wherein the additional immunomodulating agent comprises IL-2.  
     
     
         25 . The method of  claim 23  wherein the additional immunomodulating agent comprises a protein kinase C agonist.  
     
     
         26 . The method of  claim 22  wherein the CD5 +  B cell lymphoma cells are contacted with the IRM in vivo.  
     
     
         27 . A method of increasing the killing of CD5 +  B cell lymphoma cells by autologous T cells in a subject suffering from a CD5 +  B cell lymphoma, the method comprising administering to the subject an IRM that is a TLR7 and/or TLR8 agonist.  
     
     
         28 . The method of  claim 27  further comprising administering IL-2.  
     
     
         29 . The method of  claim 27  further comprising administering a protein kinase C agonist.  
     
     
         30 . The method of  claim 27  further comprising administering IL-2 and a protein kinase C agonist.  
     
     
         31 . A method of treating a subject suffering from a CD5 +  B cell lymphoma, the method comprising administering to the subject an IRM effective to increase the expression of at least one cell surface molecule of the CD5 +  B cell lymphoma cells in an amount effective to increase the expression of at least one cell surface molecule of the CD5 +  B cell lymphoma cells.  
     
     
         32 . The method of  claim 31  wherein the IRM is a TLR7 and/or TLR8 agonist.  
     
     
         33 . The method of  claim 31  further comprising administering IL-2.  
     
     
         34 . The method of  claim 31  further comprising administering a protein kinase C agonist.  
     
     
         35 . The method of  claim 31  further comprising administering IL-2 and a protein kinase C agonist.  
     
     
         36 . The method of  claim 31  wherein at least one cell surface molecule whose expression is increased is a target of a therapeutic agent, and the method further comprises administering to the subject an effective amount of the therapeutic agent.  
     
     
         37 . The method of  claim 26  wherein the cell surface molecule is CD20, CD22, or CD23.  
     
     
         38 . The method of  claim 31  wherein the cell surface molecule is a costimualtory molecule.  
     
     
         39 . A method of treating a CD5 +  B cell lymphoma, the method comprising administering to a subject in need of such treatment an IRM effective to ameliorate at least one symptom or clinical sign characteristic of a the CD5 +  B cell lymphoma.  
     
     
         40 . The method of  claim 39  wherein the IRM is administered in an amount effective to demonstrate at least a 50% decrease in peripheral blood lymphocytes, lymphadenopathy, or splenomegaly for at least two months.  
     
     
         41 . The method of  claim 39  wherein the IRM is administered in an amount effective to prevent the development of progressive disease, wherein progressive disease is at least a 50% increase in circulating lymphocytes or a progression to a more aggressive histology.  
     
     
         42 . The method of  claim 39  wherein the IRM is administered in an amount effective to ameliorate erythematous lesions.  
     
     
         43 . A vaccine comprising isolated CD5 +  B cell lymphoma cells or an immunologically active portion thereof, wherein isolated CD5 +  B cell lymphoma cells have been contacted with an IRM effective to increase the expression of at least one costimulatory molecule on the cell surface of the CD5 +  B cell lymphoma cells.  
     
     
         44 . The vaccine of  claim 43  wherein the IRM is a TLR7 and/or TLR8 agonist.  
     
     
         45 . The vaccine of  claim 43  wherein the isolated CD5 +  B cell lymphoma cells have further been contacted with IL-2.  
     
     
         46 . The vaccine of  claim 43  wherein the isolated CD5 +  B cell lymphoma cells have further been contacted with a protein kinase C agonist.  
     
     
         47 . The vaccine of  claim 43  wherein the isolated CD5 +  B cell lymphoma cells have further been contacted with IL-2 and a protein kinase C agonist.  
     
     
         48 . A method of preparing a vaccine comprising contacting isolated CD5 +  B cell lymphoma cells with an IRM effective to increase the expression of at least one molecule on the surface of the CD5 +  B cell lymphoma cells.  
     
     
         49 . The method of  claim 48  further comprising contacting said isolated cells with IL-2.  
     
     
         50 . The method of  claim 48  further comprising contacting said isolated cells with a protein kinase C agonist.  
     
     
         51 . The method of  claim 48  further comprising contacting said isolated cells with IL-2 and a protein kinase C agonist.  
     
     
         52 . A method of treating a subject suffering from a CD5+ lymphoma, the method comprising administering to the subject an immunologically active portion of isolated CD5 +  B cell lymphoma cells, wherein the isolated CD5 +  B cell lymphoma cells have been contacted with an IRM effective to increase the expression of at least one costimulatory molecule on the cell surface of the CD5 +  B cell lymphoma cells.  
     
     
         53 . The method of  claim 52  wherein the isolated CD5 +  B cell lymphoma cells have also been contacted with IL-2.  
     
     
         54 . The method of  claim 52  wherein the isolated the CD5 +  B cell lymphoma cells have also been contacted with a protein kinase C agonist.  
     
     
         55 . The method of  claim 52  wherein the isolated CD5 +  B cell lymphoma cells have also been contacted with IL-2 and a protein kinase C agonist.  
     
     
         56 . The method of  claim 52  wherein the isolated CD5 +  B cell lymphoma cells are derived from the subject suffering from a CD5 +  B cell lymphoma.  
     
     
         57 . The method of  claim 52  wherein the immunologically active portion of isolated CD5 +  B cell lymphoma cells comprises whole cells.  
     
     
         58 . The method of  claim 52  wherein the immunologically active portion of isolated CD5 +  B cell lymphoma cells comprises a cell membrane preparation or a protein preparation from the isolated CD5 +  B cell lymphoma cells.  
     
     
         59 . The method of  claim 52  wherein at least one cell surface molecule whose expression is increased is a target of a therapeutic agent, and the method further comprises administering to the subject an effective amount of the therapeutic agent.  
     
     
         60 . A method of initiating a CD5 +  B cell lymphoma-reactive T cell response in a subject diagnosed as having a CD5 +  B cell lymphoma, the method comprising administering to the subject a composition comprising an immunologically active portion of isolated CD5 +  B cell lymphoma cells that have been contacted with an IRM effective to increase the expression of at least one costimulatory molecule on the cell surface of the CD5 +  B cell lymphoma cells.  
     
     
         61 . The method of  claim 60  wherein the isolated CD5 +  B cell lymphoma cells have also been contacted with IL-2.  
     
     
         62 . The method of  claim 60  wherein the isolated CD5 +  B cell lymphoma cells have also been contacted with a protein kinase C agonist.  
     
     
         63 . The method of  claim 60  wherein the isolated CD5 +  B cell lymphoma cells have also been contacted with IL-2 and a protein kinase C agonist.  
     
     
         64 . The method of  claim 60  wherein the isolated CD5 +  B cell lymphoma cells are derived from the subject suffering from the CD5+ lymphoma.  
     
     
         65 . The method of  claim 60  wherein the isolated CD5 +  B cell lymphoma cells are derived from a subject suffering from CLL or SLL.  
     
     
         66 . The method of  claim 60  wherein the immunologically active portion of isolated CD5 +  B cell lymphoma cells comprises whole cells.  
     
     
         67 . The method of  claim 60  wherein the immunologically active portion of isolated CD5 +  B cell lymphoma cells comprises a cell membrane preparation or a protein preparation from the isolated CD5 +  B cell lymphoma cells.