Methods for the treatment of infections and tumors

Abstract

PD-1 antagonists are disclosed that can be used to reduce the expression or activity of PD-1 in a subject. An immune response specific to an infectious agent or to tumor cells can be enhanced using these PD-1 antagonists in conjunction with an antigen from the infectious agent or tumor. Thus, subjects with infections, such as persistent infections can be treated using PD-1 antagonists. In addition, subjects with tumors can be treated using the PD-1 antagonists. In several examples, subjects can be treated by transplanting a therapeutically effective amount of activated T cells that recognize an antigen of interest and by administering a therapeutically effective amount of a PD-1 antagonist. Methods are also disclosed for determining the efficacy of a PD-1 antagonist in a subject administered the PD-1 antagonist. In some embodiments, these methods include measuring proliferation of memory B cells in a sample from a subject administered the PD-1 antagonist.

1 . A method for determining the dose of a PD-1 antagonist that is useful to treat a subject, comprising
 measuring CD20 + CD27 + CD21 −  memory B cell proliferation and CD20 + CD21 + CD27 −  naïve B cell proliferation in a first sample from the subject administered the first dose of the PD-1 antagonist;   comparing proliferation of the CD20 + CD27 + CD21 −  memory B cells to the proliferation of CD20 + CD21 + CD27 −  naïve B cells; and   identifying the subject has having a significant increase in the proliferation of the CD20 + CD27 + CD21 −  memory B cells and an absence of a significant increase in proliferation of CD20 + CD21 + CD27 −  naïve B cells from the first sample, thereby determining that the dose of the PD-1 antagonist is effective for treating the subject,   or identifying the subject as having an absence of a significant increase in the proliferation of the CD20 + CD27 + CD21 −  memory B cells and an absence of a significant increase in proliferation of CD20 + CD21 + CD27 −  naïve B cells from the first sample, thereby determining that the dose of the PD-1 antagonist is insufficient for treating the subject.   
     
     
         2 . The method of  claim 1 , further comprising
 measuring proliferation of CD20 + CD27 + CD21 −  memory B cells and proliferation of CD20 + CD21 + CD27 −  naïve B cells in a second sample from the subject following the administration of the second dose;   identifying the subject as having an absence of a significant_increase in the proliferation of CD20 + CD27 + CD21 −  memory B cells and an absence of a significant increase in proliferation of CD20 + CD21 + CD27 −  naïve B cells from the second sample.   
     
     
         3 . The method of  claim 2 , wherein there is the absence of a significant alteration in the proliferation of memory B cells in the first sample as compared to the control, and wherein the second dose is higher than the first dose. 
     
     
         4 . The method of  claim 2 , wherein there is an increase in the proliferation of memory B cells from the first sample as compared to a control, and wherein the second dose is lower than the first dose. 
     
     
         5 . A method for treating a subject with a PD-1 antagonist, comprising
 administering the PD-1 antagonist to the subject;   isolating CD20 + CD27 + CD21 −  memory B cells from a sample from the subject administered the PD-1 antagonist wherein said isolating comprises detecting expression of CD20, CD27 and CD21;   isolating CD20 + CD21 + CD27 −  naïve B cells from a sample from the subject administered the PD-1 antagonist, wherein said isolating comprises detecting expression of CD20, CD21 and CD27;   measuring proliferation of the memory B cells and the naïve B cells;   identifying the subject as having an absence of in proliferation of the memory B cells as compared to proliferation of the naïve B cells, thereby determining that the PD-1 antagonist was not efficacious for inducing the immune response in the subject; and   administering a second dose of the PD-1 antagonist to the subject.   
     
     
         6 . The method of  claim 5 , wherein measuring proliferating memory B cells comprises measuring the expression of Ki67, measuring the incorporation of bromodeoxyuridine, or the use of fluorescence activated cells sorting (FACS). 
     
     
         7 . The method of  claim 5 , wherein the subject has a persistent viral infection or a tumor. 
     
     
         8 . The methods of  claim 5 , wherein the subject has the persistent viral infection and wherein the subject is also administered a viral antigen. 
     
     
         9 . The method of  claim 8 , wherein the viral infection is an infection with a hepatitis virus, a human immunodeficiency virus (HIV), a human T-lymphotrophic virus (HTLV), a herpes virus, an Epstein-Barr virus, or a human papilloma virus. 
     
     
         10 . The method of  claim 5 , wherein the subject has the tumor and wherein the subject is also administered a tumor antigen. 
     
     
         11 . The method of  claim 1 , wherein the PD-1 antagonist is an antibody that specifically binds PD-1, an antibody that specifically binds PD-L1, or an antibody that specifically binds PD-L2. 
     
     
         12 . The method of  claim 11 , wherein the antibody that specifically binds PD-1, the antibody that specifically binds PD-L1, or the antibody that specifically binds PD-L2 is (1) a monoclonal antibody or a functional fragment thereof, (2) a humanized antibody or a functional fragment thereof, or (3) an immunoglobulin fusion protein. 
     
     
         13 . A method of inducing an immune response in a human subject, comprising:
 administering to the subject a therapeutically effective amount of a PD-1 antagonist; and   isolating CD20 + CD27 + CD21 −  memory B cells from a sample from the subject, wherein said isolating comprises detecting expression of CD20, CD27 and CD21;   isolating CD20 + CD21 + CD27 −  naïve B cells from a sample from the subject administered the PD-1 antagonist, wherein said isolating comprises detecting expression of CD20, CD21 and CD27 and comprises the use of fluorescence activated cell sorting; and   quantifying proliferation of the memory B cells and the naïve B cells; and   identifying the subject as having an increase in the proliferation of the CD20 + CD27 + CD21 −  memory B cells and an absence of a significant increase in the proliferation of CD20 + CD21 + CD27 −  naïve B cells,   thereby producing an immune response to the antigen of interest in the mammalian subject, wherein the mammalian subject has a persistent infection with a virus or a tumor.   
     
     
         14 . The method of  claim 13 , wherein the subject has the persistent viral infection. 
     
     
         15 . The method of  claim 13 , wherein the subject is immunosuppressed. 
     
     
         16 . The method of  claim 13 , wherein the subject has a hepatitis infection. 
     
     
         17 . The method of  claim 16 , wherein the hepatitis infection is a hepatitis B infection. 
     
     
         18 . The method of  claim 13 , wherein the PD-1 antagonist is an antibody that specifically binds PD-1, an antibody that specifically binds PD-L1, an antibody that specifically binds PD-L2, a small inhibitory anti-PD-1 RNAi, a small inhibitory anti-PD-L1 RNA, an small inhibitory anti-PD-L2 RNAi, an anti-PD-1 antisense RNA, an anti-PD-L1 antisense RNA, an anti-PD-L2 antisense RNA, a dominant negative PD-1 protein, a dominant negative PD-L1 protein, a dominant negative PD-L2 protein, a small molecule inhibitor of PD-1, or combinations thereof. 
     
     
         19 . A method of selecting a PD-1 antagonist of use, comprising:
 contacting a population of cells comprising CD20 + CD27 + CD21 −  memory B cells with an agent in vitro; and   detecting the proliferation of CD20 + CD27 + CD21 −  memory B cells and/or the differentiation of CD20 + CD27 + CD21 −  memory B cells into antibody secreting cells,   wherein an increase of the proliferation of CD20 + CD27 + CD21 −  memory B cells and/or an increase in the differentiation of CD20 + CD27 + CD21 −  memory B cells into antibody secreting cells indicates that the agent is a PD-1 antagonist.   
     
     
         20 . The method of  claim 18 , wherein the PD-1 antagonist is an antibody that specifically binds PD-1, an antibody that specifically binds PD-L1, an antibody that specifically binds PD-L2, a small inhibitory anti-PD-1 RNAi, a small inhibitory anti-PD-L1 RNA, an small inhibitory anti-PD-L2 RNAi, an anti-PD-1 antisense RNA, an anti-PD-L1 antisense RNA, an anti-PD-L2 antisense RNA, a dominant negative PD-1 protein, a dominant negative PD-L1 protein, a dominant negative PD-L2 protein, a small molecule inhibitor of PD-1, or combinations thereof.