Methods for treating chronic lymphocytic leukemia (cll)

Abstract

The present invention relates generally to the treatment of PML by infusion of activated and expanded autologous lymphocytes.

1 - 26 . (canceled) 
     
     
         27 . A method for improving T cell numbers in a subject comprising:
 (a) administering to the subject an effective amount of a chemotherapy, wherein the chemotherapy induces lymphodepletion in the subject;   (b) activating a population of autologous T cells in vitro with an agent that stimulates a TCR/CD3 complex-associated signal in the autologous T cells, wherein the agent is attached on a surface of the population of autologous T cells; and   (c) stimulating a CD28 accessory molecule on the surface of the population of autologous T cells in vitro with a ligand that binds the CD28 accessory molecule on the surface of the population of autologous T cells, wherein the ligand is attached on the same surface as the agent; and   (d) administering to the subject an effective amount of the population of activated and stimulated autologous T cells;   wherein the population of autologous T cells was obtained from the subject by apheresis or leukopheresis prior to administering the chemotherapy.   
     
     
         28 - 32 . (canceled) 
     
     
         33 . The method of  claim 27 , wherein the population of autologous T cells is administered two days after ending administration of the chemotherapy. 
     
     
         34 . The method of  claim 27 , wherein the population of autologous T cells is further expanded in vitro prior to administering to the subject. 
     
     
         35 . The method of  claim 27 , wherein the activating and stimulating steps induce a proliferation of the population of autologous T cells 
     
     
         36 . The method of  claim 35 , wherein the proliferation of the population of autologous T cells increases T cell counts in the subject for at least one month after administration. 
     
     
         37 . The method of  claim 27 , wherein the population of autologous T cells comprises cytotoxic T cells, regulatory T cells, and helper T cells. 
     
     
         38 . The method of  claim 27 , wherein the population of autologous T cells is antigen-specific, and wherein the antigen is selected from the group consisting of a polyomavirus JC virus (JCV)-specific protein, a JCV-specific epitope, VP1 p36, VP1 p100, a BKV protein, and a BKV epitope. 
     
     
         39 . The method of  claim 27 , wherein the agent is selected from the group consisting of an anti-CD3 antibody or antigen-binding fragment thereof, an anti-TCR antibody or antigen-binding fragment thereof, a superantigen or derivatives thereof, an MHC-peptide tetramer, growth factors, cytokine, viral proteins, HIV gp-120, adhesion molecules, L-selectin, LFA-3, CD54, LFA-1, chemokines, small molecules, and an antigen in a form suitable to trigger a primary activation signal in the T cell when complexed with the TCR/CD3 complex. 
     
     
         40 . The method of  claim 27 , wherein the ligand is selected from the group consisting of:
 (a) an anti-CD28 antibody or an antigen-binding fragment thereof,   (b) a CD80 or a CD28-binding fragment thereof, and   (c) a CD86 or a CD28-binding fragment thereof.   
     
     
         41 . The method of  claim 27 , wherein the surface is selected from the group consisting of a bead, a lipid bilayer, a cell surface, and a tissue-culture dish. 
     
     
         42 . The method of  claim 41 , wherein the cell surface is the cell surface of a human cell line. 
     
     
         43 . The method of  claim 42 , wherein the human cell line is a K562 cell line. 
     
     
         44 . The method of  claim 41 , wherein the cell surface is the cell surface of a genetically modified human cell line. 
     
     
         45 . The method of  claim 44 , wherein the modified human cell line is genetically modified to express a human Fcγ receptor. 
     
     
         46 . The method of  claim 45 , wherein the human Fcγ receptor comprises CD32 or CD64. 
     
     
         47 . The method of  claim 45 , wherein the modified human cell line is further modified to express a co-stimulatory molecule selected from the group consisting of CD80, CD86, 4-1BBL, OX40L, ICOS-L, ICAM, PD-L1, PD-L2, and a CD28-binding fragment thereof. 
     
     
         48 . The method of  claim 44 , wherein the genetically modified human cell line is modified to express a cytokine selected from the group consisting of IL-2, IL-4, IL-7, IL-10, IL-12, IL-15, GM-CSF, TNF-α, and IFN-γ. 
     
     
         49 . The method of  claim 27 , wherein the chemotherapy is administered daily for about three days or more. 
     
     
         50 . The method of  claim 27 , wherein the chemotherapy comprises cyclophosphamide and/or fludarabine. 
     
     
         51 . The method of  claim 50 , wherein the chemotherapy comprises
 (a) cyclophosphamide at about 250 mg/m2/day and fludarabine at about 25 mg/m2/day; or   (b) fludarabine at about 25 mg/m 2 /day.