Adoptive transfer of cd8 + t cell clones derived from central memory cells

Abstract

The present invention provides a method of carrying out adoptive immunotherapy in a primate subject in need thereof by administering the subject a cytotoxic T lymphocytes (CTL) preparation in a treatment-effective amount. The method comprises administering as the CTL preparation a preparation consisting essentially of an in vitro expanded primate CTL population, the CTL population enriched prior to expansion for central memory T lymphocytes, and depleted prior to expansion of effector memory T lymphocytes. In some embodiments, the method may further comprise concurrently administering Interleukin-15 to the subject in an amount effective to increase the proliferation of the central memory T cells in the subject. Pharmaceutical formulations produced by the method, and methods of using the same, are also described.

1 . In a method of carrying out adoptive immunotherapy in a primate subject in need thereof by administering said subject a cytotoxic T lymphocytes (CTL) preparation in a treatment-effective amount, the improvement comprising:
 administering as said CTL preparation a preparation consisting essentially of an in vitro expanded primate CTL population, said CTL population enriched prior to expansion for central memory T lymphocytes, and depleted prior to expansion of effector memory T lymphocytes.   
     
     
         2 . The method of  claim 1 , wherein said CTL preparation is produced by the process of:
 (a) collecting a first CTL population from a donor;   (b) separating a CTL subpopulation enriched for CD62L +  central memory T lymphocytes and depleted of CD62L −  effector memory T lymphocytes to produce a central memory-enriched CTL subpopulation;   (c) expanding said central memory-enriched CTL subpopulation in vitro in a culture medium; and then   (d) collecting cells from said culture medium to produce said CTL preparation.   
     
     
         3 . The method of  claim 2 , wherein said separating step is carried out by: (i) contacting said first CTL population to anti-CD62L antibody, wherein said antibody is immobilized on a solid support, so that central memory cells bind to said support; then (ii) separating said support from said CTL population with central memory cells bound thereto; (iii) and then separating said central memory cells from said solid support to produce said central memory enriched CTL subpopulation. 
     
     
         4 . The method of  claim 1 , further comprising the step of concurrently administering Interleukin-15 to said subject in an amount effective to increase the proliferation of said central memory T cells in said subject. 
     
     
         5 . The method of  claim 1 , wherein said subject is a human subject. 
     
     
         6 . The method of  claim 1 , wherein said subject is afflicted with cancer. 
     
     
         7 . The method of  claim 1 , wherein said subject is afflicted with an infectious disease. 
     
     
         8 . The method of  claim 1 , wherein said subject is immunodeficient. 
     
     
         9 . The method of  claim 1 , wherein said central memory-enriched T cells are modified in vitro with at least one gene that targets cancer cells. 
     
     
         10 . A pharmaceutical formulation consisting essentially of an in vitro expanded primate cytotoxic T lymphocyte (CTL) population, said CTL population enriched prior to expansion for central memory T lymphocytes, and depleted prior to expansion of effector memory T lymphocytes. 
     
     
         11 . The formulation of  claim 10 , wherein said CTL population is produced by the process of:
 (a) collecting a first CTL population from a donor;   (b) separating a CTL subpopulation enriched for CD62L +  central memory T lymphocytes and depleted of CD62L −  effector memory T lymphocytes to produce a central memory-enriched CTL subpopulation;   (c) expanding said central memory-enriched CTL subpopulation in vitro in a culture medium; and then   (d) collecting cells from said culture medium to produce said CTL preparation.   
     
     
         12 . The formulation of  claim 11 , wherein said separating step is carried out by: (i) contacting said first CTL population to anti-CD62L antibody, wherein said antibody is immobilized on a solid support, so that central memory cells bind to said support; then (ii) separating said support from said CTL population with central memory cells bound thereto; (iii) and then separating said central memory cells from said solid support to produce said central memory enriched CTL subpopulation. 
     
     
         13 . The formulation of  claim 10 , wherein said central memory-enriched T cells are modified in vitro with at least one gene that targets cancer cells. 
     
     
         14 . A method of making a cytotoxic T lymphocyte (CTL) preparation useful for adoptive immunotherapy; said method comprising the steps of:
 (a) collecting a first CTL population from a donor;   (b) separating a CTL subpopulation enriched for CD62L +  central memory T lymphocytes and depleted of CD62L −  effector memory T lymphocytes to produce a central memory-enriched CTL subpopulation;   (c) expanding said central memory enriched CTL subpopulation in vitro in a culture medium; and then   (d) collecting cells from said culture medium to produce said CTL preparation.   
     
     
         15 . The method of  claim 14 , wherein said expanding step comprises administering Interleukin-15 to said central memory subpopulation in vitro. 
     
     
         16 . The method of  claim 14 , wherein said central memory-enriched T cells are modified in vitro with at least one gene that targets cancer cells. 
     
     
         17 . An in vitro expanded primate cytotoxic T lymphocyte (CTL) preparation produced by the process of  claim 14 .