Methods for allogenic hematopoietic stem cell transplantation

Abstract

The disclosure provides methods for improved hematopoietic stem cell transplantations, including methods to enhance protection from graft versus host disease while maintaining effective immune responses such as graft versus tumor immune responses. The disclosure provides methods for administering, for example, hematopoietic stem and progenitor cells, regulatory T cells, and conventional T cells, wherein the conventional T cells are administered after the hematopoietic stem and progenitor cells and regulatory T cells. The disclosure also provides methods for administering, for example, hematopoietic stem and progenitor cells, regulatory T cells, and conventional T cells, wherein the regulatory T cells have not been cryopreserved prior to administration.

What is claimed is: 
     
         1 . A pharmaceutical dosing system for hematopoietic cell transplantation to a human subject in need, wherein the pharmaceutical dosing system comprises:
 a) a prophylactic composition comprising one GVHD prophylactic agent;   b) a primary therapeutic composition consisting essentially of:
 i. a population of isolated hematopoietic stem and progenitor cells; and 
 ii. a population of isolated regulatory T cells; and 
   c) a secondary therapeutic composition comprising a population of isolated CD3+ conventional T cells.   
     
     
         2 . The pharmaceutical dosing system of  claim 1 , wherein the primary and secondary therapeutic compositions are administered to the human subject at different times. 
     
     
         3 . The pharmaceutical dosing system of  claim 1 , wherein the secondary therapeutic composition is administered at least 12 hours after administration of the primary therapeutic composition. 
     
     
         4 . The pharmaceutical dosing system of  claim 1 , wherein the population of hematopoietic stem and progenitor cells are administered separate from the population of regulatory T cells. 
     
     
         5 . The pharmaceutical dosing system of  claim 4 , wherein the population of hematopoietic stem and progenitor cells comprise less than 2% CD3 +  cells. 
     
     
         6 . The pharmaceutical dosing system of  claim 4 , wherein the population of regulatory T cells comprises CD45 +  cells with more than 75% of the CD45 +  cells being regulatory T cells. 
     
     
         7 . The pharmaceutical dosing system of  claim 4 , wherein the hematopoietic stem and progenitor cells are CD34 + . 
     
     
         8 . The pharmaceutical dosing system of  claim 4 , wherein the regulatory T cells are CD4 + CD25 + CD127 dim  or CD4 + FOXP3 + . 
     
     
         9 . The pharmaceutical dosing system of  claim 4 , wherein the population of hematopoietic stem and progenitor cells comprises more than 1×10 5  hematopoietic stem and progenitor cells per kilogram of body weight of the human subject. 
     
     
         10 . The pharmaceutical dosing system of  claim 4 , wherein the population of regulatory T cells comprises more than 1×10 5  regulatory T cells per kilogram of body weight of the human subject. 
     
     
         11 . The pharmaceutical dosing system of  claim 1 , wherein the population of CD3+ conventional T cells comprises fewer than 1×10 7  CD3+ conventional T cells per kilogram of body weight of the human subject. 
     
     
         12 . The pharmaceutical dosing system of  claim 1 , wherein a ratio of regulatory T cells to CD3+ conventional T cells is between about 1:1 and 1:3. 
     
     
         13 . The pharmaceutical dosing system of  claim 1 , wherein the one GVHD prophylactic agent is sirolimus or tacrolimus. 
     
     
         14 . The pharmaceutical dosing system of  claim 1 , wherein the population of regulatory T cells has not been cryopreserved. 
     
     
         15 . The pharmaceutical dosing system of  claim 1 , wherein the population of hematopoietic stem and progenitor cells, regulatory T cells, and/or CD3+ conventional T cells is allogeneic to the human subject. 
     
     
         16 . The pharmaceutical dosing system of  claim 1 , wherein the population of CD3+ conventional T cells has been cryopreserved. 
     
     
         17 . The pharmaceutical dosing system of  claim 1 , wherein the population of hematopoietic stem and progenitor cells and the populations of regulatory T cells are administered to the human subject on the same day. 
     
     
         18 . The pharmaceutical dosing system of  claim 1 , wherein the system does not elicit a stage 2 or higher graft versus host disease (GVHD) in the human subject within 30 days of its administration to the human subject. 
     
     
         19 . The pharmaceutical dosing system of  claim 1 , wherein the population of hematopoietic stem cells is obtained from a donor that is HLA-matched relative to the human subject. 
     
     
         20 . A method of administering the pharmaceutical dosing system of  claim 1 , wherein the method comprises administration of the secondary therapeutic composition at least 12 hours after administration of the primary therapeutic composition to the human subject and wherein the method does not require treatment for GVHD.