Combination therapy for a stable and long term engraftment

Abstract

A method of treating a subject in need of a non-syngeneic cell or tissue graft is disclosed. The method comprising: (a) transplanting into a subject a dose of T cell depleted immature hematopoietic cells, wherein the T cell depleted immature hematopoietic cells comprise less than 5×105 CD3+ T cells per kilogram body weight of the subject, and wherein the dose comprises at least about 5×106 CD34+ cells per kilogram body weight of the subject; and subsequently (b) administering to the subject a therapeutically effective amount of cyclophosphamide, wherein the therapeutically effective amount comprises 25-200 mg per kilogram body weight, thereby treating the subject.

What is claimed is: 
     
         1 . A method of treating a subject in need of a non-syngeneic cell or tissue graft, the method comprising:
 (a) transplanting into a subject a dose of T cell depleted immature hematopoietic cells, wherein said T cell depleted immature hematopoietic cells comprise less than 5×10 5  CD3 +  T cells per kilogram body weight of the subject, and wherein said dose comprises at least about 5×10 6  CD34+ cells per kilogram body weight of the subject; and subsequently   (b) administering to the subject a therapeutically effective amount of cyclophosphamide, wherein said therapeutically effective amount comprises 25-200 mg per kilogram body weight, thereby treating the subject.   
     
     
         2 . The method of  claim 1 , further comprising conditioning the subject under reduced intensity conditioning prior to step (a). 
     
     
         3 . The method of  claim 2 , wherein said conditioning is effected 1-10 days prior to said transplanting. 
     
     
         4 . The method of  claim 1 , wherein a dose of said T cell depleted immature hematopoietic cells comprises 5-40×10 6  CD34+ cells per kilogram body weight of the subject. 
     
     
         5 . The method of  claim 1 , wherein said T cell depleted immature hematopoietic cells are obtained from a non-syngeneic donor. 
     
     
         6 . The method of  claim 2 , wherein said reduced intensity conditioning comprises a non-myeloablative conditioning. 
     
     
         7 . The method of  claim 1 , wherein said concentration of said cyclophosphamide is about 100-200 mg per kg body weight. 
     
     
         8 . The method of  claim 1 , wherein said cyclophosphamide is administered in a single dose or in two doses. 
     
     
         9 . The method of  claim 8 , wherein each of said two doses:
 (i) comprises a concentration of about 50 mg per kg body weight; or   (ii) is administered on days 3 and 4 following step (a).   
     
     
         10 . The method of  claim 10 , wherein said cell or tissue graft is transplanted into the subject prior to, concomitantly with or following said transplanting said dose of T cell depleted immature hematopoietic cells into said subject. 
     
     
         11 . The method of  claim 10 , wherein said cell or tissue graft and said T cell depleted immature hematopoietic cells are obtained from the same donor. 
     
     
         12 . A method of treating a subject in need of an immature hematopoietic cell transplantation, the method comprising:
 (a) transplanting into a conditioned subject a dose of T cell depleted immature hematopoietic cells, wherein said T cell depleted immature hematopoietic cells comprise less than 5×10 5  CD3+ T cells per kilogram body weight of the subject, and wherein said dose comprises at least about 5×10 6  CD34+ cells per kilogram body weight of the subject; and subsequently   (b) administering to the subject a therapeutically effective amount of cyclophosphamide, wherein said therapeutically effective amount comprises 25-200 mg per kilogram body weight, thereby treating the subject.   
     
     
         13 . The method of  claim 12 , wherein said conditioned subject has been conditioned under reduced intensity conditioning. 
     
     
         14 . The method of  claim 13 , wherein said reduced intensity conditioning is effected 1-10 days prior to said transplanting. 
     
     
         15 . The method of  claim 13 , wherein said reduced intensity conditioning comprises a non-myeloablative conditioning protocol. 
     
     
         16 . The method of  claim 12 , wherein a dose of said T cell depleted immature hematopoietic cells comprises at least about 5-40×10 6  CD34+ cells per kilogram body weight of the subject. 
     
     
         17 . The method of  claim 12 , wherein said T cell depleted immature hematopoietic cells are obtained from a non-syngeneic donor. 
     
     
         18 . The method of  claim 12 , wherein said concentration of said cyclophosphamide is about 100-200 mg per kg body weight. 
     
     
         19 . The method of  claim 12 , wherein said cyclophosphamide is administered in a single dose or in two doses. 
     
     
         20 . The method of  claim 19 , wherein each of said two doses:
 (i) comprises a concentration of about 50 mg per kg body weight; or   (ii) is administered on days 3 and 4 following step (a).   
     
     
         21 . The method of  claim 5 , wherein said non-syngeneic is allogeneic. 
     
     
         22 . The method of  claim 17 , wherein said non-syngeneic is allogeneic. 
     
     
         23 . The method of  claim 21 , wherein said allogeneic donor is an HLA matched sibling, an HLA matched unrelated donor, an HLA haploidentical related donor, or a related or unrelated donor displaying one or more disparate HLA determinants. 
     
     
         24 . The method of  claim 22 , wherein said allogeneic donor is an HLA matched sibling, an HLA matched unrelated donor, an HLA haploidentical related donor, or a related or unrelated donor displaying one or more disparate HLA determinants.