Methods for stem cell transplantation

Abstract

The present disclosure provides methods of hematopoietic stem cell transplantation (HSCT). In particular, the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method, with an ex-vivo method of γδ T cell expansion and αβ T cell depletion. The in-vivo T-cell depletion method depletes (in-vivo) the alloreactive T cells that would otherwise increase the risk of GvHD.

What is claimed: 
     
         1 . A method for allogeneic hematopoietic stem cell transplantation (HSCT) comprising the steps of:
 i. administering to a subject on day 0 a allogeneic hematopoietic stem cell first graft infusion comprising peripheral blood stem cells (PBSC);   ii. After day 0, administering to the subject an agent which provides in vivo T cell depletion; and   iii. After day 0, administering to the subject a second graft infusion comprising T cells enriched in γδ T cells and depleted in αβ T cells.   
     
     
         2 . The method of  claim 1 , wherein the second graft infusion is administered about +7 to about +25 days relative to day 0. 
     
     
         3 . The method of  claim 1 , wherein the second graft infusion is administered about +7 to about +9 days relative to day 0. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 1 , wherein the agent for in vivo T cell depletion is cyclophosphamide (CY). 
     
     
         8 . The method of  claim 1 , further comprising administering a Graft vs. Host Disease (GvHD) prophylaxis treatment regimen after day 0. 
     
     
         9 . The method of  claim 8 , wherein the GvHD prophylaxis treatment regimen comprises administering to the subject and immunosuppressive agent selected from cyclophosphamide (CY), mycophenolate mofetil (MMF), tacrolimis, or any combination thereof. 
     
     
         10 . The method of  claim 1 , further comprising administering a growth factor after day 0. 
     
     
         11 . The method of  claim 10 , wherein the growth factor is granulocyte-colony stimulating factor (G-CSF) and wherein the G-CSF is administered to the subject on any one or more days from about day +5 relative to day 0 to about day +20 relative to day 0. 
     
     
         12 . (canceled) 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 1 , wherein the number of infused γδ T cells in the second graft infusion is selected from the group consisting of: less than about 5×10 8  γδ T cells/kg of the subject's weight, less than about 1×10 7  γδ T cells/kg of the subject's weight, and less than about 5×10 6  γδ T cells/kg of the subject's weight. 
     
     
         15 . The method of  claim 1 , wherein the composition of the second graft infusion is selected from the group consisting of: greater than or equal to 60% γδ T cells; greater than or equal to 60% γδ T cells and less than or equal to 5% αβ T cells; and greater than or equal to 60% γδ T cells, less than or equal to 5% αβ T cells, and less than or equal to 25% NK cells. 
     
     
         16 . (canceled) 
     
     
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         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . The method of  claim 1  wherein the in vivo T cell depletion agent is administered to the subject on any one or more days between days +1 and +10 relative to day 0. 
     
     
         36 . The method of  claim 1  wherein the allogeneic hematopoietic stem cells of the first graft are haploidentical hematopoietic stem cells. 
     
     
         37 . The method of  claim 1  wherein the subject has a condition that is treatable by HSCT wherein the condition is selected from: acute lymphoblastic leukemia (ALL); relapsed ALL; Hodgkin lymphoma (HL); Non-Hodgkin lymphoma (NHL); relapsed HL or NHL; acute myeloid leukemia (AML); relapsed AML; chronic myeloid leukemia (CML); myelodysplastic syndrome (MDS); refractory MDS; astrocytoma; Atypical Teratoid Rhaboid Tumor; brain stem glioma; choroid plexus tumors, carcinoma and papilloma; craniopharyngioma; desmoplastic infantile astrocytoma; germ cell tumor; medulloblastoma; neurofibromatosis; oligodendroglioma; optic glioma; neuroblastoma; Ewing's Sarcoma; Primitive Neuroectodermal Tumor, and infection. 
     
     
         38 . The method of  claim 1 , wherein the composition of the second graft infusion comprises greater than 60% γδ T cells, less than about 5% T cells and less than about 25% natural killer (NK) cells. 
     
     
         39 . The method of  claim 1 , further comprising the step of administering a preparatory chemotherapy regimen. 
     
     
         40 . The method of  claim 39  wherein the preparatory chemotherapy regimen comprises administering to the subject, Busulfan, Fludarabine, CY, full body irradiation (TBI) or any combination thereof. 
     
     
         41 . The method of  claim 1 , further comprising the step of expanding γδ T cells ex vivo prior to the administering of step (iii).