Methods for stem cell transplantation
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 as 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.
1 . A method for allogeneic hematopoietic stem cell transplantation (HSCT) in a subject suffering from a hematologic malignancy comprising the steps of:
(a) administering to the subject on day 0 an allogeneic hematopoietic stem cell first graft infusion, wherein the allogenic hematopoietic stem cells are haploidentical and minimally manipulated;
(b) After day 0, administering to the subject an agent which provides in vivo T cell depletion, wherein the agent is cyclophosphamide; and
(c) After administering the agent which provides in vivo T cell depletion, administering to the subject a γδ T cell product, wherein the γδ cell product comprises an expanded population of γδ T cells and is depleted in αβ T cells, and further wherein the γδ cell product comprises 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 as determined by flow cytometric analysis;
wherein the method further comprises administering a preparatory chemotherapy regimen prior to day 0, and
wherein the method reduces the risk of relapse of the hematologic malignancy.
2 . The method of claim 1 , wherein the γδ T cell product is administered about +7 to about +25 days-relative to day 0.
3 . The method of claim 1 , further comprising administering a Graft vs. Host Disease (GvHD) prophylaxis treatment regimen after day 0.
4 . The method of claim 3 , wherein the GvHD prophylaxis regimen comprises administering to the subject an immunosuppressive agent selected from cyclophosphamide (CY), mycophenolate mofetil (MMF), tacrolimus, or any combination thereof.
5 . The method of claim 1 , further comprising administering a growth factor after day 0.
6 . The method of claim 5 , wherein the growth factor is granulocyte-colony stimulating factor (G-CSF), the administration of which is selected from day +5 relative to day 0 to about day +20 relative to day 0.
7 . The method of claim 1 , wherein the number of infused γδ T cells in the γδ cell product is less than about 5×10 8 γδ T cells/kg of the subject's weight.
8 . The method of claim 1 wherein the agent that provides in vivo T cell depletion is administered to the subject on any one or more days between +1 and +10 days relative to day 0.
9 . The method of claim 1 wherein the hematologic malignancy is selected from: acute lymphoblastic leukemia (ALL); Hodgkin lymphoma (HL); Non-Hodgkin lymphoma (NHL); acute myeloid leukemia (AML); chronic myeloid leukemia (CML); and myelodysplastic syndrome (MDS).
10 . The method of claim 1 , wherein the preparative chemotherapy regimen is selected from Fludarabine/Busulfan/total body irradiation for myeloid diseases; total body irradiation/cyclophosphamide (TBI/CY) for acute lymphoblastic leukemia (ALL) or aggressive Non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) in patients <40 years of age with no major comorbidities; and Fludarabine/total body irradiation for ALL or lymphoma in patients who are older than 40 years, or at any age with major comorbidities that portends high non-relapse mortality (NRM) with high intensity TBI/CY.
11 . The method of claim 1 , wherein the γδ T cell product is prepared by a method comprising ex vivo expansion.
12 . The method of claim 1 , wherein the agent which provides in vivo T cell depletion is administered at day +3 or +4 relative to day 0.
13 . The method of claim 1 , wherein the first graft infusion comprises PBSCs.
14 . The method of claim 7 , wherein the number of infused γδ T cells in the cell product is about 1×10 7 γδ T cells/kg of the subject's weight.
15 . The method of claim 7 , wherein the number of infused γδ T cells in the cell product is about 5×10 6 γδ T cells/kg of the subject's weight.
16 . The method of claim 9 , wherein the hematologic malignancy is relapsed ALL, relapsed HL, relapsed NHL or refractory MDS.