METHODS FOR ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Various embodiments of the present disclosure provide therapeutic compositions and associated 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.
1 . A multi-component cellular therapy product comprising:
a) a first single dose transfer bag comprising a first population of isolated CD45 + cells comprising a dose of approximately 1.0×10 5 to approximately 1.0×10 8 CD34 + hematopoietic stem and progenitor cells (HSPCs) per kilogram of body weight of a human subject receiving the product, wherein the first population of CD45 + cells is formulated with an excipient at a neutral pH;
b) a second single dose transfer bag comprising a second population of isolated CD45 + cells comprising a dose of approximately 1.0×10 5 to approximately 2.0×10 7 fresh CD4 + CD25 + CD127 dim regulatory T cells (Tregs) per kilogram of body weight of the human subject receiving the product, wherein the second population of isolated CD45 + cells is formulated with an excipient at a neutral pH, optionally wherein the first single dose transfer bag and the second single dose transfer bag are the same transfer bag; and
c) a third single dose transfer bag comprising a third population of isolated CD45 + cells comprising a dose of approximately 1.0×10 5 to approximately 4.0×10 7 conventional CD3 + T cells (Tcons) per kilogram of body weight of the human subject receiving the product, wherein the third population of isolated CD45 + cells is formulated with an excipient at a neutral pH, wherein the excipient comprises one more cryoprotectants.
2 . (canceled)
3 . The multi-component cellular therapy product of claim 1 , wherein the product further comprises a pharmaceutical composition comprising a dose of tacrolimus sufficient to maintain a trough blood level of approximately 5 ng/ml to approximately 10 ng/ml in the human subject receiving the product.
4 . The multi-component cellular therapy product of claim 1 , wherein:
the first population of isolated CD45 + cells, the second population of isolated CD45 + cells, and/or the third population of isolated CD45 + cells is formulated at a volume that ranges from approximately 5 mL to approximately 1 L.
5 . The multi-component cellular therapy product of claim 1 , wherein the first population of isolated CD45 + cells, the second population of isolated CD45 + cells, and the third population of isolated CD45+ cells are from an allogeneic donor having at least one HLA mismatch relative to the human subject receiving the product.
6 . A method of treating a human subject having or suspected of having a hematologic malignancy, the method comprising administering to the human subject the multi-component cellular therapy product of claim 1 .
7 . A method of preparing a multi-component cellular therapy product comprising:
a) obtaining an HSPC-mobilized peripheral blood apheresis sample from a donor that is allogeneic with respect to a human subject receiving the product; and
b) selecting from the apheresis sample a first sample comprising from approximately 1.0×10 5 to approximately 1.0×10 8 CD34 + hematopoietic stem and progenitor cells (HSPCs) per kilogram of body weight of the human subject receiving the product, a second sample comprising from approximately 1.0×10 5 to approximately 2.0×10 7 CD4 + CD25 + CD127 dim regulatory T cells (Tregs) per kilogram of body weight of the human subject receiving the product, and a third sample comprising from approximately 1.0×10 5 to approximately 4.0×10 7 conventional CD3 + T cells (Tcons) per kilogram of body weight of the human subject receiving the product, wherein the multi-component cellular therapy product comprises the Tcons, the HSPCs, and the Tregs, wherein the HSPCs are selected by sorting the first sample with one or more ISPs specific for CD34 and selecting a CD34-enriched population, wherein the Tregs are selected by soring the second sample with one or more ISPs specific for CD25, one or more ISPs specific for CD4, and/or one or more ISPs specific for CD127, and selecting the CD4 + and CD127 dim cell population.
8 . A multi-component cellular therapy product produced by the method of claim 7 .
9 . A method of treating a human subject having or suspected of having acute leukemia in complete remission, active leukemia, primary refractory acute leukemia, or acute leukemia with minimal residual disease, wherein the method comprises administering to the human subject the multi-component cellular therapy product of claim 1 .
10 . A method of treating a human subject having or suspected of having low-risk acute myeloid leukemia (AML), high-risk AML in complete remission, or chronic myelogenous leukemia (CML), wherein the method comprises administering to the human subject the multi-component cellular therapy product of claim 1 .
11 . A method of treating a human subject having or suspected of having high-risk myelodysplastic syndrome, therapy-related myelodysplastic syndrome, and/or secondary myelodysplastic syndrome, wherein the method comprises administering to the human subject the multi-component cellular therapy product of claim 1 .
12 . A method of treating a human subject having or suspected of having a myeloproliferative syndrome, the method comprising administering to the human subject the multi-component cellular therapy product of claim 1 .
13 . A method of treating a human subject having or suspected of having non-Hodgkin lymphoma with poor risk features not suitable for autologous hematopoietic cell transplant (HCT), the method comprising administering to the human subject the multi-component cellular therapy product of claim 1 .
14 . The method of claim 6 , wherein the third population of isolated CD45 + cells is administered from approximately 24 to approximately 120 hours after administration of the first population of isolated CD45 + cells and the second population of isolated CD45 + cells.
15 . A cellular therapy kit comprising the multi-component cellular therapy product of claim 1 , wherein the kit further comprises written instructions for using the cellular therapy for treating a hematologic malignancy in a human subject.
16 . The multi-component cellular therapy product of claim 1 , wherein the neutral pH ranges from approximately 6.8 to approximately 7.6.
17 . The multi-component cellular therapy product of claim 1 , wherein the excipient comprises a transport buffer, wherein the transport buffer is selected from the group consisting of: phosphate-buffered saline (PBS), human serum, PlasmaLyte, and any combination thereof.
18 . The multi-component cellular therapy product of claim 17 , wherein the transport buffer further comprises approximately 0.1% weight by volume to approximately 10% weight by volume of a human carrier protein, wherein the human carrier protein is selected from the group consisting of: human serum albumin (HSA), intravenous immune globulin (IVIG), AB serum, and any combination thereof.
19 . The multi-component cellular therapy product of claim 1 , wherein any of the first single dose bag, the second single dose bad, and the third single dose bag is a polyvinyl chloride (PVC) transfer bag or an ethylene vinyl acetate (EVA) transfer bag.
20 . The multi-component cellular therapy product of claim 1 , wherein the one or more cryoprotectants are selected from the group consisting of: sorbitol, dimethyl sulfoxide (DMSO), propylene glycol, glycerol, polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG), serum, HSA, hetastarch, CRYOSTOR CS2, CRYOSTOR CS5, and CRYOSTOR CS10.
21 . The method of claim 6 , wherein the administering comprises infusing into the human subject the first population of isolated CD45+ cells, the second population of isolated CD45+ cells, and the third population of isolated CD45+ cells.