Compositions and methods of hematopoietic stem cell transplants
The present disclosure provides distinct therapeutic populations of cells that form a pharmaceutical composition useful in hematopoietic stem/progenitor cell transplant. For example, the present disclosure provides a therapeutic population of cells, comprising an enriched population of hematopoietic stem/progenitor cells, memory T cells, regulatory T cells, and wherein the population of cells is depleted of naïve conventional αβ-T cells. The present disclosure further provides methods of treatment using the therapeutic population of cells. In other embodiments, the present disclosure provides methods of producing a therapeutic population of cells.
1. A therapeutic composition comprising one or more unit doses of a cellular graft, wherein each unit dose of the cellular graft comprises a population of cells that is enriched for:
CD25+ regulatory T cells (Tregs); and
CD45RA− memory T cells (Tmems);
wherein the population of cells is depleted of CD45RA+CD25− naïve conventional αβ-T cells; wherein the population of cells comprises a ratio of CD45RA+CD25− naïve conventional αβ-T cells to CD25+ Tregs that is less than 1:5; wherein said therapeutic composition further comprises one or more pharmaceutically acceptable excipients; and wherein said therapeutic composition has a reduced incidence of Graft versus Host Disease (GVHD) following administration to a subject compared to administration of a composition comprising the ratio of CD45RA+CD25− naïve conventional αβ-T cells to CD25+ Tregs present in an unprocessed biological sample.
2. The therapeutic composition of claim 1 , wherein the CD45RA− Tmems are CD3+CD45RA− CD45RO+.
3. The therapeutic composition of claim 1 , wherein the CD25+ Tregs comprise naïve CD25+CD45RA+ regulatory T cells (naïve Tregs).
4. The therapeutic composition of claim 3 , wherein the CD25+ Tregs comprise a population of memory Tregs.
5. The therapeutic composition of claim 4 , wherein the memory Tregs are CD4+CD25+CD 127−/lo CD45RA−/loCD45RO+.
6. The therapeutic composition of claim 4 , wherein the population of cells comprises a ratio of CD45RA+CD25− naïve conventional αβ-T cells to memory Tregs that is less than 1:1.
7. The therapeutic composition of claim 3 , wherein the naïve Tregs are CD3+CD4+CD25+CD127−/loCD45RA+FoxP3+CD45RO−.
8. The therapeutic composition of claim 3 , wherein the population of cells comprises a ratio of CD25−CD45RA+naïve conventional αβ-T to CD25+CD45RA+naïve Tregs is less than 1:10.
9. The therapeutic composition of claim 1 , wherein the CD25+ Tregs are CD3+CD4+CD25+CD127−/lo.
10. The therapeutic composition of claim 1 , wherein the population of cells further comprises invariant natural killer T (iNKT) cells.
11. The therapeutic composition of claim 10 , wherein the iNKT cells are CD3+Va24Ja18+CD1d-tetramer+.
12. The therapeutic composition of claim 10 , wherein the population of cells comprises a ratio of CD45RA+CD25− naïve conventional αβ-T cells to iNKT that is less than 20:1.
13. The therapeutic composition of claim 1 , wherein the one or more pharmaceutically acceptable excipients is a saline solution and/or human serum albumin or an equivalent thereof.
14. The therapeutic composition of claim 1 , wherein the population of cells is prepared by isolating the CD25+Tregs and the CD45RA− Tmems from a biological sample.
15. The therapeutic composition of claim 14 , wherein the biological sample is selected from mobilized peripheral blood, a mobilized apheresis product, bone marrow, umbilical cord blood, non-mobilized blood, non-mobilized apheresis product, peripheral blood mononuclear cells, or any combination thereof.
16. The therapeutic composition of claim 1 , wherein the population of cells comprises a ratio of CD45RA+CD25− naïve conventional αβ-T cells to CD45RA− Tmems that is less than 1:3.
17. The therapeutic composition of claim 1 , wherein the CD25+ Tregs, CD45RA− Tmems, or a combination thereof are haploidentical to a subject receiving the therapeutic composition.
18. The therapeutic composition of claim 1 , wherein the CD25+ Tregs, CD45RA− Tmems, or a combination thereof are human leukocyte antigen (HLA) matched with a subject receiving the therapeutic composition.
19. The therapeutic composition of claim 1 , wherein at least a portion of the CD25+ Tregs, CD45RA− Tmems, or a combination thereof are autologous to a subject receiving the therapeutic composition.
20. The therapeutic composition of claim 1 , wherein the population of cells further comprises hematopoietic stem/progenitor cells (HSPCs).
21. The therapeutic composition of claim 20 , wherein the HSPCs are CD34+.