Combined organ and hematopoietic cells for transplantation tolerance of grafts
View Patent ↗Methods and compositions are provided for combined transplantation of a solid organ and hematopoietic cells to a recipient, where tolerance to the graft is established through development of a persistent mixed chimerism. An individual with persistent mixed chimerism, usually for a period of at least six months, is able to withdraw from the use of immunosuppressive drugs after a period of time sufficient to establish tolerance.
1. A method for maintaining mixed chimerism for at least six months and withdrawal of immunosuppressive drugs without a rejection episode or graft versus host disease (GVHD) in a recipient of a solid human organ transplantation, wherein a donor of the solid human organ and the recipient are HLA-matched, the method comprising:
administering a pharmaceutically effective dosage of an engineered hematopoietic cell composition to the recipient, wherein the engineered hematopoietic cell composition comprises:
greater than 5×10 5 purified CD34 + cells/kilogram recipient weight and from about 1.5×10 5 to about 1×10 10 CD3 + T cells/kilogram recipient weight,
wherein the purified CD34 + cells in the engineered hematopoietic cell composition are purified to a purity of greater than 85%,
wherein a concentration of iron associated with the purified CD34 + cells is higher than the concentration of iron associated with CD34 + cells prior to the purification, and wherein the engineered hematopoietic cell composition comprises a ratio of the CD3 + T cells to the purified CD34 + cells of greater than 0.25.
2. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises less than 1.7×10 7 purified CD34 + cells/kilogram recipient weight.
3. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises between about 5×10 5 to about 1.7×10 7 purified CD34 + cells/kilogram recipient weight.
4. The method of claim 1 , wherein the donor is living or deceased.
5. The method of claim 1 , wherein the engineered hematopoietic composition comprises:
greater than 5×10 5 purified CD34 + cells/kilogram recipient weight and greater than 1×10 6 CD3 + T cells/kilogram recipient weight when the recipient does not have lupus.
6. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises greater than 1×10 6 purified CD34 + cells/kilogram recipient weight and greater than 1×10 6 CD3 + T cells/kilogram recipient weight.
7. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises greater than 4×10 6 purified CD34 + cells/kilogram recipient weight and greater than 1.5×10 6 CD3 + T cells/kilogram recipient weight.
8. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises between about 1×10 6 to about 1.7×10 7 purified CD34 + cells/kilogram recipient weight and greater than 1.5×10 6 CD3 + T cells/kilogram recipient weight.
9. The method of claim 1 , wherein the purified CD34 + cells are purified to a purity of greater than 95%.
10. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises greater than 4×10 6 purified CD34 + cells/kilogram recipient weight and greater than 5×10 6 CD3 + T cells/kilogram recipient weight.
11. The method of claim 1 , wherein the engineered hematopoietic cell composition is formulated to comprise a ratio of the CD3 + T cells to the purified CD34 + cells of greater than 1.
12. The method of claim 1 , wherein the solid human organ is selected from the group consisting of a heart, intestine, liver, lung, pancreas and kidney.
13. The method of claim 1 , wherein HLA-matched comprises HLA-A, HLA-B and HLA-DR being the same between the donor and the recipient.
14. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises less than 1.7×10 7 purified CD34 + cells/kilogram recipient weight and greater than 1×10 6 CD3 + T cells/kilogram recipient weight.
15. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises between about 1×10 6 to about 1.7×10 7 purified CD34 + cells/kilogram recipient weight and greater than 1×10 6 CD3 + T cells/kilogram recipient weight.
16. The method of claim 1 , wherein the engineered hematopoietic cell composition is isolated from the donor of the solid human organ.
17. The method of claim 1 , wherein the mixed chimerism is defined and monitored as having at least 1% and less than 95% of circulating donor hematopoietic cells.