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 an immunosuppressive drug 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 are purified to a purity of greater than 85% prior to being combined with the CD3 + T cells in the engineered hematopoietic cell composition.
2. The method of claim 1 , further comprising treating the recipient with non-myeloablative conditioning.
3. The method of claim 2 , wherein the non-myeloablative conditioning comprises total lymphoid irradiation (TLI).
4. The method of claim 1 , wherein the purified CD34 + cells are purified to a purity of greater than 95% prior to being combined with the CD3 + T cells in the engineered hematopoietic cell composition.
5. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises at least 1×10 6 purified CD34 + cells/kilogram recipient weight.
6. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises about 1×10 6 CD3 + T cells/kilogram recipient weight.
7. The method of claim 1 , wherein the donor and a donor of the engineered hematopoietic cell composition are the same.
8. The method of claim 1 , wherein a donor of the engineered hematopoietic cell composition is a human.
9. The method of claim 1 , wherein the solid human organ is selected from a group consisting of a kidney, a heart, an intestine, a liver, a lung, and a pancreas.
10. The method of claim 1 , wherein the donor is deceased or living.
11. The method of claim 1 , further comprising maintaining the recipient on an immunosuppressive regimen for a period of time.
12. The method of claim 11 , wherein the period of time is sufficient for the recipient to develop mixed chimerism.
13. The method of claim 1 , further comprising:
monitoring the recipient for mixed chimerism, wherein mixed chimerism is defined as one of the following:
(i) having at least 1% and less than 95% circulating donor hematopoietic cells,
(ii) having at least 1% and less than 95% circulating immune cells, or
(iii) having at least 1% and less than 95% of combined circulating hematopoietic cells and immune cells.
14. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises about 4×10 6 purified CD34 + cells/kilogram recipient weight.
15. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises greater than or equal to 4×10 6 purified CD34 + cells/kilogram recipient weight.
16. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises greater than or equal to 4×10 6 purified CD34 + cells/kilogram recipient weight and about 1×10 6 CD3 + T cells/kilogram recipient weight.
17. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises about 10×10 6 purified CD34 + cells/kilogram recipient weight.
18. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises less than 15×10 6 purified CD34 + cells/kilogram recipient weight.
19. The method of claim 1 , wherein the purified CD34 + cells are obtained by a method comprising:
i. obtaining an apheresis product from the donor,
ii. contacting the apheresis product with an immunomagnetic label;
iii. purifying CD34 + cells from the apheresis product by passing the apheresis product through an immunomagnetic column, wherein CD34 + cells are retained within the immunomagnetic column; and
iv. collecting at least a portion of the CD34 + cells from the immunomagnetic column;
v.
20. The method of claim 19 , wherein the apheresis product comprises mononuclear cells collected at a hematocrit of 0.5-1.5%.
21. The method of claim 1 , wherein the engineered hematopoietic cell composition comprises less than 25×10 6 purified CD34 + cells/kilogram recipient weight.