Tumor suppression using human placental perfusate and human placenta-derived intermediate natural killer cells

1. A method of treating an individual having tumor cells, comprising administering to said individual a therapeutically effective amount of human placental perfusate cells, wherein said placental perfusate cells comprise CD56 + placental intermediate natural killer cells.

2. The method of claim 1 , wherein the tumor cells are blood cancer cells.

3. The method of claim 1 , wherein the tumor cells are solid tumor cells.

4. The method of claim 1 , wherein the tumor cells are primary ductal carcinoma cells, leukemia cells, acute T cell leukemia cells, chronic myeloid lymphoma (CML) cells, acute myelogenous leukemia cells, chronic myelogenous leukemia (CML) cells, lung carcinoma cells, colon adenocarcinoma cells, histiocytic lymphoma cells, colorectal carcinoma cells, colorectal adenocarcinoma cells, or retinoblastoma cells.

5. The method of claim 1 , wherein said perfusate comprises a culture medium.

6. The method of claim 1 , wherein said perfusate has been treated to remove a plurality of erythrocytes.

7. The method of claim 1 , wherein said placental intermediate natural killer cells are administered intravenously.

8. The method of claim 1 , wherein said plurality of placental perfusate cells are total nucleated cells from placental perfusate.

9. The method of claim 1 , wherein said placental perfusate cells comprise at least about 50% CD56 + placental cells.

10. A method of treating an individual comprising tumor cells comprising administering to said individual a therapeutically effective amount of CD56+, CD16− placental intermediate natural killer cells.

11. The method of claim 10 , wherein said tumor cells are primary ductal carcinoma cells, leukemia cells, acute T cell leukemia cells, chronic myeloid lymphoma (CML) cells, acute myelogenous leukemia cells, chronic myelogenous leukemia (CML) cells, lung carcinoma cells, colon adenocarcinoma cells, histiocytic lymphoma cells, multiple myeloma cells, colorectal carcinoma cells, colorectal adenocarcinoma cells, or retinoblastoma cells.

12. The method of claim 10 , wherein said placental intermediate natural killer cells are contacted with an immunomodulatory compound in an amount and for a time sufficient for said placental intermediate natural killer cells to express detectably more granzyme B than an equivalent number of placental intermediate natural killer cells not contacted with said immunomodulatory compound.

13. The method of claim 12 , wherein said immunomodulatory compound is lenalidomide or pomalidomide.

14. A method of treating an individual having tumor cells, comprising administering to said individual a therapeutically effective amount of combined natural killer cells, wherein said combined natural killer cells comprise placental intermediate natural killer cells isolated from placental perfusate and natural killer cells isolated from umbilical cord blood, and wherein said umbilical cord blood is isolated from the placenta from which said placental perfusate is obtained.

15. The method of claim 14 , wherein said tumor cells are primary ductal carcinoma cells, leukemia cells, acute T cell leukemia cells, chronic myeloid lymphoma (CML) cells, acute myelogenous leukemia cells, chronic myelogenous leukemia (CML) cells, lung carcinoma cells, colon adenocarcinoma cells, histiocytic lymphoma cells, multiple myeloma cells, colorectal carcinoma cells, colorectal adenocarcinoma cells, or retinoblastoma cells.

16. The method of claim 14 , wherein said combined natural killer cells comprise:

a detectably higher number of CD3−CD56+CD16− natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably lower number of CD3−CD56+CD16+ natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably higher number of CD3−CD56+KIR2DL2/L3+ natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably lower number of CD3−CD56+NKp46+ natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably higher number of CD3−CD56+NKp30+ natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably higher number of CD3−CD56+2B4+ natural killer cells than an equivalent number of natural killer cells from peripheral blood; or

a detectably higher number of CD3−CD56+CD94+ natural killer cells than an equivalent number of natural killer cells from peripheral blood.

17. The method of claim 16 , wherein said natural killer cells have not been cultured.

18. The method of claim 14 , wherein said combined natural killer cells comprise:

a detectably lower number of CD3 − CD56 + KIR2DL2/L3 + natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably higher number of CD3 − CD56 + NKp46 + natural killer cells than an equivalent number of natural killer cells from peripheral blood;

a detectably higher number of CD3 − CD56 + NKp44 + natural killer cells than an equivalent number of natural killer cells from peripheral blood; or

a detectably higher number of CD3 − CD56 + NKp30 + natural killer cells than an equivalent number of natural killer cells from peripheral blood.

19. The method of claim 18 , wherein said natural killer cells have been cultured.

20. The method of claim 19 , wherein said natural killer cells have been cultured for about 21 days.

21. The method of claim 1 , wherein said placental perfusate cells comprise at least about 50% CD56 + , CD16 − placental intermediate natural killer cells.

22. The method of claim 10 , wherein said placental perfusate cells comprise at least about 50% CD56 + , CD16 − placental intermediate natural killer cells.

23. The method of claim 1 , wherein said placental intermediate natural killer cells express one or more of the microRNAs hsa-miR-100, hsa-miR-127, hsa-miR-211, hsa-miR-302c, hsa-miR-326, hsa-miR-337, hsa-miR-497, hsa-miR-512-3p, hsa-miR-515-5p, hsa-miR-517b, hsa-miR-517c, hsa-miR-518a, hsa-miR-518e, hsa-miR-519d, hsa-miR-520g, hsa-miR-520h, hsa-miR-564, hsa-miR-566, hsa-miR-618, or hsa-miR-99a at a detectably higher level than peripheral blood natural killer cells.

24. The method of claim 10 , wherein said placental intermediate natural killer cells express one or more of the microRNAs hsa-miR-100, hsa-miR-127, hsa-miR-211, hsa-miR-302c, hsa-miR-326, hsa-miR-337, hsa-miR-497, hsa-miR-512-3p, hsa-miR-515-5p, hsa-miR-517b, hsa-miR-517c, hsa-miR-518a, hsa-miR-518e, hsa-miR-519d, hsa-miR-520g, hsa-miR-520h, hsa-miR-564, hsa-miR-566, hsa-miR-618, or hsa-miR-99a at a detectably higher level than peripheral blood natural killer cells.

25. The method of claim 14 , wherein said placental intermediate natural killer cells express one or more of the microRNAs hsa-miR-100, hsa-miR-127, hsa-miR-211, hsa-miR-302c, hsa-miR-326, hsa-miR-337, hsa-miR-497, hsa-miR-512-3p, hsa-miR-515-5p , hsa-miR-517b, hsa-miR-517c, hsa-miR-518a, hsa-miR-518e, hsa-miR-519d, hsa-miR-520g, hsa-miR-520h, hsa-miR-564, hsa-miR-566, hsa-miR-618, or hsa-miR-99a at a detectably higher level than peripheral blood natural killer cells.

26. The method of claim 1 , wherein said placental intermediate natural killer cells express one or more of aminopeptidase N protein, apolipoprotein E protein, atrophin-1 interacting protein 1, innexin inx-3 protein, integrin alpha-2 precursor protein, integrin beta-5 precursor, mast cell surface glycoprotein GP49B precursor protein, or ryanodine receptor 1 protein; and do not express one or more of fibroblast growth factor receptor 4 precursor protein, immunity-associated nucleotide 4-like protein, integrin alpha-L precursor protein, integrin beta 2 precursor protein, integrin beta 4 precursor protein, membrane-bound lytic murein transglycosylase D precursor protein, oxysterol binding protein-related protein 8, or perforin 1 precursor 1 protein.

27. The method of claim 10 , wherein said placental intermediate natural killer cells express one or more of aminopeptidase N protein, apolipoprotein E protein, atrophin-1 interacting protein 1, innexin inx-3 protein, integrin alpha-2 precursor protein, integrin beta-5 precursor, mast cell surface glycoprotein GP49B precursor protein, or ryanodine receptor 1 protein; and do not express one or more of fibroblast growth factor receptor 4 precursor protein, immunity-associated nucleotide 4-like protein, integrin alpha-L precursor protein, integrin beta 2 precursor protein, integrin beta 4 precursor protein, membrane-bound lytic murein transglycosylase D precursor protein, oxysterol binding protein-related protein 8, or perforin 1 precursor 1 protein.

28. The method of claim 14 , wherein said placental intermediate natural killer cells express one or more of aminopeptidase N protein, apolipoprotein E protein, atrophin-1 interacting protein 1, innexin inx-3 protein, integrin alpha-2 precursor protein, integrin beta-5 precursor, mast cell surface glycoprotein GP49B precursor protein, or ryanodine receptor 1 protein; and do not express one or more of fibroblast growth factor receptor 4 precursor protein, immunity-associated nucleotide 4-like protein, integrin alpha-L precursor protein, integrin beta 2 precursor protein, integrin beta 4 precursor protein, membrane-bound lytic murein transglycosylase D precursor protein, oxysterol binding protein-related protein 8, or perforin 1 precursor 1 protein.

29. The method of claim 1 , additionally comprising administering to said individual an anti-cancer agent.

30. The method of claim 10 , additionally comprising administering to said individual an anti-cancer agent.

31. The method of claim 14 , additionally comprising administering to said individual an anti-cancer agent.