Generation of donor natural killer cells from CD34+ progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study

Abstract

Post transplant infusion of donor-type natural killer (NK) cells has been shown to have an anti-leukemia-enhancing effect without evoking GVHD in murine hematopoietic cell transplantation (HCT) models. Here, we tested 14 patients (age, 23-65 years), 12 with acute leukemia and 2 with myelodysplastic syndrome, who underwent HLAmismatched HCT and subsequently received donor NK cell infusions. Cell donors (age, 16-51 years), comprising seven siblings, five offspring, and two mothers of the patients, underwent growth factor-mobilized leukapheresis for 3-5 days. Cells collected on the first 2-4 days were used for HCT, whereas those collected on the last day were CD34 selected by magnetic-activated cell sorting (median, 2.22 Â 10 6 cells/kg; range, 0.29-5.66). Donor NK cells were generated from the CD34 þ cells by ex vivo cell culture over a 6-week period (median, 9.28 Â 10 6 cells/ kg; range, 0.33-24.50; CD122/CD56 þ 64%; CD3 þ 1.0%; and viability 88%). There were no signs of acute toxicity in patients infused with these cells 6-7 weeks post transplant. Overall, one and five patients developed acute and chronic GVHD during post transplant period, respectively. These results showed that clinical-grade donor NK cell production from CD34 þ cells is feasible.

T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect

“…Although no acute toxicity was observed, six patients developed acute or chronic GVHD after NK cell infusion. 95 A group in Switzerland administered purified allogeneic NK cells on days 3, 40, and 100 after haploidentical T-cell-depleted HSCT. The NK infusions did not, however, seem to have an effect on relapse rates (compared to those in historical controls).…”

Combined IL-15 and IL-12 drives the generation of CD34+-derived natural killer cells with superior maturation and alloreactivity potential following adoptive transfer

“…[15][16][17][18][19][20] Alternatively, NK cells can be generated from hematopoietic progenitor cells (HPCs). [21][22][23][24][25] Previously, we reported a good manufacturing practice (GMP)-compliant, cytokine-based culture protocol for the ex vivo generation of allogeneic NK cells from CD34 C HPCs isolated from cryopreserved umbilical cord blood (UCB) units, bone marrow (BM), or G-CSF-mobilized blood (see ref. 23 and unpublished data).…”

Ezh2 regulates differentiation and function of natural killer cells through histone methyltransferase activity

“…Altered NK cell numbers or function have a profound impact on overall immune status and often correlate with cancer prognosis (6,7). NK cell-based immunotherapy against both hematopoietic and solid tumors (8,9) is under active clinical study and has shown reduced relapse and improved prognosis in many aggressive cancers (10,11). Increased understanding of NK cell biology is required to improve the efficacy of these therapeutic approaches.…”