We previously demonstrated that autologous natural killer (NK)-cell therapy after hematopoietic cell transplantation (HCT) is safe but does not provide an antitumor effect. We hypothesize that this is due to a lack of NK-cell inhibitory receptor mismatching with autologous tumor cells, which may be overcome by allogeneic NK-cell infusions. Here, we test haploidentical, related-donor NK-cell infusions in a nontransplantation setting to determine safety and in vivo NK-cell expansion. Two lower intensity outpatient immune suppressive regimens were tested: (1) low-dose cyclophosphamide and methylprednisolone and (2) fludarabine. A higher intensity inpatient regimen of high-dose cyclophosphamide and fludarabine (Hi-Cy/Flu) was tested in patients with poor-prognosis acute myeloid leukemia (AML). All patients received subcutaneous interleukin 2 (IL-2) after infusions. Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells. In contrast, infusions after the more intense Hi-Cy/Flu resulted in a marked rise in endogenous IL-15, expansion of donor NK cells, and induction of complete hematologic remission in 5 of 19 poor-prognosis patients with AML. These findings suggest that haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to HCT.
Acute graft-versus-host disease (aGVHD) is associated with high risk of morbidity and mortality and is a common complication after double umbilical cord blood (UCB) transplantation. To reduce these risks, we established a method of CD4 ؉ CD25 ؉ FoxP3 ؉ T regulatory cell (Treg) enrichment from cryopreserved UCB followed by a 18 ؉ 1-day expansion culture including anti-CD3/anti-CD28 antibody-coated beads and recombinant human interleukin-2. In a "first-in-human"
We evaluated the efficacy of umbilical cord blood (UCB) in the setting of a nonmyeloablative regimen consisting of fludarabine (200 mg/m 2 ), cyclophosphamide (50 mg/kg), and a single fraction of total body irradiation (200 cGy) with cyclosporine and mycophenolate mofetil for posttransplantation immunoprophylaxis. The target cell dose for the UCB graft was 3.0 ؋ 10 7 nucleated cells/kg, resulting in the selection of a second partially human leukocyte antigen-matched UCB unit in 85%. One hundred ten patients with hematologic disease were enrolled. Neutrophil recovery was achieved in 92% at a median of 12 days. Incidences of grades III and IV acute and chronic graft-versushost disease (GVHD) were 22% and 23%, respectively. Transplantation-related mortality was 26% at 3 years. Survival and event-free survival (EFS) at 3 years were 45% and 38%, respectively. Favorable risk factors for survival were absence of highrisk clinical features (Karnofsky 50-60, serious organ dysfunction, recent fungal infection, P < .01) and absence of severe GVHD (P ؍ .04), and favorable risk factors for EFS were absence of high-risk clinical features (P < .01) and use of 2 UCB units (P ؍ .07). These findings support the use of UCB after a nonmyeloablative conditioning as a strategy for extending the availability of transplantation therapy, particularly for older patients.
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