Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

Abstract

Adoptive immunotherapy with allogeneic purified natural killer (NK) cell products might exert graft-versus-tumor alloreactivity with little risk of GVHD. In a prospective phase II study in two centers, we administered purified NK cell products to high-risk patients treated with haploidentical T-cell-depleted SCT. Sixteen patients received a total of 29 NK cell infusions on days þ 3, þ 40 and þ 100 after transplantation. Median doses (and ranges) of infused NK-and T-cells per product were 1.21 (0.3-3.8) Â 10 7 /kg and 0.03 (0.004-0.72) Â 10 5 /kg, respectively. With a median follow-up of 5.8 years 4/16 patients are alive. Cause of death was relapse in five, GVHD in three, graft failure in three, and transplant related neurotoxicity in one patient. Four patients developed acute GVHDXgrade II, all receiving a total of X0.5 Â 10 5 T cells/kg. Compared with historical controls, NK cell infusions had no apparent effect on the rates of graft failure or relapse. Adoptive transfer of allogeneic NK cells is safe and feasible, but further studies are needed to determine the optimal dose and timing of NK cell therapy. Moreover, NK cell activation/expansion may be required to attain clinical benefit, while careful consideration must be given to the number of T cells infused.

Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing’s sarcoma patients

“…[38][39][40] Transfer of expanded or activated haploidentical NK cells could be used to enhance antitumor activity and has been shown to be feasible and safe in numerous pilot studies. 41,42 In conclusion, multimodal treatment of primary metastatic and relapsed metastatic stage IV EWS including haploidentical stem cell transplantation can facilitate long-term remission and survival. Even patients with PR might benefit from the exchange of the immune system.…”

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

“…The NK infusions did not, however, seem to have an effect on relapse rates (compared to those in historical controls). 96 A group in France reported in vivo expansion of infused alloreactive NK cells in a patient who received NK cells and IL-2 for relapsed AML following haploidentical HSCT and salvage chemotherapy. 97 While the NK cells detected in vivo retained their activity as measured in functional in vitro assays, the patient still relapsed after NK cell infusion and subsequently died of his disease.…”

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“…Whereas we did not observe a significant difference in the gene expression profiles between unstimulated and IL-2 prestimulated NK cells (data not shown), prestimulation with other cytokines such as IL-12 or IL-18 may have different effects on NK cells [14]. Although our approach of prestimulating with IL-2 over 7-10 days is currently the standard setting for many clinical trials using NK cells, the effect of fungi on NK cells prestimulated with different protocols has to be assessed in the future [15,16]. The transcript levels of perforin and granzyme B, which play a central role in NK cell mediated killing of fungi [5,9,13], increase in IL-2 prestimulated NK cells in the absence of A. fumigatus, but decrease in the presence of the fungus.…”