Larger Size of Donor Alloreactive NK Cell Repertoire Correlates with Better Response to NK Cell Immunotherapy in Elderly Acute Myeloid Leukemia Patients

Abstract

Purpose: In acute myeloid leukemia (AML), alloreactive natural killer (NK) cells are crucial mediators of immune responses after haploidentical stem cell transplantation. Allogeneic NK cell infusions have been adoptively transferred with promising clinical results. We aimed at determining whether the composition of NK graft in terms of frequency of alloreactive NK cells influence the clinical response in a group of elderly AML patients undergoing NK immunotherapy.Experimental Design: Seventeen AML patients, in first complete remission (CR; median age 64 years, range 53-73) received NK cells from haploidentical KIR-ligand-mismatched donors after fludarabine/cyclophosphamide chemotherapy, followed by IL2. To correlate donor NK cell activity with clinical response, donor NK cells were assessed before and after infusion.Results: Toxicity was moderate, although 1 patient died due to bacterial pneumonia and was censored for clinical follow-up. With a median follow-up of 22.5 months (range, 6-68 months), 9 of 16 evaluable patients (0.56) are alive disease-free, whereas 7 of 16 (0.44) relapsed with a median time to relapse of 9 months (range, 3-51 months). All patients treated with molecular disease achieved molecular CR. A significantly higher number of donor alloreactive NK cell clones was observed in responders over nonresponders. The infusion of higher number of alloreactive NK cells was associated with prolonged disease-free survival (0.81 vs. 0.14, respectively; P ¼ 0.03).Conclusions: Infusion of purified NK cells is feasible in elderly AML patients as post-CR consolidation strategy. The clinical efficacy of adoptively transferred haploidentical NK cells may be improved by infusing high numbers of alloreactive NK cells.

What Fuels Natural Killers? Metabolism and NK Cell Responses

“…Adoptive transfer of allogeneic haploidentical NK cells is currently used as a treatment for AML (54–56). One benefit of allogeneic NK cells is the ability to culture the cells ex vivo , e.g., in the presence of cytokine, to increase immune function.…”

Bone marrow produces sufficient alloreactive natural killer (NK) cells in vivo to cure mice from subcutaneously and intravascularly injected 4T1 breast cancer

“…Adaptive transfer of alloreactive NK cells may at first glance seem the most preferable therapy as it evades the possible risks resulting from haploidentical HSCT like GVHD and infections. The toxicity of adaptive NK cell therapy in human patients is anticipated to be low based on present-day experience, although the numbers of transferred NK cells were not as high as we would aim at based on our dose–response experiment [75–77]. It remains to be seen if the application of higher numbers of alloreactive NK cells resulting in short-term engraftment will be as curative as in our mouse model.…”

Advances in Immunotherapy for Acute Myeloid Leukemia

“…A Phase IIb study in Korea is evaluating the effects of donor NK cell infusion on day +13 and +20 after alloSCT for RR-AML (NCT02477787). Clinical responses to haploidentical NK cells appear to correlate with NK cell repertoire in recipients [29]. Among 17 patients in morphologic complete remission, those who received more than eight of 100 alloreactive NK clones demonstrated an improved mean relapse-free survival (RFS; 43 vs 21.6 months in patients with less than eight of 100 NK clones).…”