Clearance of acute myeloid leukemia by haploidentical natural killer cells is improved using IL-2 diphtheria toxin fusion protein

Abstract

Key Points• Depletion of host regulatory T cells with IL2DT improves efficacy of haploidentical NK cell therapy for refractory acute myeloid leukemia.• Depletion of Treg and persistence of NK cells for $7 days after NK cell adoptive transfer predicts beneficial clinical responses.Haploidentical natural killer (NK) cell infusions can induce remissions in some patients with acute myeloid leukemia (AML) but regulatory T-cell (Treg) suppression may reduce efficacy. We treated 57 refractory AML patients with lymphodepleting cyclophosphamide and fludarabine followed by NK cell infusion and interleukin (IL)-2 administration. In 42 patients, donor NK cell expansion was detected in 10%, whereas in 15 patients receiving host Treg depletion with the IL-2-diphtheria fusion protein (IL2DT), the rate was 27%, with a median absolute count of 1000 NK cells/mL blood. IL2DT was associated with improved complete remission rates at day 28 (53% vs 21%; P 5 .02) and disease-free survival at 6 months (33% vs 5%; P < .01). In the IL2DT cohort, NK cell expansion correlated with higher postchemotherapy serum IL-15 levels (P 5 .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P 5 .02). In vitro assays demonstrated that Tregs cocultured with NK cells inhibit their proliferation by competition for IL-2 but not for IL-15. Together with our clinical observations, this supports the need to optimize the in vivo cytokine milieu where adoptively transferred NK cells compete with other lymphocytes to improve clinical efficacy in patients with refractory AML. This study is registered at clinicaltrials.gov, identifiers: NCT00274846 and NCT01106950. (Blood. 2014;123(25):3855-3863)

PD-L1 blockade enhances anti-tumor efficacy of NK cells

“…18,42 In several trials testing efficacy of haploidentical NK cells in patients with advanced relapsed or refractory tumors, responses were observed only in a small subgroup of patients and were hampered by co-expansion of Tregs which were thought to be of patient origin. 43-46 Our results suggest that expansion of Tregs may arise in the tumor microenvironment upon PD-L1 expression, and can even occur by expansion from the very small amount of T cells transferred as part of an adoptive NK cell product. To mitigate such in situ Treg generation, PD-L1 blockade may prevent Tregs induction and improve overall efficacy of adoptive NK cell therapy.…”

Prophylactic use of low-dose interleukin-2 and the clinical outcomes of hematopoietic stem cell transplantation: A randomized study

“…11 Bachanova et al conducted an adoptive NK cell infusion clinical trial, which demonstrated that depletion of host regulatory T cells with IL-2 diphtheria toxin fusion protein (IL-2DT) improves the efficacy of haploidentical (HID) NK-cell therapy for patients with refractory AML. 12 Therefore, higher levels of Treg cells in the tumor environment might inhibit the GVL effects of NK cells in vivo as well as other cytotoxic T cells post-transplantation. 13 These data indicated that even though IL-2 could prevent cGVHD, relapse is still an important problem that should be addressed.…”

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

“…Patients treated with the toxin and NK infusion had higher IL-15 levels and improved efficacy of haploidentical NK cell therapy for AML. 98 Finally, a group from the University of Arkansas reported the use of KIR mismatched haploidentical NK cells in the setting of an autologous HSCT for multiple myeloma. The donors' NK cells persisted transiently after infusion, but five patients still relapsed early, two patients had progressive disease, one patient had stable disease, and two patients subsequently relapsed.…”