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

ABSTRACT: 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/?L blood. IL2DT was associated with improved complete remission rates at day 28 (53% vs 21%; P = .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 = .002), effective peripheral blood Treg depletion (<5%) at day 7 (P < .01), and decreased IL-35 levels at day 14 (P = .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.

SUBMITTER: Bachanova V

PROVIDER: S-EPMC4064329 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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

Bachanova Veronika V Cooley Sarah S Defor Todd E TE Verneris Michael R MR Zhang Bin B McKenna David H DH Curtsinger Julie J Panoskaltsis-Mortari Angela A Lewis Dixie D Hippen Keli K McGlave Philip P Weisdorf Daniel J DJ Blazar Bruce R BR Miller Jeffrey S JS

Blood 20140409 25

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 ( ...[more]

PMID: 24719405

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Project description:Refractory acute myeloid leukemia (AML), defined as failure of two cycles of induction therapy at diagnosis or of one cycle at relapse, represents a subgroup with poor outcomes. Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (fludarabine + cytosine + granulocyte colony-stimulating factor ± idarubicin or mitoxantrone + etoposide) followed by 1-week rest and then reduced-intensity transplant with fludarabine + melphalan. We used the same backbone for this trial (CTRI/2019/02/017505) with the addition of CD56-positive cells from a family donor infused 1 day after the completion of chemotherapy. CD56-positive selection was done using a CliniMACS Prodigy system (Miltenyi Biotec, Bergisch Gladbach, Germany) followed by overnight incubation in autologous plasma with 2 micromolar arsenic trioxide and 500 U/mL of interleukin-2. From February 2019, 14 patients with a median age of 29 years (interquartile range [IQR]: 16.5-38.5) were enrolled in this trial. Six were females. Six had primary refractory AML while eight had relapsed refractory AML. The median CD56-cell dose infused was 46.16 × 106/kg (IQR: 25.06-70.36). One patient withdrew consent after NK cell infusion. Of the 13 patients who proceeded to transplant, five died of immediate post-transplant complications while two did not engraft but were in morphologic leukemia-free state (both subsequently died of infective complications after the second transplant). Of the remaining six patients who engrafted and survived beyond 1 month of the transplant, two developed disease relapse and died. The remaining four patients are alive and relapse free at the last follow-up (mean follow-up duration of surviving patients is 24 months). The 2-year estimated overall survival for the cohort was 28.6% ± 12.1% while the treatment-related mortality (TRM) with this approach was 38.5% ± 13.5%. Haploidentical NK cell therapy as an adjunct to transplant is safe and needs further exploration in patients with AML. For refractory AML, post-transplant NK infusion and strategies to reduce TRM while using pre-transplant NK infusion merit exploration.

Project description:Consolidation therapies for children with intermediate- or high-risk acute myeloid leukemia (AML) are urgently needed to achieve higher cure rates while limiting therapy-related toxicities. We determined if adoptive transfer of natural killer (NK) cells from haploidentical killer immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA)-mismatched donors may prolong event-free survival in children with intermediate-risk AML who were in first complete remission after chemotherapy. Patients received cyclophosphamide (Day - 7), fludarabine (Days - 6 through - 2), and subcutaneous interleukin-2 (Days - 1, 1, 3, 5, 7, and 9). Purified, unmanipulated NK cells were infused on Day 0, and NK cell chimerism and phenotyping from peripheral blood were performed on Days 7, 14, 21, and 28. As primary endpoint, the event-free survival was compared to a cohort of 55 patients who completed chemotherapy and were in first complete remission but did not receive NK cells. Donor NK cell kinetics were determined as secondary endpoints. Twenty-one patients (median age at diagnosis, 6.0 years [range, 0.1-15.3 years]) received a median of 12.5 × 106 NK cells/kg (range, 3.6-62.2 × 106 cells/kg) without major side effects. All but 3 demonstrated transient engraftment with donor NK cells (median peak donor chimerism, 4% [range, 0-43%]). KIR-HLA-mismatched NK cells expanded in 17 patients (81%) and contracted in 4 (19%). However, adoptive transfer of NK cells did not decrease the cumulative incidence of relapse (0.393 [95% confidence interval: 0.182-0.599] vs. 0.35 [0.209-0.495]; P = .556) and did not improve event-free (60.7 ± 10.9% vs. 69.1 ± 6.8%; P = .553) or overall survival (84.2 ± 8.5% vs. 79.1 ± 6.6%; P = .663) over chemotherapy alone. The lack of benefit may result from insufficient numbers and limited persistence of alloreactive donor NK cells but does not preclude its potential usefulness during other phases of therapy, or in combination with other immunotherapeutic agents. TRIAL REGISTRATION: www.clinicaltrials.gov , NCT00703820 . Registered 24 June 2008.

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

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

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