Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients

Curti, Antonio; Ruggeri, Loredana; D'Addio, Alessandra; Bontadini, Andrea; Dan, Elisa; Motta, Maria Rosa; Trabanelli, Sara; Giudice, Valeria; Urbani, Elena; Martinelli, Giovanni; Paolini, Stefania; Fruet, Fiorenza; Isidori, Alessandro; Parisi, Sarah; Bandini, Giuseppe; Baccarani, Michele; Velardi, Andrea; Lemoli, Roberto M.

doi:10.1182/blood-2011-01-329508

Cited by 355 publications

(305 citation statements)

References 20 publications

(19 reference statements)

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“…They can be used to elucidate basic mechanisms of human NK cell differentiation and can be employed to generate defined NK cell products for the treatment of malignancies such as leukemias [20,21]. A better understanding of the differentiation process will facilitate the production of therapeutic NK cells with specific and improved properties.…”

Section: Discussionmentioning

confidence: 99%

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Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

Lehmann

Spanholtz

Osl

et al. 2012

Stem Cells and Development

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Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56 bright and CD56dim NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56 bright and CD56 dim NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A + NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56 dim NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy.

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Section: Discussionmentioning

confidence: 99%

“…Clinical studies have already revealed the principal potential of allogeneic NK cells for adoptive cancer immunotherapy [20,21,41,42]. These prospects seem to be especially promising for treatment of certain leukemias, for which haploidentical or close to haploidentical stem cell transplantation has been shown to be effective.…”

Section: Lehmann Et Almentioning

confidence: 99%

Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

Lehmann

Spanholtz

Osl

et al. 2012

Stem Cells and Development

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“…should be limited to o 1-5 × 10 5 /kg, 125,126 especially in the context of HLA-mismatched allogeneic stem cell transplantation, to minimize the risk of GvHD. This can be achieved by CD3 depletion.…”

Section: Lymphoyte Contamination Of the Graft T-cell Contaminationmentioning

confidence: 99%

Umbilical cord blood graft engineering: challenges and opportunities

Thompson

Rezvani

Hosing

et al. 2015

Bone Marrow Transplant

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We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specificT-cells or chimeric-antigen receptor T-cells which are reviewed in this study.

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“…11 Adoptive immunotherapy with highly purified NK cells has been investigated by several groups showing the feasibility of NK cell application without severe side effects. [11][12][13] With regard to NK cell efficiency, a recent study 14 reported that NK cell infusion to 10 pediatric patients with AML in first CR led to a two-year EVS of 100%. Preliminary results appear encouraging, but crucial issues such as patient and donor selection, best timing for NK cell infusions, NK cell target dose, and possible gains by in vitro activation and expansion remain unresolved.…”

Section: Introductionmentioning

confidence: 99%

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

Stangel

Passweg

Meyer-Monard

et al. 2012

Bone Marrow Transplant

160

124

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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.

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Successful transfer of alloreactive haploidentical KIR ligand-mismatched natural killer cells after infusion in elderly high risk acute myeloid leukemia patients

Cited by 355 publications

References 20 publications

Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

Ex Vivo Generated Natural Killer Cells Acquire Typical Natural Killer Receptors and Display a Cytotoxic Gene Expression Profile Similar to Peripheral Blood Natural Killer Cells

Umbilical cord blood graft engineering: challenges and opportunities

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

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