title: Successful Transfer of Umbilical Cord Blood CD34+Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients.
abstract: Purpose:Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generatedex vivofrom CD34+hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units.Experimental Design:Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 106/kg body weight) after lymphodepleting chemotherapy without cytokine boosting.Results:HSPC-NK cell products contained a median of 75% highly activated NK cells, with <1 × 104T cells/kg and <3 × 105B cells/kg body weight. HSPC-NK cells were well tolerated, and neither graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting being given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, which was accompanied by augmented IL15 plasma levels. Moreover, donor chimerism up to 3.5% was found in bone marrow. Interestingly,in vivoHSPC-NK cell maturation was observed, indicated by the rapid acquisition of CD16 and KIR expression, while expression of most activating receptors was sustained. Notably, 2 of 4 patients with minimal residual disease (MRD) in bone marrow before infusion became MRD negative (<0.1%), which lasted for 6 months.Conclusions:These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential "off-the-shelf" translational immunotherapy approach in AML.Clin Cancer Res; 23(15); 4107-18. ©2017 AACR.
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands. harry.dolstra@radboudumc.nl.
authors.forename: Harry
authors.initials: H
authors.lastname: Dolstra
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.|Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Mieke W H
authors.initials: MWH
authors.lastname: Roeven
authors.affiliation: Glycostem Therapeutics, Oss, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Spanholtz
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Basav N
authors.initials: BN
authors.lastname: Hangalapura
authors.affiliation: Glycostem Therapeutics, Oss, the Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Tordoir
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Frans
authors.initials: F
authors.lastname: Maas
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Marij
authors.initials: M
authors.lastname: Leenders
authors.affiliation: Glycostem Therapeutics, Oss, the Netherlands.
authors.forename: Fenna
authors.initials: F
authors.lastname: Bohme
authors.affiliation: Glycostem Therapeutics, Oss, the Netherlands.
authors.forename: Nina
authors.initials: N
authors.lastname: Kok
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Carel
authors.initials: C
authors.lastname: Trilsbeek
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Paardekooper
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Anniek B
authors.initials: AB
authors.lastname: van der Waart
authors.affiliation: Albert Schweitzer Hospital, Dordrecht, the Netherlands.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Westerweel
authors.affiliation: Medical Hospital Twente, Enschede, the Netherlands.
authors.forename: Tjeerd J F
authors.initials: TJF
authors.lastname: Snijders
authors.affiliation: Department of Hematology, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Cornelissen
authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Bos
authors.affiliation: Department of Internal Medicine, Jeroen Bosch Hospital, 's-Hertogenbosch, the Netherlands.
authors.forename: Hans F M
authors.initials: HFM
authors.lastname: Pruijt
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Aniek O
authors.initials: AO
authors.lastname: de Graaf
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Bert A
authors.initials: BA
authors.lastname: van der Reijden
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Joop H
authors.initials: JH
authors.lastname: Jansen
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Arnold
authors.initials: A
authors.lastname: van der Meer
authors.affiliation: Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Huls
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Cany
authors.affiliation: Department of Laboratory Medicine - Laboratory of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Preijers
authors.affiliation: Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicole M A
authors.initials: NMA
authors.lastname: Blijlevens
authors.affiliation: Department of Hematology, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
authors.forename: Nicolaas M
authors.initials: NM
authors.lastname: Schaap
mesh_terms: D000368:Aged; D018952:Antigens, CD34 / Q000235:genetics / Q000276:immunology; D064987:Cell- and Tissue-Based Therapy; D036101:Cord Blood Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019409:Interleukin-15 / Q000097:blood; D007694:Killer Cells, Natural / Q000637:transplantation; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008297:Male; D009365:Neoplasm Regression, Spontaneous / Q000473:pathology; D011379:Prognosis
chemical_list: D018952:Antigens, CD34; D019409:Interleukin-15