title: Ex vivo-expanded natural killer cells demonstrate robust proliferation in vivo in high-risk relapsed multiple myeloma patients.
abstract: Highly activated/expanded natural killer (NK) cells can be generated by stimulation with the human leukocyte antigen-deficient cell line K562, genetically modified to express 41BB-ligand and membrane-bound interleukin (IL)15. We tested the safety, persistence, and activity of expanded NK cells generated from myeloma patients (auto-NK) or haploidentical family donors (allo-NK) in heavily pretreated patients with high-risk relapsing myeloma. The preparative regimen comprised bortezomib only or bortezomib and immunosuppression with cyclophosphamide, dexamethasone, and fludarabine. NK cells were shipped overnight either cryopreserved or fresh. In 8 patients, up to 1×10⁸ NK cells/kg were infused on day 0 and followed by daily administrations of IL2. Significant in vivo expansion was observed only in the 5 patients receiving fresh products, peaking at or near day 7, with the highest NK-cell counts in 2 subjects who received cells produced in a high concentration of IL2 (500 U/mL). Seven days after infusion, donor NK cells comprised >90% of circulating leukocytes in fresh allo-NK cell recipients, and cytolytic activity against allogeneic myeloma targets was retained in vitro. Among the 7 evaluable patients, there were no serious adverse events that could be related to NK-cell infusion. One patient had a partial response and in another the tempo of disease progression decreased; neither patient required further therapy for 6 months. In the 5 remaining patients, disease progression was not affected by NK-cell infusion. In conclusion, infusion of large numbers of expanded NK cells was feasible and safe; infusing fresh cells was critical to their expansion in vivo.
authors.affiliation: *Myeloma Institute for Research and Therapy §Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR †Center for Cell and Gene Therapy, The Methodist Hospital, Texas Children's Hospital, Houston, TX ‡Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore ∥Department of Pediatrics, Baylor College of Medicine, Houston, TX.
authors.forename: Susann
authors.initials: S
authors.lastname: Szmania
authors.forename: Natalia
authors.initials: N
authors.lastname: Lapteva
authors.forename: Tarun
authors.initials: T
authors.lastname: Garg
authors.forename: Amy
authors.initials: A
authors.lastname: Greenway
authors.forename: Joshuah
authors.initials: J
authors.lastname: Lingo
authors.forename: Bijay
authors.initials: B
authors.lastname: Nair
authors.forename: Katie
authors.initials: K
authors.lastname: Stone
authors.forename: Emily
authors.initials: E
authors.lastname: Woods
authors.forename: Junaid
authors.initials: J
authors.lastname: Khan
authors.forename: Justin
authors.initials: J
authors.lastname: Stivers
authors.forename: Susan
authors.initials: S
authors.lastname: Panozzo
authors.forename: Dario
authors.initials: D
authors.lastname: Campana
authors.forename: William T
authors.initials: WT
authors.lastname: Bellamy
authors.forename: Molly
authors.initials: M
authors.lastname: Robbins
authors.forename: Joshua
authors.initials: J
authors.lastname: Epstein
authors.forename: Shmuel
authors.initials: S
authors.lastname: Yaccoby
authors.forename: Sarah
authors.initials: S
authors.lastname: Waheed
authors.forename: Adrian
authors.initials: A
authors.lastname: Gee
authors.forename: Michele
authors.initials: M
authors.lastname: Cottler-Fox
authors.forename: Cliona
authors.initials: C
authors.lastname: Rooney
authors.forename: Bart
authors.initials: B
authors.lastname: Barlogie
authors.forename: Frits
authors.initials: F
authors.lastname: van Rhee
mesh_terms: D000368:Aged; D015153:Blotting, Western; D049109:Cell Proliferation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology / Q000637:transplantation*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000276:immunology / Q000628:therapy*; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy; D012307:Risk Factors