Efficacy of third-party chimeric antigen receptor modified peripheral blood natural killer cells for adoptive cell therapy of B-cell precursor acute lymphoblastic leukemia

C. Quintarelli, S. Sivori, S. Caruso, S. Carlomagno, M. Falco, I. Boffa, D. Orlando, M. Guercio, Z. Abbaszadeh, M. Sinibaldi, S. Di Cecca, A. Camera, B. Cembrola, A. Pitisci, M. Andreani, L. Vinti, S. Gattari, F. Del Bufalo, M. Algeri, G. Li PiraA. Moseley, B. De Angelis, L. Moretta, F. Locatelli

Research output: Contribution to journalArticlepeer-review

Abstract

We developed an innovative and efficient, feeder-free culture method to genetically modify and expand peripheral blood-derived NK cells with high proliferative capacity, while preserving the responsiveness of their native activating receptors. Activated peripheral blood NK cells were efficiently transduced by a retroviral vector, carrying a second-generation CAR targeting CD19. CAR expression was demonstrated across the different NK-cell subsets. CAR.CD19-NK cells display higher antileukemic activity toward CD19+ cell lines and primary blasts obtained from patients with B-cell precursor ALL compared with unmodified NK cells. In vivo animal model data showed that the antileukemia activity of CAR.CD19-NK cell is superimposable to that of CAR-T cells, with a lower xenograft toxicity profile. These data support the feasibility of generating feeder-free expanded, genetically modified peripheral blood NK cells for effective “off-the-shelf” immuno-gene-therapy, while their innate alloreactivity can be safely harnessed to potentiate allogeneic cell therapy. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Original languageEnglish
Pages (from-to)1102-1115
Number of pages14
JournalLeukemia
Volume34
Issue number4
DOIs
Publication statusPublished - 2020

Keywords

  • CD19 antigen
  • chimeric antigen receptor
  • retrovirus vector
  • acute lymphoblastic leukemia
  • adoptive transfer
  • alloimmunity
  • animal experiment
  • animal model
  • antileukemic activity
  • antineoplastic activity
  • Article
  • cell proliferation
  • chimeric antigen receptor natural killer cell immunotherapy
  • clinical article
  • controlled study
  • DNA modification
  • flow cytometry
  • human
  • human cell
  • in vivo study
  • mouse
  • natural killer cell
  • nonhuman
  • peripheral blood mononuclear cell
  • pre B lymphocyte
  • priority journal
  • protein expression
  • therapy effect
  • tumor xenograft
  • adoptive immunotherapy
  • animal
  • apoptosis
  • biological therapy
  • cytotoxicity
  • drug screening
  • immunology
  • mononuclear cell
  • nonobese diabetic mouse
  • pathology
  • procedures
  • SCID mouse
  • transplantation
  • tumor cell culture
  • Animals
  • Antigens, CD19
  • Apoptosis
  • Cell Proliferation
  • Cell- and Tissue-Based Therapy
  • Cytotoxicity, Immunologic
  • Humans
  • Immunotherapy, Adoptive
  • Killer Cells, Natural
  • Leukocytes, Mononuclear
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
  • Receptors, Chimeric Antigen
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

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