Abstract
Background aims
Adoptive cell therapy employing natural killer group 2D (NKG2D) chimeric antigen receptor
(CAR)-modified T cells has demonstrated preclinical efficacy in several model systems,
including hematological and solid tumors. We present comprehensive data on manufacturing
development and clinical production of autologous NKG2D CAR T cells for treatment
of acute myeloid leukemia and multiple myeloma (ClinicalTrials.gov Identifier: NCT02203825). An NKG2D CAR was generated by fusing native full-length
human NKG2D to the human CD3ζ cytoplasmic signaling domain. NKG2D naturally associates
with native costimulatory molecule DAP10, effectively generating a second-generation
CAR against multiple ligands upregulated during malignant transformation including
MIC-A, MIC-B and the UL-16 binding proteins.
Methods
CAR T cells were infused fresh after a 9-day process wherein OKT3-activated T cells
were genetically modified with replication-defective gamma-retroviral vector and expanded
ex vivo for 5 days with recombinant human interleukin-2.
Results
Despite sizable interpatient variation in originally collected cells, release criteria,
including T-cell expansion and purity (median 98%), T-cell transduction (median 66%
CD8+ T cells), and functional activity against NKG2D ligand-positive cells, were met for
100% of healthy donors and patients enrolled and collected. There was minimal carryover
of non–T cells, particularly malignant cells; both effector memory and central memory
cells were generated, and inflammatory cytokines such as granulocyte colony-stimulating
factor, RANTES, interferon-γ and tumor necrosis factor-α were selectively up-regulated.
Conclusions
The process resulted in production of required cell doses for the first-in-human phase
I NKG2D CAR T clinical trial and provides a robust, flexible base for further optimization
of NKG2D CAR T-cell manufacturing.
Key Words
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Article info
Publication history
Published online: July 02, 2018
Accepted:
May 2,
2018
Received:
January 11,
2018
Identification
Copyright
© 2018 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.
