Highlights from

ASH 2019

61st Annual Meeting & Exposition of the American Society of Hematology

Orlando, Florida (USA) 7 - 10 December 2019

Off-the-shelf natural killer cells

Preclinical studies have provided the first evidence that cellular immunotherapy for B-cell cancers could ultimately become an off-the-shelf product, capable of being uniformly manufactured in large quantities, independent of the individual patient. FT596 is among the first cellular immunotherapies to be based on natural killer cells mass produced by inducible pluripotent stem cells (iPSCs) in the lab, and is the first cellular immunotherapy to be genetically engineered to contain 3 active anti-tumour components.

Dr Jode Goodridge (Fate Therapeutics, USA) described the chimeric antigen receptor (CAR)-induced natural killer cell product, referred to as FT596 [1]. The FT596 platform circumvents some of the hurdles posed by conventional CAR19 T-cell therapy, such as product heterogeneity, and persistence of effect. Producing FT596 begins with human iPSCs that are capable of unlimited self-renewal and can differentiate into more than 200 types of human cells. The iPSCs are genetically engineered, after which a single clone is selected and grown in the laboratory to create a master engineered cell line that can be repeatedly used to generate cancer-fighting immune-system cells, such as natural killer and T cells.

The researchers modified FT596 to carry a CAR targeting the CD19 protein, as well as CD16, which boosts and broadens the natural killer cells’ ability to kill cancer cells, and IL-15, which stimulates FT596 to proliferate and persist.

To test it in vitro, the researchers used CD19+ CD20+ B lymphoblast target cells to demonstrate that the anti-tumour activity of FT596 is roughly comparable with the activity of primary CD19-targeted CAR T cells. When combined with the anti-CD20 monoclonal rituximab, activity was even more effective at eliminating CD19- CD20+ B lymphoblast target cells than the monoclonal antibody alone (64% vs 30% clearance, respectively, at 36 hours).

In vivo, the researchers used mouse models with B-cell malignancy to demonstrate that FT596 was superior at eradicating B-cell lymphoma, compared with mice treated with induced natural killer cells alone or induced natural killer cells modified with CD19-CAR alone (P<0.002).

Dr Goodridge: “From 106 iPSCs, we can generate 1011 to 1012 induced natural killer cells at a 100-liter scale, and the output is continuous.” The cost of a treatment with FT596 is about $2,500. First-in-human studies have yet to report.

Keywords: Chimaeric Antigen Receptors; Immunotherapy; Lymphoma; FT596; Natural Killer Cells; Induced Pluripotent Stem Cells; Genetic Engineering

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