Cellular therapy: Adoptive immunotherapy with expanded natural killer cells

• Published in: Immunological reviews Vol. 290; no. 1; pp. 85 - 99
• Main Author: Lee, Dean A.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01-07-2019
• Subjects: Adoptive immunotherapy; Animals; Apheresis; Blood volume; Brain; Brain tumors; CD3 antigen; CD56 antigen; Cell Culture Techniques; Cell therapy; Cell- and Tissue-Based Therapy - adverse effects; Cell- and Tissue-Based Therapy - methods; Children; Clinical Studies as Topic; Clinical trials; Cryopreservation; Cytokines; Cytotoxicity, Immunologic; Depletion; Dosage; Feeder Cells; Humans; IL‐21; Immunotherapy; Immunotherapy, Adoptive - adverse effects; Immunotherapy, Adoptive - methods; Interleukins - metabolism; Killer Cells, Natural - cytology; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Leukemia; Medical research; Models, Animal; Natural killer cells; Parents; Peripheral blood mononuclear cells; Senescence; Signal Transduction; Solid tumors; STAT3 Transcription Factor - metabolism; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Treatment Outcome; Tumor cell lines; Tumors; natural killer cells; IL-21; adoptive immunotherapy; feeder cells
• ISSN: 0105-2896; 1600-065X
• DOI: 10.1111/imr.12793

Adoptive immunotherapy with natural killer cells was pioneered 30 years ago in human clinical trials with the development of cytokine‐induced killer cells—unfractionated peripheral blood mononuclear cell (PBMC) populations activated overnight with IL‐2. Higher doses were subsequently made possible through the advent of steady‐state apheresis, allowing the collection of PBMC numbers equivalent to an entire adult blood volume, and increased purity made feasible through magnetic CD3‐depletion and/or CD56‐selection methods. Still, these approaches rarely achieved clinical dosing above a single infusion of 108 NK cells/kg, except with substantial donor‐recipient size mismatch (eg, parents donating cells to children). To address this shortcoming, leukemia cell lines with NK cell‐like function or ex vivo expansion approaches centered on the homeostatic cytokine IL‐15 were developed. Here, we describe the development of an ex vivo expansion system based on a feeder cell expressing membrane‐bound IL‐21 that enables log‐phase growth of primary NK cells for many weeks without inducing senescence, and describe the biology, correlative science, and translation to clinical trials for patients with leukemia, brain tumors, and solid tumors.