Journal Article

Expression of IL-15 in NK cells results in rapid enrichment and selective cytotoxicity of gene-modified effectors that carry a tumor-specific antigen receptor

Sahm, Christiane, Wels, Winfried S., Schönfeld, Kurt

2012

Overview

Natural killer (NK) cells hold promise for adoptive cancer immunotherapy but are dependent on cytokines such as interleukin (IL)-2 for growth and cytotoxicity. Here, we investigated the consequences of ectopic expression of IL-15 in human NK cells. IL-2 and IL-15 belong to the common γ chain family of cytokines and have overlapping activities. Transduction of clinically applicable NK-92 cells with lentiviral vectors encoding human IL-15 resulted in predominantly intracellular expression of the cytokine, and STAT5 activation, proliferation and cytotoxicity of the producer cells in the absence of IL-2. Growth of non-transduced bystander cells was not supported, allowing rapid enrichment of gene-modified cells solely by IL-2 withdrawal. This was also the case upon transduction of NK-92 and NKL cells with a bicistronic lentiviral vector encoding IL-15 and a chimeric antigen receptor (CAR) targeting the pancarcinoma antigen EpCAM. Effector cells co-expressing CAR and IL-15 continued to proliferate in the absence of exogenous cytokines and displayed high and selective cell-killing activity against EpCAM-expressing breast carcinoma cells that were resistant to the natural cytotoxicity of unmodified NK cells. This strategy facilitates rapid isolation and continuous expansion of retargeted NK cells and may extend their potential clinical utility.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Animals / Antibodies / Antigens / Antigens, Neoplasm - biosynthesis / Antigens, Neoplasm - genetics / Antigens, Neoplasm - immunology / Antineoplastic agents / Biological and medical sciences / Blood & organ donations / Breast cancer / Breast carcinoma / Breast Neoplasms - immunology / Breast Neoplasms - therapy / Cancer Research / Cell Adhesion Molecules - biosynthesis / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - immunology / Cell Line, Tumor / Cell proliferation / Cytokines / Cytokines - biosynthesis / Cytokines - genetics / Cytokines - immunology / Cytotoxicity / Cytotoxicity, Immunologic - genetics / Cytotoxicity, Immunologic - immunology / DNA, Complementary - genetics / Effector cells / Epithelial Cell Adhesion Molecule / Expression vectors / Humans / Immunology / Immunotherapy / Immunotherapy - methods / Interleukin 15 / Interleukin 2 / Interleukin-15 - biosynthesis / Interleukin-15 - genetics / Interleukin-15 - immunology / Interleukin-2 - immunology / Interleukin-2 - pharmacology / K562 Cells / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Leukemia, Erythroblastic, Acute - immunology / Leukemia, Erythroblastic, Acute - therapy / Lymphocytes / Lymphoma / Medical sciences / Medicine / Medicine & Public Health / Melanoma - immunology / Melanoma - therapy / Mice / Natural killer cells / Oncology / Original / Original Article / Pharmacology. Drug treatments / Producer cells / Receptors, Antigen - biosynthesis / Receptors, Antigen - genetics / Receptors, Antigen - immunology / RNA, Messenger - biosynthesis / RNA, Messenger - genetics / Stat5 protein