Journal Article

Antigen Presenting Cell-Mediated Expansion of Human Umbilical Cord Blood Yields Log-Scale Expansion of Natural Killer Cells with Anti-Myeloma Activity

Yang, Hong, Parmar, Simrit, Ku, Stephanie, Rezvani, Katy, Martin-Antonio, Beatriz, Najjar, Amer, Cooper, Laurence J. N., Gribben, John, Burks, Jared, Shah, Nina, Shpall, Elizabeth J., Sekine, Takuya, Yvon, Eric, Robinson, Simon N., Wang, Michael, Bollard, Catherine M., Champlin, Richard E., Li, Sufang, Lee, Dean A., Kaur, Indreshpal, Decker, William K.

2013

Overview

Natural killer (NK) cells are important mediators of anti-tumor immunity and are active against several hematologic malignancies, including multiple myeloma (MM). Umbilical cord blood (CB) is a promising source of allogeneic NK cells but large scale ex vivo expansion is required for generation of clinically relevant CB-derived NK (CB-NK) cell doses. Here we describe a novel strategy for expanding NK cells from cryopreserved CB units using artificial antigen presenting feeder cells (aAPC) in a gas permeable culture system. After 14 days, mean fold expansion of CB-NK cells was 1848-fold from fresh and 2389-fold from cryopreserved CB with >95% purity for NK cells (CD56(+)/CD3(-)) and less than 1% CD3(+) cells. Though surface expression of some cytotoxicity receptors was decreased, aAPC-expanded CB-NK cells exhibited a phenotype similar to CB-NK cells expanded with IL-2 alone with respect to various inhibitory receptors, NKG2C and CD94 and maintained strong expression of transcription factors Eomesodermin and T-bet. Furthermore, CB-NK cells formed functional immune synapses with and demonstrated cytotoxicity against various MM targets. Finally, aAPC-expanded CB-NK cells showed significant in vivo activity against MM in a xenogenic mouse model. Our findings introduce a clinically applicable strategy for the generation of highly functional CB-NK cells which can be used to eradicate MM.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antigen-presenting cells / Antigen-Presenting Cells - immunology / Antigens / Biocompatibility / Blood / Bone marrow / Cancer / CD3 antigen / CD3 Complex - immunology / CD3 Complex - metabolism / CD56 antigen / CD56 Antigen - immunology / CD56 Antigen - metabolism / Cell culture / Cell Culture Techniques / Cell Line, Tumor / Cell Proliferation / Cells, Cultured / Coculture Techniques / Cord blood / Cryopreservation / Cytokines / Cytotoxicity / Cytotoxicity, Immunologic - drug effects / Cytotoxicity, Immunologic - immunology / Expansion / Fetal Blood - cytology / Fetal Blood - immunology / Fetal Blood - metabolism / Gene therapy / Humans / Immunity / Immunoglobulins / Immunological synapses / Immunotherapy / Interleukin 2 / Interleukin Receptor Common gamma Subunit - deficiency / Interleukin Receptor Common gamma Subunit - genetics / Interleukin Receptor Common gamma Subunit - immunology / Interleukin-2 - immunology / Interleukin-2 - pharmacology / K562 Cells / Killer cells / Killer Cells, Natural - immunology / Killer Cells, Natural - metabolism / Leukemia / Ligands / Medicine / Mice / Mice, Inbred NOD / Mice, Knockout / Mice, SCID / Microscopy, Confocal / Multiple myeloma / Multiple Myeloma - immunology / Multiple Myeloma - pathology / Multiple Myeloma - therapy / Natural killer cells / NK Cell Lectin-Like Receptor Subfamily C - immunology / NK Cell Lectin-Like Receptor Subfamily C - metabolism / NK Cell Lectin-Like Receptor Subfamily D - immunology / NK Cell Lectin-Like Receptor Subfamily D - metabolism / NKG2 antigen / Pediatrics / Permeability / Receptors / Stem cells / Studies / Synapses / Toxicity / Transcription factors / Transplants & implants / Umbilical cord / Xenograft Model Antitumor Assays - methods