By culturing notch ligand-transduced stroma cells with CD34+ hematopoietic progenitor cells that had been differentiated from human fibroblast-derived induced pluripotent stem cells, Cichocki and Bjordahl et al. generated large numbers of highly enriched proliferating CD3-CD56+ NK cells that were phenotypically and transcriptionally similar to primary blood NK cells. These NK cells killed hematopoietic and solid tumor cell lines, infiltrated and killed solid tumor spheroids in vitro, and recruited activated human CD3+ T cells in vivo. In a xenogeneic mouse adoptive transfer model, combining NK and T cells with anti-PD-1 optimally reduced human ovarian tumor burden.
Contributed by Paula Hochman
ABSTRACT: The development of immunotherapeutic monoclonal antibodies targeting checkpoint inhibitory receptors, such as programmed cell death 1 (PD-1), or their ligands, such as PD-L1, has transformed the oncology landscape. However, durable tumor regression is limited to a minority of patients. Therefore, combining immunotherapies with those targeting checkpoint inhibitory receptors is a promising strategy to bolster antitumor responses and improve response rates. Natural killer (NK) cells have the potential to augment checkpoint inhibition therapies, such as PD-L1/PD-1 blockade, because NK cells mediate both direct tumor lysis and T cell activation and recruitment. However, sourcing donor-derived NK cells for adoptive cell therapy has been limited by both cell number and quality. Thus, we developed a robust and efficient manufacturing system for the differentiation and expansion of high-quality NK cells derived from induced pluripotent stem cells (iPSCs). iPSC-derived NK (iNK) cells produced inflammatory cytokines and exerted strong cytotoxicity against an array of hematologic and solid tumors. Furthermore, we showed that iNK cells recruit T cells and cooperate with T cells and anti-PD-1 antibody, further enhancing inflammatory cytokine production and tumor lysis. Because the iNK cell derivation process uses a renewable starting material and enables the manufacturing of large numbers of doses from a single manufacture, iNK cells represent an "off-the-shelf" source of cells for immunotherapy with the capacity to target tumors and engage the adaptive arm of the immune system to make a "cold" tumor "hot" by promoting the influx of activated T cells to augment checkpoint inhibitor therapies.
Author Info: (1) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (2) Fate Therapeutics, San Diego, CA 92121, USA. (3) Fate Therapeutics, San Diego, CA 92121, USA. (
Author Info: (1) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (2) Fate Therapeutics, San Diego, CA 92121, USA. (3) Fate Therapeutics, San Diego, CA 92121, USA. (4) Fate Therapeutics, San Diego, CA 92121, USA. (5) Fate Therapeutics, San Diego, CA 92121, USA. (6) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (7) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (8) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (9) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (10) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. (11) Fate Therapeutics, San Diego, CA 92121, USA. (12) Fate Therapeutics, San Diego, CA 92121, USA. (13) Fate Therapeutics, San Diego, CA 92121, USA. (14) Fate Therapeutics, San Diego, CA 92121, USA. (15) Fate Therapeutics, San Diego, CA 92121, USA. (16) Fate Therapeutics, San Diego, CA 92121, USA. (17) Fate Therapeutics, San Diego, CA 92121, USA. (18) Fate Therapeutics, San Diego, CA 92121, USA. (19) Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. (20) Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA. (21) Fate Therapeutics, San Diego, CA 92121, USA. mille011@umn.edu bob.valamehr@fatetherapeutics.com. (22) Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. mille011@umn.edu bob.valamehr@fatetherapeutics.com.
