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  • iPSC-derived NK cells maint...
    Cichocki, Frank; Bjordahl, Ryan; Gaidarova, Svetlana; Mahmood, Sajid; Abujarour, Ramzey; Wang, Hongbo; Tuininga, Katie; Felices, Martin; Davis, Zachary B; Bendzick, Laura; Clarke, Raedun; Stokely, Laurel; Rogers, Paul; Ge, Moyar; Robinson, Megan; Rezner, Betsy; Robbins, David L; Lee, Tom T; Kaufman, Dan S; Blazar, Bruce R; Valamehr, Bahram; Miller, Jeffrey S

    Science translational medicine, 11/2020, Letnik: 12, Številka: 568
    Journal Article

    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.