- 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
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.