1. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti-PD-1 therapy
- Author
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Frank Cichocki, Martin Felices, Svetlana Gaidarova, Ryan Bjordahl, Bahram Valamehr, David Robbins, Laurel Stokely, Jeffrey S. Miller, Betsy Rezner, Hongbo Wang, Bruce R. Blazar, Moyar Q. Ge, Raedun Clarke, Ramzey Abujarour, Laura Bendzick, Megan Robinson, Tom Tong Lee, Zachary Davis, Paul Rogers, Dan S. Kaufman, Katie Tuininga, and Sajid Mahmood
- Subjects
medicine.medical_treatment ,T cell ,T-Lymphocytes ,Cell ,Induced Pluripotent Stem Cells ,Programmed Cell Death 1 Receptor ,Medical and Health Sciences ,Article ,Cell therapy ,Vaccine Related ,Immune system ,Neoplasms ,medicine ,Killer Cells ,Humans ,Induced pluripotent stem cell ,Cancer ,biology ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Chemistry ,General Medicine ,Immunotherapy ,Biological Sciences ,Stem Cell Research ,Killer Cells, Natural ,medicine.anatomical_structure ,Cytokine ,biology.protein ,Cancer research ,Natural ,Immunization ,Antibody ,Biotechnology - 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.
- Published
- 2020