TY - JOUR
T1 - iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy
AU - Cichocki, Frank
AU - Bjordahl, Ryan
AU - Gaidarova, Svetlana
AU - Mahmood, Sajid
AU - Abujarour, Ramzey
AU - Wang, Hongbo
AU - Tuininga, Katie
AU - Felices, Martin
AU - Davis, Zachary B.
AU - Bendzick, Laura
AU - Clarke, Raedun
AU - Stokely, Laurel
AU - Rogers, Paul
AU - Ge, Moyar
AU - Robinson, Megan
AU - Rezner, Betsy
AU - Robbins, David L.
AU - Lee, Tom T.
AU - Kaufman, Dan S.
AU - Blazar, Bruce R.
AU - Valamehr, Bahram
AU - Miller, Jeffrey S.
N1 - Publisher Copyright:
Copyright © 2020 The Authors,
PY - 2020/10/4
Y1 - 2020/10/4
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.aaz5618
DO - 10.1126/scitranslmed.aaz5618
M3 - Article
C2 - 33148626
AN - SCOPUS:85095676550
SN - 1946-6234
VL - 12
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 568
M1 - eaaz5618
ER -