Research ArticleCancer

iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy

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Science Translational Medicine  04 Nov 2020:
Vol. 12, Issue 568, eaaz5618
DOI: 10.1126/scitranslmed.aaz5618

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Unleashing the killer in stem cells

Immune checkpoint blockade and other immunotherapies for cancer have shown promising results but are still limited in their effectiveness. Adding natural killer cells to immunotherapy regimens offers some promise in this regard, but it can be limited by cell availability. To overcome this constraint, Cichocki et al. developed a method for manufacturing natural killer cells from induced pluripotent stem cells. These manufactured natural killer cells produced inflammatory cytokines, killed tumor cells, and cooperated effectively with antitumor T cells both in vitro and in mouse models, supporting their potential as an off-the-shelf anticancer treatment.

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.

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