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

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.

CAR‐NK cells: the next wave of cellular therapy for cancer

“…[49][50][51] Moreover, iPSC-derived NK cells develop activating and inhibitory receptors (including KIRs, natural cytotoxic receptors and CD16) that are typical of their mature counterparts, and they demonstrate in vitro and in vivo antitumor activity. 49,50,52 After differentiation of iPSCs into NK cells, they can be expanded by co-culture with feeder cells, such as genetically modified artificial antigen-presenting cells (aAPCs). 51 Not surprisingly, iPSC-derived NK cells have been genetically modified to express CARs.…”

Engineering Anti-Tumor Monoclonal Antibodies and Fc Receptors to Enhance ADCC by Human NK Cells

“…iPSCs are amenable to genetic modification and the derived NK cells can be produced in a clonal and clinically scalable manner [125,126]. Moreover, these cells demonstrate similar phenotypic markers and anti-tumor effector functions as peripheral blood NK cells [127]. High-affinity FcγR-modified iPSC-derived NK cells have the potential to be a promising cancer immunotherapy by allowing for universal tumor antigen targeting by mAb therapies.…”

Allogeneic CAR Cell Therapy—More Than a Pipe Dream

“…More recently, exosomes or plasma membrane particles derived from mbIL21 expressing K562 cells have also been successfully used for the ex vivo expansion of NK cells ( 133 ). iPSCs present an attractive source for generating NK cells without feeder cells ( 134 , 135 ), and an early phase clinical study with unmodified iPSC-derived NK cells is in progress (NCT03841110). In addition, iPSC cells can be genetically modified and/or gene edited prior to NK cell differentiation, enabling the provision of an unlimited supply of modified NK cells ( 136 – 138 ).…”