Induced Pluripotent Stem Cell-Derived Natural Killer Cells for Treatment of Ovarian Cancer

Abstract

Natural killer (NK) cells can provide effective immunotherapy for ovarian cancer. Here, we evaluated the ability of NK cells isolated from peripheral blood (PB-) and NK cells derived from induced pluripotent stem cell (iPSC-) to mediate killing of ovarian cancer cells in a mouse xenograft model. A mouse xenograft model was used to evaluate the intraperitoneal delivery of three different NK cell populations: iPSC-derived NK cells, PB-NK cells that had been activated and expanded in long-term culture, and overnight activated PB-NK cells that were isolated through CD3/CD19 depletion of peripheral blood B and T cells. Bioluminescent imaging was used to monitor tumor burden of luciferase expressing tumor lines. Tumors were allowed to establish prior to administering NK cells via intraperitoneal injection. These studies demonstrate a single dose of any of the three NK cell populations significantly reduced tumor burden. When mice were given 3 doses of either iPSC-NK cells or expanded PB-NK cells, the median survival improved from 73 days in mice untreated to 98 and 97 days for treated mice, respectively. From these studies, we conclude iPSC-derived NK cells mediate anti-ovarian cancer killing at least as well as PB-NK cells, making these cells a viable resource for immunotherapy for ovarian cancer. Due to their ability to be easily differentiated into NK cells and their long-term expansion potential, iPSCs can be used to produce large numbers of well-defined NK cells that can be banked and used to treat a large number of patients including treatment with multiple doses if necessary.

Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential

“…In turn, hPSC-derived NK cells exhibit potent antitumor activity without the need for human leukocyte antigen matching and without prior antigen exposure [16]. These cells were also recently employed for treatment of ovarian cancer in a mouse model [50]. Our study substantiates an efficient, controllable, and less expensive approach to hematopoietic cell derivation compared to existing technologies, which may fulfill a growing need for translational medicine for a scalable production of lymphoid and myeloid cells.…”

Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy

“…Since clinical protocols of PB‐NK cells typically treat patients with approximately 10 7 NK cells per kg, this three‐stage system can effectively be used for clinical‐scale NK cell production . Using these conditions, NK cells have been effectively produced from multiple different hESC and iPSC lines . Both these hESC‐ and iPSC‐derived NK cells express a typical repertoire of activating and inhibitory receptors found on PB‐NK and UCB‐NK .…”

NK cell therapy after hematopoietic stem cell transplantation: can we improve anti-tumor effect?

“…Autologous as well as allogeneic NK cells can be purified from peripheral blood apheresis products or obtained from umbilical cord blood (UCB) [18,19]. Additionally, NK cells can be developed from CD34 + UCB stem cells or from induced pluripotent stem cells [20,21]. However, differences among NK cells obtained from these sources have not been adequately described.…”