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A scalable, spin‐free approach to generate enhanced induced pluripotent stem cell–derived natural killer cells for cancer immunotherapy

ABSTRACT: Traditional sources of NK cells, such as peripheral blood, are limited by availability and donor variability. Additionally, in vitro expansion can lead to functional exhaustion and gene editing challenges. This study aims to harness iPSC technology to provide a consistent and scalable source of NK cells, overcoming the limitations of traditional sources and enhancing the potential for cancer immunotherapy applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE271952 | GEO | 2024/09/13

REPOSITORIES: GEO

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Different developmental pathways generate functionally distinct populations of natural killer cells

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A scalable, spin‐free approach to generate enhanced induced pluripotent stem cell–derived natural killer cells for cancer immunotherapy

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Resting natural killer cell homeostasis relies on tryptophan/NAD+ metabolism and HIF-1α

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Project description:Cell-based immunotherapy can control bulky tumors, but effector cell persistence, tumor resistance, inconsistencies of the manufactured product, and treatment cost continue to pose challenges. To address these limitations, we developed a triple gene-edited induced pluripotent stem cell (iPSC) platform for broad patient-based adoptive cell therapy. iPSCs were engineered to express a high affinity, non-cleavable version of the Fc receptor CD16a to augment antibody-mediated activity and a membrane-bound IL-15/IL-15R fusion (IL-15RF) protein to promote survival and maturation. The third edit was knockout of the ecto-enzyme CD38 that hydrolyzes NAD+ and is the target of the therapeutic antibody daratumumab. Natural killer (NK) cells derived from these iPSCs displayed metabolic features and gene expression profiles similar to those of adaptive NK cells that arise in response to cytomegalovirus (CMV) infection. These engineered iPSC-derived NK cells, termed iADAPT, persisted in vivo in the absence of exogenous cytokine and could be combined with daratumumab for efficient killing of multiple myeloma and acute myeloid leukemia cells both in vitro and in vivo. This strategy has broad off-the-shelf potential for the treatment of patients with advanced cancer.

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