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Clin Cancer Res. 2019 Apr 22. pii: clincanres.3183.2018. doi: 10.1158/1078-0432.CCR-18-3183. [Epub ahead of print]

Engineering the TGFβ receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma.

Author information

1
Institute for Biomedical Sciences, George Washington University.
2
GW Cancer Center, George Washington University.
3
Department of Medicine, George Washington University.
4
Sheikh Zayed Institute, Children's National Health System.
5
CRI, Children's National Health System CBollard@childrensnational.org.

Abstract

PURPOSE:

The ability of natural killer (NK) cells to lyse allogeneic targets, without the need for explicit matching or priming, makes them an attractive platform for cell-based immunotherapy. Umbilical cord blood is a practical source for generating banks of such third party NK cells for "off the shelf" cell therapy applications. NK cells are highly cytolytic, and their potent antitumor effects can be rapidly triggered by a lack of HLA expression on interacting target cells, as is the case for a majority of solid tumors, including neuroblastoma. Neuroblastoma is a leading cause of pediatric cancer-related deaths and an ideal candidate for NK cell therapy. However, the antitumor efficacy of NK cells is limited by immunosuppressive cytokines in the tumor microenvironment, such as TGFβ, which impair NK cell function and survival.

EXPERIMENTAL DESIGN:

To overcome this, we genetically modified NK cells to express variant TGFβ receptors which couple a mutant TGFβ dominant negative receptor to NK-specific activating domains. We hypothesized that with these engineered receptors, inhibitory TGFβ signals are effectively converted to activating signals.

RESULTS:

Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFβ-rich environment in vitro and superior progression-free survival in vivo, as compared to their unmodified controls.

CONCLUSIONS:

Our results support the development of "off the shelf" gene-modified NK cells, that overcome TGFβ-mediated immune evasion, in patients with neuroblastoma and other TGFβ-secreting malignancies.

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