Engineering the TGFb receptor to enhance the therapeutic potential of natural killer cells as an immunotherapy for neuroblastoma

Document Type

Journal Article

Publication Date

1-1-2019

Journal

Clinical Cancer Research

Volume

25

Issue

14

DOI

10.1158/1078-0432.CCR-18-3183

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 TGFb, which impair NK cell function and survival. Experimental Design: To overcome this, we genetically modified NK cells to express variant TGFb receptors, which couple a mutant TGFb dominant-negative receptor to NK-specific activating domains. We hypothesized that with these engineered receptors, inhibitory TGFb signals are effectively converted to activating signals. Results: Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFb-rich environment in vitro and superior progression-free survival in vivo, as compared with their unmodified controls. Conclusions: Our results support the development of "off-the-shelf" gene-modified NK cells, that overcome TGFb-mediated immune evasion, in patients with neuroblastoma and other TGFb-secreting malignancies.

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