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

Authors

Rachel A. Burga, School of Medicine and Health Sciences
Eric Yvon, The George Washington University
Elizabeth Chorvinsky, The George Washington University
Rohan Fernandes, School of Medicine and Health Sciences
C. Russell Cruz, School of Medicine and Health Sciences
Catherine M. Bollard, School of Medicine and Health Sciences

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.

APA Citation

Burga, R., Yvon, E., Chorvinsky, E., Fernandes, R., Cruz, C., & Bollard, C. (2019). Engineering the TGFb receptor to enhance the therapeutic potential of natural killer cells as an immunotherapy for neuroblastoma. Clinical Cancer Research, 25 (14). http://dx.doi.org/10.1158/1078-0432.CCR-18-3183