Data from Engineering the TGFβ Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma

Abstract

<div>AbstractPurpose:<p>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.</p>Experimental Design:<p>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.</p>Results:<p>Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGFβ-rich environment <i>in vitro</i> and superior progression-free survival <i>in vivo</i>, as compared with their unmodified controls.</p>Conclusions:<p>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.</p></div>