Engineering the TGF beta Receptor to Enhance the Therapeutic Potential of Natural Killer Cells as an Immunotherapy for Neuroblastoma

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-theshelf" 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 TGF beta, which impair NK cell function and survival. Experimental Design: To overcome this, we genetically modified NK cells to express variant TGF beta receptors, which couple a mutant TGF beta dominant-negative receptor to NKspecific activating domains. We hypothesized that with these engineered receptors, inhibitory TGF beta signals are effectively converted to activating signals. Results: Modified NK cells exhibited higher cytotoxic activity against neuroblastoma in a TGF beta-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 TGF beta-mediated immune evasion, in patients with neuroblastoma and other TGF beta-secreting malignancies.