Harnessing NK Cells to Overcome Checkpoint Resistance: The Role of FT500 in T-Cell Activation and Recruitment

The introduction of PD1/PDL1 checkpoint inhibitors has significantly altered the field of oncology, offering long-lasting remissions across various cancer types. However, some tumor types are not responsive to this therapy, and the issue of relapse is still prevalent. There is a pressing need for new treatments that can counteract resistance to checkpoint inhibitors and enhance T-cell activation and recruitment when used in conjunction with these inhibitors.

Healthy donor-derived NK cell transfer has the potential to attract T cells to the tumor microenvironment and boost their activation at the site of the tumor. NK cells possess direct anti-tumor capabilities and can release inflammatory cytokines and chemokines upon activation, which allows them to play a pivotal role in modulating anti-tumor T cell responses. The study aimed to evaluate the potential of FT500, an NK cell product from a clonal master pluripotent cell line, to work alongside checkpoint inhibitors to alleviate local immunosuppression and improve T-cell activation and recruitment.

FT500 lacks PD1 on the cell surface, and tumor line PDL1 expression had no impact on its cytotoxicity. The addition of a PDL1 blocking antibody did not affect FT500's cytotoxicity or degranulation, indicating that it is naturally resistant to PDL1-PD1 inhibition. Moreover, FT500 activation led to the release of soluble factors that promote T-cell activation, as shown by increased CD69 expression.

The hypothesis was that FT500 might also enhance the effect of checkpoint inhibitors by facilitating T cell recruitment to the tumor site. Using standard in vitro transwell migration assays, it was found that FT500 produced factors that encouraged the movement of activated T cells. Further analysis confirmed that FT500 generates a variety of chemokines, including CCL3, CCL4, CXCL10, and CCL22. In an in vivo recruitment model, FT500 was capable of drawing T cells from the bloodstream into the peritoneal cavity. Additionally, in a three-dimensional tumor spheroid model, the infiltration of T cells into the tumor was significantly improved when combined with FT500, indicating that FT500 can boost the infiltration of T cells into tumors.

The findings indicate that FT500 is an effective producer of chemokines and can help bring T cells to the tumor site. Beyond its direct cytotoxic capabilities, FT500 also enhances T-cell activation, suggesting it can work synergistically with checkpoint inhibitors to decrease the tumor burden. The data support the combination of FT500, a ready-to-use NK cell cancer immunotherapy, with checkpoint inhibitors to overcome resistance to checkpoint blockade.

Citation: Ryan Bjordahl et al. FT500, a ready-to-use NK cell cancer immunotherapy from a master pluripotent cell line, boosts T-cell activation and recruitment to tackle checkpoint blockade resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; Chicago, IL, April 14-18, 2018. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3576.