372 IPSC-Derived NK cells Exhibit Potent In Vitro and In Vivo Tumorcidal Activity Against Patient-Derived Glioblastoma Stem Cells (GSCs)

Abstract

INTRODUCTION: Natural Killer (NK) cells play pivotal roles in cancer immune surveillance and harbor potent anti-tumor activities. We have engineered an induced pluripotent stem cells (iPSCs) derived, NK cell (termed FT538) that express 1) a high-affinity non-cleavable CD16 Fc receptor to facilitate antibody engagement 2) a membrane-bound IL-15/IL-15 receptor fusion to enhance NK activity and persistence and 3) a knock-out of CD38 to enhance NK metabolic fitness. FT538 is produced in a GMP-compliant manner as an off-the-shelf immunotherapy. Clinical experiences with FT538 have shown evidence of durable anti-tumor immunity after single administration in select lymphoma patients. METHODS: Laboratory characterization and murine modeling. RESULTS: Without specific antibody to engage CD16, FT538 exhibited potent in vitro activity against ∼80% of a panel of isocitrate dehydrogenase wild-type patient derived xenograft (PDX) glioblastoma lines, including MGG8. When directly injected into the murine brain, 50% of the FT538 persisted for >2 weeks without addition of exogenous cytokine. Moreover, the mice exhibited no evidence of neurologic compromise, and brains harvested after injection show no signs of FT538 activation. In vivo intratumoral injection of FT538 into an orthotopically established MGG8 glioblastoma caused an ∼20 fold increase in granzyme B release by FT538, with a comparable increase of cleaved Caspase 3 in the tumor proper. In independent experiments, >90% of mice orthotopically implanted MGG8 survived beyond 100 days after intra-tumoral FT538 while all mice treated with mock injection died by 60 days. For glioblastoma PDX refractory to FT538, such as MGG4, tumoricidal activity of FT583 can be induced in vitro and in vivo by the addition of a tri-specific engager targeting B7H3, a surface protein highly expressed in glioblastomas. CONCLUSIONS: Our results suggest that FT538 great promise as a glioblastoma therapy, with plans for translation into a first-in-human clinical trial.