TPS2080 Background: CYNK-001 is a CD56+CD3- enriched, off-the-shelf, allogeneic natural killer (NK) cell product expanded from placental CD34 cells. CYNK-001 exhibits in vitro cytotoxicity against patient-derived GBM cell lines and secretes cytolytic cytokines during co-culture with cancer cells. CYNK-001 administered via the intracranial (IC) route exhibited in vivo antitumor activity in a U-87MG orthotopic mouse model. Methods: A Phase I/IIa clinical trial is enrolling IDH1 wild-type GBM patients at first or second recurrence with contrast-enhancing measurable disease (per RANO criteria) who are candidate for surgical resection. Screening MRI scans for inclusion are performed within 14 days prior to Day -5 lymphodepletion with Cyclophosphamide 900mg/m2 and fludarabine 30mg/m2 plus mesna. Using a standard 3+3 dose escalation schema, patients will receive the first cycle of CYNK-001 intravenously (IV) at an initial dose of 2.4 x109 cells on Days 1, 8 and 15 after lymphodepletion. Cell supportive IL-2 at 6M IU administered SQ on Days 1, 3, 5, 8, 10, 12, and 15 within 3 hours prior to CYNK-001 IV infusion where applicable. Cycle 2 begins with surgical resection on Day 22 in which CYNK-001 is administered directly into the tumor cavity wall at an initial dose of 100 x106 NK cells and an Ommaya catheter placement. Subsequent CYNK-001 IC administrations via the Ommaya are on days 29 and 36 with 6M IU IL-2 SQ. DLT is evaluated for all dosing cohorts from day 1 to 7 days post last dose of cycle 2. Once a maximum tolerated dose is identified, a safety lead-in cohort with an additional 3 cycles of CYNK-001 IC will be administered prior to initiating the Phase IIa portion of the study. Endpoints: The primary endpoint is dose-limiting toxicity for the Phase I analysis and 6-month progression free survival post tumor resection for the Phase IIa component. Post-resected tumor tissue will be characterized for effector immune cell function and immune suppression with assessments directed at CYNK-001 tumor distribution using methodology developed at Celularity Inc. Approximately 66 patients are planned for this Phase I/IIa study. Approximately 66 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05218408.