Background: CYNK-101 is a human placental hematopoietic stem/progenitor cell derived NK cell product, that is genetically modified to express a variant of CD16, FcγRIII, via lentiviral vector transduction. The CD16 variant has amino acid modifications to enable high affinity and proteolytic cleavage-resistance for ADCC enhancement. Results from preclinical studies demonstrated enhanced ADCC activity of CYNK-101 in combination with trastuzumab against HER2+ gastric cancer cell lines in vitro, ex vivo and in vivo. Methods: A Phase I/IIa study is a first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Patients are required to have confirmation of HER2 positivity defined as either IHC 3+ or IHC 2+ with a positive FISH or FISH + alone. Following the completion of screening assessments, patients are enrolled to the initial induction period of the trial and receive pembrolizumab, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy for up to six 21-day cycles. In Phase I, patients may skip the initial induction period if they had previously been treated with pembrolizumab or, trastuzumab and a fluoropyrimidine/platinum based-chemotherapy and have not achieved an adequate response. Patients complete a disease assessment and then proceed to a lymphodepletion regimen of cyclophosphamide 900 mg/m² and fludarabine 30 mg/m² with MESNA for 3 days. Following 2 days of rest, the NK-cell re-induction period of the study begins with pembrolizumab 200 mg and trastuzumab 6 mg/kg on Day 1 of that cycle and 6M IU of rhIL-2 with CYNK-101 on days 1, 8, 15. CYNK-101 will be administered based on the calculated number of transduced cells per body weight as measured in kilograms (kg). Two dose levels of CYNK-101 (36 x 10⁶ transduced cells/kg, and 72 x 10⁶ transduced cells/kg) will be evaluated for the NK-Cell reinduction period during the Phase 1 portion of the study in a standard “3+3” dose escalation fashion. Once the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) is determined in Phase I, the designated dosing Cohort level of the NK-Cell re-induction period will be used for the Phase IIa Expansion portion of the study. Both study periods will contain maintenance dosing of pembrolizumab 200 mg, trastuzumab 6 mg/kg and 6M IU rhIL-2 with 3.6 x 10⁶ transduced cells/kg of CYNK-101 on Day 1 of a 21-day cycle. Endpoints: Primary endpoints for Phase I, include the incidence of adverse events defined as dose-limiting toxicities (DLTs). Phase IIa will evaluate efficacy as measured by overall response rate and a complete response rate as determined by RECIST 1.1. Approximately 52 patients are planned for this Phase I/IIa study. Clinical trial information: NCT05207722.