Background: Tumor cells can escape immunosurveillance through upregulation of PD-L1, which inhibits the proliferation and antitumor activity of T cells. T cells genetically altered to express chimeric antigen receptors (CARs) that recognize tumor-associated antigens have mediated potent responses in patients with hematologic cancers, but have shown limited efficacy in solid tumor cancers and can be associated with severe toxicity, ie, cytokine release syndrome (CRS). Like T cells, NK cells can be genetically modified to express CARs that can specifically recognize and lyse cancer cells. Unlike T cells, NK cell cytotoxicity does not require prior sensitization and is not HLA-restricted, making NK cells an attractive choice for clinical immunotherapy. In addition to their innate cytotoxicity, NK cells mediate antibody-dependent cellular cytotoxicity (ADCC) via expression of CD16. PD-L1 t-haNK is an off-the-shelf, human, allogeneic, NK cell line engineered to express a CAR targeting PD-L1. It can be easily and continuously expanded in culture and preclinical in vitro and in vivo studies have demonstrated effective PD-L1 CAR–mediated antitumor activity against PD-L1⁺ MDSCs. PD-L1 t-haNK has also been engineered to express the high-affinity variant of the Fcγ receptor (FcγRIIIa/CD16a 158V), and thus has enhanced CD16-targeted ADCC capabilities, particularly when combined with a monoclonal antibody. As such, a dual-targeted NK approach may be more effective at potentiating antitumor activity and reversing suppression in multiple cancers that express PD-L1 in the tumor microenvironment. Methods: This is a dose-escalation study of PD-L1 t-haNK in subjects with locally advanced or metastatic solid cancers, regardless of PD-L1 expression. Dose escalation will involve a standard 3 + 3 design. The primary objectives are to determine safety, maximum tolerated dose (MTD), and designate a recommended phase 2 dose. Secondary objectives include estimates of preliminary efficacy by objective response rate, progression-free survival, and overall survival. Subjects in Cohort 1 will receive ~2 × 10⁹ PD-L1 t-haNK cells twice per week and assessed for dose-limiting toxicities (DLTs). If no DLTs occur, the dose may increase to ~4 × 10⁹ cells twice per week in Cohort 2. Dose expansion will occur when the MTD has been determined. PD-L1 t-haNK is administered by IV infusion in an outpatient setting. Enrollment in Cohort 1 has been completed (N = 6, > 100 doses total) without DLTs or CRS. Enrollment into Cohort 2 began December 2019. Clinical trial information: NCT04050709.