A phase I clinical trial of NK510 combined with PD-1 blockade in patients with advanced non-small cell lung cancer

Resistance to immune checkpoint inhibitors remains a major challenge in advanced non–small cell lung cancer (NSCLC), particularly in patients without actionable driver alterations. Natural killer (NK) cells offer a mechanistically distinct immunotherapeutic strategy. NK510 is an allogeneic, base-edited NK-cell product designed to disrupt TIGIT and enhance NK-cell activation in the tumor microenvironment. We conducted a first-in-human phase I study to evaluate the safety and preliminary antitumor activity of NK510 in combination with PD-1 blockade in patients with advanced, PD-1-pretreated NSCLC. In this open-label, single-center, dose-escalation study, nine patients received weekly NK510 infusions at doses of 6 × 10 9 , 9 × 10 9 , or 12 × 10 9 cells for six consecutive infusions, in combination with the same PD-1 inhibitor used before enrollment, following a conventional 3 + 3 dose-escalation design. The primary endpoint was safety, including assessment of dose-limiting toxicities (DLTs). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and duration of response (DoR). No DLTs were observed across the evaluated dose levels, including the highest tested dose of 12 × 10 9 cells. The combination regimen was generally well tolerated, with fever and chills being the most common treatment-related adverse events. No unexpected safety signals or grade ≥ 3 immune-related adverse events were identified. In the all-treated population, the ORR was 11.1% (95% CI, 0.3–48.2%) and the DCR was 66.7% (95% CI, 29.9–92.5%). Median PFS was estimated at 8.6 months (95% CI, 1.53-not reached). Exploratory cytokine analyses showed variable changes across patients and timepoints. TIGIT-disrupted NK510 could be feasibly and safely combined with PD-1 blockade in patients with advanced, PD-1-pretreated NSCLC. Preliminary signals of disease control observed in this phase I study warrant further investigation of NK510-based strategies in larger prospective trials. This clinical trial is registered with ClinicalTrials.gov (Identifier: NCT06097962).