Safety and feasibility of 5T4 antibody-coupled allogeneic NK cell therapy for solid tumors: a first-in-human phase 1 trial.

Abstract

Patients with unresectable locally advanced or metastatic solid tumors have limited therapeutic options. Antibody-guided allogeneic natural killer (NK) cell therapy represents a novel immunotherapeutic strategy to enhance tumor targeting and cytotoxicity by coupling NK cells with tumor-specific antibodies targeting antigens such as 5T4. To evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of IBR854, a non-viral, non-genetically modified, 5T4 antibody-coupled allogeneic NK cell therapy, in patients with advanced solid tumors. This open-label, first-in-human phase 1 dose-escalation study enrolled 19 patients with unresectable locally advanced or metastatic solid tumors across five dose cohorts (3.0 × 10⁹-12.0 × 10⁹ cells per dose). Patients received intravenous IBR854 in a 3 + 3 escalation design. Safety, dose-limiting toxicities, adverse events, pharmacokinetics, anti-drug antibodies, and antitumor activity (RECIST v1.1) were assessed. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were elevated interleukin levels (42.1%), infusion-related reactions (31.6%), and fever (21.1%). No anti-drug antibodies were detected. The disease control rate was 43.8%. Median progression-free survival was 43 days. Pharmacokinetic analysis based on transgene copy number showed a dose-dependent prolongation of T_max (0.867-3.433 h), with a relatively consistent half-life (1.390-2.648 h). IBR854 demonstrated an acceptable safety and tolerability profile and achieved disease stabilization in a subset of heavily pretreated patients with advanced solid tumors. These findings support further clinical development of 5T4-targeted antibody-coupled allogeneic NK cell therapy. Trial registration This study was registered at ClinicalTrials.gov (registration number: NCT06001684).