Allogeneic NK cells with a bispecific innate cell engager in refractory relapsed lymphoma: a phase 1 trial

Outcomes of patients with CD30-positive (CD30⁺) lymphomas have improved with the advent of brentuximab vedotin (BV) and, in Hodgkin lymphoma, anti-PD1 checkpoint inhibitors (CPI). However, there is a need for new therapies for patients with tumors refractory to both BV and CPI, who face dismal outcomes. AFM13—a CD30/CD16A bispecific antibody—activates natural killer (NK) cells to kill CD30⁺ cells. Here we studied cord-blood-derived cytokine-preactivated and expanded NK cells precomplexed with AFM13 (AFM13-NK) in patients with CD30⁺ lymphoma refractory to BV and CPI. The primary endpoint of this phase 1 trial was to establish the safety and recommended phase 2 dose of AFM13-NK followed by intravenous AFM13 infusions. Secondary endpoints included the overall response rate and complete response (CR) rate, event-free survival and overall survival, and persistence of infused AFM13-NK cells. This is the final analysis of this trial; 42 heavily pretreated patients received 2 to 4 cycles of lymphodepletion followed by AFM13-NK cell infusion at 3 dose levels (10⁶, 10⁷ and 10⁸ kg⁻¹) and 3 weekly AFM13 infusions. No cytokine release syndrome, neurotoxicity or graft-versus-host disease was observed. The highest NK dose was established as the recommended phase 2 dose. Donor NK cells peaked in blood 1 day postinfusion, persisted up to 3 weeks and trafficked to tumor sites. The overall response and CR rates were 92.9% and 66.7%, respectively. At a median follow-up of 20 months, the 2-year event-free and overall survival rates were 26.2% and 76.2%, respectively. Eleven patients (6 with and 5 without consolidation) remained in CR at 14–40 months. This therapy showed encouraging preliminary safety and efficacy. ClinicalTrials.gov Identifier: NCT04074746.