Abstract Pts with R/R CD30+ lymphoma have few effective therapies available. We previously developed a promising therapy using CB-derived NK that were first IL-12/IL-15/IL-18-preactivated followed by expansion (P+E) with K562 feeder cells ex vivo and subsequently complexed with ICE® AFM13 (a first-in-class CD30/CD16A bispecific antibody construct) prior to infusion. These cytokine-induced memory-like NK showed greater in vivo antitumor activity than either P+E NK or AFM13 alone. This single-center phase I-II trial (NCT04074746) evaluates AFM13-precomplexed CB-NK cells in pts ages 15-75 with R/R CD30+ lymphoma. Pts receive 2 cycles of fludarabine/cyclophosphamide (days −5 to −3) followed by AFM13-CB NK cells (day 0) and 3 weekly intravenous infusions of AFM13 (200 mg, days 7, 14 and 21). Pts were enrolled at 3 dose levels: DL1 (106 NK/Kg), DL2 (107 NK/Kg) and DL3 (108 NK/Kg). 19 pts have been treated to date at DL1 (N=3), DL2 (N=3) and DL3 (N=13); 18 have completed both planned cycles. All pts had active progressive disease at enrollment and no bridging therapy was given. Cords were selected for the 37 cycles without consideration for HLA match, which was 0/6 (N=16), 1/6 (N=17), 2/6 (N=2), 3/6 (N=1) and 4/6 (N=1). There were no cases of CRS, ICANS or GVHD; 6 infusion-related reactions (1 G3, 5 G2) in 110 infusions of AFM13 alone and no reactions to the AFM13-loaded NK cells. DL3 was established as the RP2D. There were 17/19 responses (8 CR, 9 PR, 2 PD). All 13 pts treated at the RP2D responded (6 CR, 7 PR). 2 pts subsequently received an autologous SCT. At median follow-up of 6 (2-16) months PFS/OS across all dose levels are 58%/79%. Expansion of CB NK cells occurred as early as 3 days post infusion and persisted for up to a month. In conclusion, the preliminary results of this first clinical trial of ICE®-precomplexed NK cells for R/R CD30+ lymphoma indicate excellent tolerability and high activity and warrant further investigation of this approach. Baseline patient characteristics (N=19) Age, median (range) 37 (20-68) Gender (male/female) 13/6 Diagnosis (Hodgkin/T-NHL) 17/2 No. prior lines therapy, median (range) 6 (1-14) Prior brentuximab vedotin 19 Prior anti-PD-1 18 Prior SCT (autologous/allogeneic) 13 (8/5) Prior cellular therapy (CAR-T) 2 No. prior relapses/progressive disease, median (range 5 (1-14) Citation Format: Yago Nieto, Pinaki Banerjee, Indreshpal Kaur, Roland Bassett, Lucila Kerbauy, Rafet Basar, Mecit Kaplan, Lori Griffin, Daniel Esqueda, Christina Ganesh, Melissa Barnett, Amin Alousi, Chitra Hosing, Jeremy Ramdial, Neeraj Saini, Samer Srour, Karenza Alexis, Andreas Harstrick, Elizabeth J. Shpall, Katayoun Rezvani. Innate cell engager (ICE®) AFM13 combined with preactivated and expanded cord blood (CB)-derived NK cells for patients with refractory/relapsed CD30+ lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT003.