Allogeneic memory-like natural killer (NK) cell therapy with IL-15 superagonist with or without ipilimumab for advanced, incurable head and neck cancer: A phase 1 trial

Abstract Purpose: Patients with recurrent incurable, or metastatic (R/M) head and neck cancers (HNCs) refractory to platinum and immunotherapy have poor survival. Cellular therapies have emerged as treatments with potential activity in solid tumors. This proof-of-concept trial investigated an allogeneic cytokine-induced, memory-like (CIML) NK cell infusion followed by IL-15 superagonist (sa) after lead-in CTLA-4 inhibition (ipilimumab) plus lymphodepleting (LD) chemotherapy in advanced HNC. Methods: This phase 1 single-center trial enrolled patients (pts) with R/M HNC (n=7 HNSCC, n=3 salivary cancer) regardless of human papillomavirus (HPV) status who had prior platinum and immunotherapy. Pts in cohort 1 received LD fludarabine (25 mg/m2) and cyclophosphamide (60 mg/m2/kg) on days -6 to -2 prior to haploidentical CIML NK cell infusion on day 0 (5-10 × 106 viable cells/kg=dose level 0) followed by N-803 (IL-15sa, 15 mcg/kg subcutaneously) starting on day +1 every 21-days for 4-doses; in cohort 2, pts received the same regimen with a dose of lead-in ipilimumab on day -7. Cohort 1 treated 3 pts at dose level 0; <2 DLTs triggered an additional 3 pts (n=6). Cohort 2 treated an additional 4 pts. Primary objective: safety, maximum tolerated dose of CIML NK cells. Secondary objectives: objective response rate, progression-free survival (PFS), overall survival (OS), and phenotypic expansion and function of adoptively transferred NK cells. Results: From 9/8/20 to 12/2/22, 10 pts enrolled. One DLT was observed at dose level 0. Median age: 58; 9/10 (90%) were men; 8 (80%) had oropharyngeal primaries (6 HPV+) with a median 6 prior lines of therapy for R/M disease (range: 3-8). Eight (80%) had offspring donors. Grade (G) 3-4 hematologic adverse events were common (10/10, 100%). One patient died of G5 febrile neutropenia and infection (DLT). Median days hospitalized: 15 (range: 9-37). Mild CRS was observed in 6/10 (60%); 5/6 received anti-IL6 therapy; no neurotoxicity was observed. One (10%) partial response (PR) lasted 6.5 months; 6 (60%) had stable disease, 3 (30%) had progression. Tumor regression was observed in 5/10 (50%) at day +30. At a median follow-up of 20.2 mos, median PFS: 2.6 mos (95%CI 1-3.9); median OS: 3.5 mos (95%CI 1-4.7). CIML NK expansion in the peripheral blood (PB) occurred on day +7 in 9/10 of pts. A donor-specific antibody was found in the one patient without expansion. In pts with tumor regression at day +30 compared to those without, CD56dimCD16+ NK cell clusters expanded by day +14 (93.7% vs. 37.3% of PB NK cells). The CD16+KIR+CD57+ NK cell cluster was more prevalent in the ipilimumab-treated pts at the time of tumor regression (16% vs. 4%, p<0.05). Conclusion: Allogeneic CIML NK cells can induce tumor regression associated with persistent CIML NK cell expansion in advanced HNC pts. Tumor regression was associated with CD56dimCD16+ NK cell expansion. We demonstrate safety and feasibility with the expected toxicity of LD. These findings have important implications for the development of cellular therapies in solid tumors. Citation Format: Glenn J. Hanna, Roman M. Shapiro, Michal Sheffer, Michela Ansuinelli, Grace Birch, Robert A. Redd, Alejandro Alonso, Denbaa Bat-Erdene, Samantha Himberg, Heather Daley, Diego E. Hernandez-Rodriquez, Katharin L. Shaw, Jerome Ritz, Sarah Nikiforow, Robert J. Soiffer, Rizwan Romee. Allogeneic memory-like natural killer (NK) cell therapy with IL-15 superagonist with or without ipilimumab for advanced, incurable head and neck cancer: A phase 1 trial [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR11.