S261: FIRST IN HUMAN DATA OF NKX019, AN ALLOGENEIC CAR NK FOR THE TREATMENT OF RELAPSED/REFRACTORY (R/R) B-CELL MALIGNANCIES

Abstract

Background: Autologous CAR T-cell therapies have altered the treatment landscape for many patients with advanced B-cell malignancies, however custom manufacturing precludes prompt treatment and can result in manufacturing failure. Further, T-cell mediated toxicities are common and can be severe, thereby limiting the population of eligible patients. Due to these challenges, CAR T-cell therapy administration is limited to certified treatment centers, further restricting patient access. NKX019 is a cryopreserved, allogeneic CD19-targeting CAR NK-cell therapy, derived from healthy donor NK cells, which utilizes CD3 zeta and OX40 costimulatory domains and a separate membrane bound IL-15 for activation. NKX019 has shown encouraging in vitro and in vivo cytotoxicity. Development of an on demand allogeneic NK-cell therapy may address the challenges associated with CAR-T therapy. Aims: This Phase 1 study evaluates the safety and preliminary anti-tumor activity of NKX019, an allogeneic NK cell therapy. Methods: This is an open label, phase 1 trial (NCT05020678) for adults with relapsed/refractory (r/r) B-cell malignancies who received ≥2 prior lines of therapy, which excluded prior autologous CD19 CAR T-cell therapy. Following 3 days of lymphodepletion (LD) with fludarabine at 30 mg/m2/d and cyclophosphamide at 300 mg/m2/d, patients received NKX019 at 3 dose levels (3 × 108, 1 × 109, or 1.5 × 109 CAR+ NK cells/dose x 3 doses on days 0, 7, and 14 of a 28-day cycle). Results: As of November 2022, 19 subjects in the US and Australia with r/r B-cell malignancies (14 with non-Hodgkin lymphoma (NHL) (LBCL, FL, MZL, or MCL)) and 5 with leukemia (ALL or CLL)) received treatment with NKX019. Median age was 59 years (range 21-82). Patients had received a median of 4 prior lines of therapy. A recommended phase 2 dose (RP2D) of 1.5 × 109 cells in each of 3 doses (Days 0, 7, and 14 of a 28-day cycle) was determined based on safety and preliminary anti-tumor activity. The rate of grade 3/4 hematologic toxicity was 84%, consistent with expected myelosuppression related to LD. There was one grade 3 infection. There were no treatment related AEs leading to discontinuation of NKX019. No dose limiting toxicities (DLTs), neurotoxicity, or GvHD were reported. Five of 19 subjects (26%) developed transient fever within 8 hours of NKX019 dosing, but no patients developed signs of cytokine release syndrome beyond 24 hours after cell infusion. As shown in the accompanying figure, responses for patients with NHL were as follows: 2 out of 4 at the 3 × 108 dose level, 5 out of 6 at the 1 × 109 dose level and 3 out of 4 at the 1.5 × 109 dose level. Of the 8 patients who achieved CR, 3 with indolent lymphoma subsequently relapsed, each after more than 6 months of remission. While one patient with CLL achieved stable disease, no other responses were seen in patients with leukemia in this limited sample. Pharmacokinetic data showed a correlation between higher cell doses and higher peak measured NKX019 concentration (Cmax), and trend towards higher Cmax in patients achieving CR (median 298 transgene copies/ug DNA vs <6.7 copies/ug DNA in responders vs non-responders, p <0.001). No association was observed between clinical response and elevation of serum cytokine concentrations at any time point following NKX019 administration. Summary/Conclusion: These preliminary data suggest that NKX019 has a manageable safety profile with monotherapy activity across multiple histologies of B-cell NHL. Enrollment into the expansion cohorts is currently ongoing and will evaluate the RP2D in multiple cohorts: (1) CAR-T naïve LBCL, (2) CAR-T exposed LBCL, and (3) in combination with rituximab to evaluate for enhanced anti-tumor activity via ADCC.Keywords: NK cell, Cellular therapy, Non-Hodgkin’s lymphoma