First in human data of NKX019, an allogeneic CAR NK for the treatment of relapsed/refractory (R/R) B‐cell malignancies

Background: Autologous CAR T-cell therapies have altered the treatment landscape for many patients (pts) with advanced B-cell malignancies, however custom manufacturing precludes prompt treatment and can result in manufacturing failure. T-cell mediated toxicities are common and can be severe, thereby limiting the population of eligible pts. These challenges limit CAR T-cell therapy administration 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, with 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 challenges associated with CAR-T therapy. Methods: This is an open label, phase 1 trial (NCT05020678) for adults with r/r B-cell malignancies with ≥2 prior lines of therapy excluding prior auto CD19 CAR T-cell therapy. Following 3 days of lymphodepletion (LD) with fludarabine and cyclophosphamide, pts received NKX019 at 3 dose levels (3 × 108, 1 × 109, or 1.5 × 109 CAR+ NK cells/dose on days 0, 7, and 14 of a 28-day cycle). Additional cycles were allowed to deepen response. Tolerability, anti-tumor activity, cellular kinetics, and immune responses were evaluated. Results: As of November 2022, 19 pts 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 NKX019. Median age was 59 years (range 21–82), with median 4 prior lines of therapy. RP2D of 1.5 × 109 cells was determined. 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, neurotoxicity, or GvHD were reported. Five of 19 pts (26%) developed transient fever within 8 hours of NKX019 dosing, but no pts developed signs of cytokine release syndrome beyond 24 hours after cell infusion. Responses for pts with NHL were as follows: 2 out of 4 (3 × 108 dose level), 5 out of 6 (1 × 109 dose level) and 3 out of 4 (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. One pt with CLL had stable disease. Pharmacokinetic data showed a correlation between higher cell doses and higher peak concentration (Cmax), with a trend toward higher Cmax in pts achieving CR. No association was observed between clinical response and elevation of serum cytokines. Encore Abstract - previously submitted to EHA 2023 Keywords: Aggressive B-cell non-Hodgkin lymphoma, Cellular therapies, Ongoing Trials Conflicts of interests pertinent to the abstract. M. Dickinson Consultant or advisory role: AbbVie, BMS, Gilead, Novartis, Roche; Janssen; Genmab Honoraria: Roche; Amgen; Janssen; BMS; Novartis; Gilead; Abbvie Research funding: Celgene; Gilead, Novartis, Roche; Takeda; Lilly; MSD Educational grants: Roche N. Hamad Consultant or advisory role: Novartis C. E. Bryant Consultant or advisory role: Janssen, BMS/Celgene, Skyline Diagnostics, Antengene Honoraria: Amgen N. Kothari Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics P. Ojeras Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics A. Vohra Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics M. Lin Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics M. Tohme Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics J. Trager Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics D. Shook Employment or leadership position: Nkarta Therapeutics Stock ownership: Nkarta Therapeutics B. T. Hill Consultant or advisory role: Novartis; Epizyme; AstraZeneca; Beigene; Kite; Pfizer; Karyopharm; Incyte; Genentech; Celgene; AbbVie Honoraria: Novartis; Epizyme; AstraZeneca; Beigene; Kite; Pfizer; Karyopharm; Incyte; Genentech; Celgene; AbbVie Research funding: Novartis; Beigene; Kite; Karyopharm; Incyte; Genentech; Celgene; AbbVie Educational grants: Kite