作者
Melissa M. Berrien-Elliott,Jennifer A. Foltz,David A. Russler‐Germain,Carly C. Neal,Jennifer Tran,Margery Gang,Pamela Wong,Bryan Fisk,Celia C. Cubitt,Nancy D. Marin,Alice Y. Zhou,Michael Jacobs,Mark P. Foster,Timothy Schappe,Ethan McClain,Samantha Kersting-Schadek,Sweta Desai,Patrick Pence,Michelle Becker-Hapak,Jeremy Eisele,Matthew Mosior,Lynne Marsala,Obi L. Griffith,Malachi Griffith,Saad Khan,David H. Spencer,John F. DiPersio,Rizwan Romee,Brian Uy,Camille N. Abboud,Armin Ghobadi,Peter Westervelt,Keith Stockerl-Goldstein,Mark A. Schroeder,Fei Wan,Wen-Rong Lie,Patrick Soon‐Shiong,Allegra A. Petti,Amanda F. Cashen,Todd A. Fehniger
摘要
Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA -haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.