Natural killer (NK) cells are innate lymphoid cells that protect against infection and mediate anti-tumor immune responses. NK cell immunotherapy is a promising cellular therapy approach for leukemia, lymphoma, and other cancers. Multiple laboratories have advanced our understanding of innate NK cell memory and memory-like responses over the past decade, with a unifying definition of enhanced response to re-stimulation after an initial activation event. We identified that human cytokine-induced memory-like (memory) NK cells differentiate after a brief activation with IL-12, IL-15, and IL-18 and mediate enhanced responses against leukemia and other cancer targets. Pre-clinical studies have demonstrated their enhanced anti-tumor potential in vitro, and in vivo in syngeneic murine models and human xenografts. We translated this concept into a first-in-human clinical trial that demonstrated safe adoptive transfer of donor memory NK cells for patients with relapsed or refractory acute myeloid leukemia (AML) resulting in complete remissions. Correlative mass cytometry from this phase 1 study revealed the memory NK cell multidimensional phenotype and identified NKG2A as a major checkpoint for memory NK cell response to AML. Additional clinical trials of donor memory NK cells the HCT setting have demonstrated safety and anti-leukemia activity the immune compatible setting and has provided insights into persistence. Memory NK cells functionally persist for more than 60 days with a unique multidimensional phenotype in two clinical trials in leukemia patients. Further, CITE-seq single cell profiling reveals a unique memory NK cell transcriptomic signature. We have also developed approaches to gene edit and engineer memory-like NK cells with chimeric antigen receptors, expanding the spectrum of cancers for memory-like NK cellular therapy. CAR memory NK cells exhibit enhanced responses, compared with CAR conventional NK cells. Further, pairing with tumor targeting monoclonal antibodies can result in CAR-like responses via CD16/FcγRIIIa, providing additional activating signals that direct memory NK cell response. These studies identify a promising memory NK cell platform for cancer immunotherapy and highlight the importance of correlative studies during clinical trials to advance our understanding of human immunology.

Citation Format: Todd A. Fehniger. NK cells remember: Engineering NK cell memory-like responses for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr SY30-02.