Human Cytokine-Induced Memory-Like Nk Cells Expand In Patients With Aml And Display Enhanced Anti-Leukemia Responses.

Abstract NK cells are innate lymphoid cells that mediate anti-tumor responses. Relapsed/refractory AML patients have a poor prognosis and new therapy approaches are needed. Recently, memory-like properties of NK cells have been discovered, including cytokine-induced memory-like NK cells. Human NK cells briefly pre-activated with IL-12, IL-15, and IL-18 and then allowed to differentiate in vitro have greater re-stimulation responses compared to control cells. We hypothesized that such human memory-like NK cells possess enhanced anti-leukemia functionality. Indeed, memory-like NK cells produced increased IFN-γ in response to primary AML blasts in vitro, compared to controls. Multi-dimensional mass cytometry analyses revealed minimal alterations of memory-like NK cell inhibitory KIR repertoire, and both KIR-ligand matched and mismatched memory-like NK cells responded to primary AML blasts. In the context of a first-in-human clinical trial, allogeneic memory-like NK cells expanded to become the majority of the cells in the blood and bone marrow from AML patients 7–14 days after infusion. Furthermore, donor memory-like NK cells displayed enhanced leukemia-triggered IFN-γ production compared to recipient NK cells in the same samples, and clinical responses have been observed in 3 of 6 evaluable patients. In one patient, mass cytometry revealed expansion of CD3− CD56+ CD8+ NK cells with restricted KIR expression and multiple activating receptors. Deep NK cell immunophenotyping of in vivo expanded memory-like NK cells in additional patients is ongoing. Since memory-like NK cells expand in vivo and display enhanced anti-leukemia functionality, they represent a promising immunotherapy approach for patients with AML.