Use of CD122+ natural killer cell precursors for superior anti-leukemia responses

Abstract

Acute Myeloid Leukemia (AML) is an aggressive blood cancer in adults. Intensive induction therapy successfully induces a complete response in up to 80% of adult patients, but a fraction of them are refractory or relapses. The fraction of non-responsive or relapsing patients is exceptionally high amongst medically unfit and older patients who cannot undergo aggressive chemotherapy treatment. Therefore, offering patients failing on first-line intensive chemotherapy and medically unfit and older patients an effective treatment option for long-term control or even cure of disease represents a significant yet unmet clinical need. As a component of innate immunity, NK cells have recently shown great promise for treating patients with different malignancies. Here, we show that injection of human interleukin-2 (IL-2) complexes (IL-2cx) induce de novo generation and massive expansion of NK cell precursors in vivo. Furthermore, IL-2cx-expanded NK cells exert effector functions with the capacity to control the growth of non-self MHC class I-deficient RMA-S lymphoma cells in vivo while remaining tolerant towards MHC class-expressing self-RMA cells. In an experimental setup mimicking the clinical case of refractory patients after intensive AML induction therapy, IL-2cx treatment mediated strong anti-AML responses following haploidentical bone marrow transplantation without the need for adoptive transfer of donor-derived or in vitro autologous expanded NK cells. Thus, this study demonstrates that IL-2cx immunotherapy allows the in vivo generation and expansion of functionally mature NK cells to achieve long-term response in AML, paving the way to an effective treatment option.