Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

SIMPLE SUMMARY: Several strategies have been under investigation on how to enhance anti-tumor responses in patients with poor prognosis. Considering the heterogeneity of antigens expressed by different hematological and solid neoplasia, it is difficult to develop specific immunotherapy approaches. The capacity of Natural Killer (NK) cells to kill tumor cells without specific Ag recognition provides an advantage over T cells and makes them appealing candidate effectors for immunotherapy, even if the effectiveness of their therapeutic use is limited by short-term persistence in vivo. After providing proof of concept regarding the feasibility of inducing NK cells endowed with anti-tumor activity and ability to persist for a protracted period in vivo, considering the relatively short period of in vitro activation, this approach could easily be translated into clinical practice to control tumor growth in high-risk patients. ABSTRACT: The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies.