Infusion of haplo‐identical killer immunoglobulin‐like receptor ligand mismatched NK cells for relapsed myeloma in the setting of autologous stem cell transplantation

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Abstract
Summary: Killer immunoglobulin‐like receptor (KIR)‐ligand mismatched natural killer (NK) cells play a key role in achieving durable remission after haplo‐identical transplantation for acute myeloid leukaemia. We investigated the feasibility of transfusing haplo‐identical, T‐cell depleted, KIR‐ligand mismatched NK cells, after conditioning therapy with melphalan and fludarabine, to patients with advanced multiple myeloma (MM) followed by delayed rescue with autologous stem cells. No graft‐versus‐host disease or failure of autologous stem cells to engraft was observed. There was significant variation in the number of allo‐reactive NK cells transfused. However, all NK products containing allo‐reactive NK cells killed the NK cell target K562, the MM cell line U266, and recipient MM cells when available. Post NK cell infusion there was a rise in endogenous interleukin‐15 accompanied by increasing donor chimaerism. Donor chimaerism was eventually lost, which correlated with the emergence of potent host anti‐donor responses indicating that the immunosuppressive properties of the conditioning regimen require further optimization. Further, blocking of inhibitory KIR‐ligands with anti‐human leucocyte antigen antibody substantially enhanced killing of MM cells thus highlighting the potential for modulating NK/MM cell interaction. Encouragingly, 50% of patients achieved (near) complete remission. These data set the stage for future studies of KIR‐ligand mismatched NK cell therapy in the autologous setting.