Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients

<b>Purpose:</b> Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated <i>ex vivo</i> from CD34⁺ hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units.<b>Experimental Design:</b> Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 10⁶/kg body weight) after lymphodepleting chemotherapy without cytokine boosting.<b>Results:</b> HSPC-NK cell products contained a median of 75% highly activated NK cells, with <1 × 10⁴ T cells/kg and <3 × 10⁵ B cells/kg body weight. HSPC-NK cells were well tolerated, and neither graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting being given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, which was accompanied by augmented IL15 plasma levels. Moreover, donor chimerism up to 3.5% was found in bone marrow. Interestingly, <i>in vivo</i> HSPC-NK cell maturation was observed, indicated by the rapid acquisition of CD16 and KIR expression, while expression of most activating receptors was sustained. Notably, 2 of 4 patients with minimal residual disease (MRD) in bone marrow before infusion became MRD negative (<0.1%), which lasted for 6 months.<b>Conclusions:</b> These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential "off-the-shelf" translational immunotherapy approach in AML. <i>Clin Cancer Res; 23(15); 4107-18. ©2017 AACR</i>.