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Background Patients with high-risk, relapsed/refractory pediatric solid tumors continue to have poor clinical outcomes. NK cell immunotherapies, though promising, face challenges with NK cell expansion, persistence, and signal inhibition in the treatment of solid tumors, creating a need to enhance these therapies. Interleukin-15 (IL-15) plays an essential role in NK cell development, expansion, survival and cytotoxic activity, and may improve NK cell therapy.Methods In this single-institution Phase I trial, we evaluated the feasibility of manufacturing and safety of infusing activated NK cells ± rhIL-15 (3+3 dose escalation design) to children and young adults with relapsed/refractory solid tumors. Autologous NK cells were expanded ex vivo using artificial antigen-presenting cells (aAPC) expressing human 4-1BBL and human IL-15Rα and administered after lymphodepleting cyclophosphamide without (Cohort A) and with (Cohort B) continuous rhIL-15 infusion. Correlative studies included spectral flow cytometry, serum cytokine analysis, and characterization of tumor burden.Results Ex vivo NK cell expansion supported dose levels up to 1x107 cells/kg of an activated NK cell product. Though the cell product could not be specifically tracked post-infusion, peak in vivo NK cell expansion occurred earlier and trended higher in Cohort B.Three of sixteen patients achieved a partial response (PR) at day +28 post-infusion, with stable disease (SD) in the remaining patients. Early increases in circulating T and NK cells and decreases in monocytes correlated significantly with decreases in target lesion size. Patients with PR had higher CD3+ T cell counts at day +14 (p=0.044) and increase in gamma delta T cells at day +28 (p=0.038) compared to those with SD. The myeloid compartment also exhibited changes in chemokine receptor expression on day +28. Serum cytokine analysis was performed.Conclusions Expanding and administering aAPC-activated autologous NK cells was safe and feasible. The addition of rhIL-15 was safe and correlated with increased NK cell expansion in vivo, but effects did not persist beyond discontinuation of the infusion. Differences in the immune milieu, suggestive of increased immune activation in patients with PR compared to patients with SD were investigated and are an area for further exploration. This clinical trial and its intriguing correlative analyses provide a platform to build iterative approaches to enable future cell therapy trials to induce a more complete immune response. Continued research is necessary to determine the best method to maintain sustained activation of NK cells in an immune surveillance role.Ethics Approval This study was approved by the Institutional Review Board of the National Cancer Institute (NCI) at the NIH, approval number 13-C-0152, and was conducted in accordance with good clinical practices and the Declaration of Helsinki.