PT - JOURNAL ARTICLE AU - Sigrid P Dubois AU - Milos D Miljkovic AU - Thomas A Fleisher AU - Stefania Pittaluga AU - Jennifer Hsu-Albert AU - Bonita R Bryant AU - Michael N Petrus AU - Liyanage P Perera AU - Jürgen R Müller AU - Joanna H Shih AU - Thomas A Waldmann AU - Kevin C Conlon TI - Short-course IL-15 given as a continuous infusion led to a massive expansion of effective NK cells: implications for combination therapy with antitumor antibodies AID - 10.1136/jitc-2020-002193 DP - 2021 Apr 01 TA - Journal for ImmunoTherapy of Cancer PG - e002193 VI - 9 IP - 4 4099 - http://jitc.bmj.com/content/9/4/e002193.short 4100 - http://jitc.bmj.com/content/9/4/e002193.full SO - J Immunother Cancer2021 Apr 01; 9 AB - Background Full application of cytokines as oncoimmunotherapeutics requires identification of optimal regimens. Our initial effort with intravenous bolus recombinant human interleukin-15 (rhIL-15) was limited by postinfusional reactions. Subcutaneous injection and continuous intravenous infusion for 10 days (CIV-10) provided rhIL-15 with less toxicity with CIV-10 giving the best increases in CD8+ lymphocytes and natural killer (NK) cells. To ease rhIL-15 administration, we shortened time of infusion. Treatment with rhIL-15 at a dose of 3–5 µg/kg as a 5-day continuous intravenous infusion (CIV-5) had no dose-limiting toxicities while effector cell stimulation was comparable to the CIV-10 regimen.Methods Eleven patients with metastatic cancers were treated with rhIL-15 CIV-5, 3 µg (n=4), 4 µg (n=3), and 5 µg/kg/day (n=4) in a phase I dose-escalation study (April 6, 2012).Results Impressive expansions of NK cells were seen at all dose levels (mean 34-fold), including CD56bright NK cells (mean 144-fold for 4 µg/kg), as well as an increase in CD8+ T cells (mean 3.38-fold). At 5 µg/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 µg/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56bright and CD56dim NK cells was increased by interleukin-15 assayed by antibody-dependent cellular cytotoxicity (ADCC), natural cytotoxicity and natural killer group 2D-mediated cytotoxicity. The best response was stable disease.Conclusions IL-15 administered as CIV-5 substantially expanded NK cells with increased cytotoxic functions. Tumor-targeting monoclonal antibodies dependent on ADCC as their mechanism of action including alemtuzumab, obinutuzumab, avelumab, and mogamulizumab could benefit from those NK cell expansions and provide a promising therapeutic strategy.Trial registration numbers NCT01572493, NCT03759184, NCT03905135, NCT04185220 and NCT02689453.Data are available upon reasonable request. Tabulated data will be posted on clinicaltrials.gov. Deidentified patient data and clinical trial protocol available by request from corresponding author.