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

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 mu g/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 mu g (n=4), 4 mu g (n=3), and 5 mu g/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 CD56(bright) NK cells (mean 144-fold for 4 mu g/kg), as well as an increase in CD8(+) T cells (mean 3.38-fold). At 5 mu g/kg/day, there were no dose-limiting toxicities but pulmonary capillary leak and slower patient recovery. This led to our choice of the 4 mu g/kg as CIV-5 dose for further testing. Cytolytic capacity of CD56(bright) and CD56(dim) 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.

Automated summary

The study demonstrated that administering IL-15 as CIV-5 significantly expanded NK cells with increased cytotoxic functions. There were no dose-limiting toxicities in the CIV-5 regimen, and a substantial increase in CD8(+) T cells was observed.