Interleukin-15 augments NK cell-mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies

Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell-mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 mu g/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.

Automated summary

IL-15 monotherapy increases NK cell and CD8+ T cell numbers and activity, but lacks clinical responses. In a mouse model, IL-15 enhances NK cell-mediated ADCC of anti-CD52 antibody and produces more durable responses. A phase 1 study was conducted on patients with CD52-positive mature T-cell malignancies to determine if IL-15 potentiates ADCC in humans. IL-15 was given subcutaneously for 2 weeks followed by alemtuzumab. No dose-limiting toxicities were observed, and the overall response rate was 45% with a median duration of response of 6 months. IL-15 treatment resulted in increased NK cell activation markers and ADCC activity. The trial was registered at www.clinicaltrials.gov as #NCT02689453.