First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation

Rizwan Romee, Sarah Cooley, Melissa M. Berrien-Elliott, Peter Westervelt, Michael R. Verneris, John E. Wagner, Daniel J. Weisdorf, Bruce R. Blazar, Celalettin Ustun, Todd E. DeFor, Sithara Vivek, Lindsey Peck, John F. DiPersio, Amanda F. Cashen, Rachel Kyllo, Amy Musiek, András Schaffer, Milan J. Anadkat, Ilana Rosman, Daniel Miller, Jack O. Egan, Emily K. Jeng, Amy Rock, Hing C. Wong, Todd A. Fehniger and Jeffrey S. Miller

Key Points

  • Single-agent IL-15/IL-15Rα-Fc (ALT-803) therapy was well tolerated and resulted in clinical responses in patients who relapsed post-HCT.

  • First-in-human use of ALT-803 promoted NK and CD8+ T-cell expansion and activation in vivo without stimulating regulatory T cells.

Publisher's Note: There is a Blood Commentary on this article in this issue.


New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 μg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at as #NCT01885897.

  • Submitted December 23, 2017.
  • Accepted February 13, 2018.
View Full Text