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


New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin (IL)-15 is a cytokine that stimulates CD8+ T cell and NK cell anti-tumor responses, and we hypothesized this cytokine may augment anti-leukemia/lymphoma immunity in vivo. To test this, we performed a first-in-human multi-center phase 1 trial ( NCT01885897) 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 intravenous (IV) or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 mcg/kg). ALT-803 was well-tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host-disease (GVHD) requiring systemic therapy were observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and IFN-γ. To mitigate these effects the subcutaneous (SQ) route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. PK analysis revealed a prolonged (>96 hours) serum concentrations following SQ, but not IV injection. ALT-803 stimulated 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 one complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell number and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment anti-tumor immunity alone and combined with other immunotherapies.

  • Submitted December 26, 2017.
  • Accepted February 13, 2018.