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 MillerJack O. Egan, Emily K. Jeng, Amy Rock, Hing C. Wong, Todd A. Fehniger, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

260 Scopus citations


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 CD81 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 mg/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-g. 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 CD81 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 CD81 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. (Blood.

Original languageEnglish
Pages (from-to)2515-2527
Number of pages13
Issue number23
StatePublished - Jun 7 2018


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