First-in-Human Trial Finds Single-Agent, Post-Transplant IL-15 Superagonist Tolerable, Effective

Allogeneic hematopoietic cell transplantation (alloHCT) is primary potentially curative option for certain patients with advanced hematologic malignancies, but disease relapse post-transplant remains a major cause of treatment failure. In a phase I trial published in Blood, investigators evaluated whether ALT-803, a superagonist complex of the cytokine interleukin (IL)-15, could enhance donor anti-tumor disease without inducing graft-versus-host response.

The ALT-803 complex consists of an IL-15 mutant bound to an IL-15 receptor α/IgG1 Fc fusion protein, explained Rizwan Romee, MD, from the Oncology Division of the Department of Medicine at Washington University School of Medicine in St. Louis, Missouri, and co-authors. “IL-15 is a cytokine that stimulates CD8-positive T cell and [natural killer (NK)] cell anti-tumor responses, [and] we hypothesized [that] this cytokine may augment anti-leukemia/lymphoma immunity in vivo.

To test this hypothesis, the investigators conducted a first-in-human, multicenter trial of 33 people (median age = 58 years; range = 22-74 years) with hematologic malignancies that relapsed more than 60 days after alloHCT. Patients were eligible for inclusion if they had Karnofsky Performance Scores ≥70 percent, no active graft-versus-host disease (GVHD), were off immune suppression for >14 days, and had ≥10 percent donor cell chimerism.

Under the original trial protocol, patients received single-agent ALT-803 intravenously (IV) at 1, 3, 6, and 10 mcg/kg. Two years into the trial, though, the protocol was amended to include subcutaneous dosing at 6 and 10 mcg/kg to avoid high fevers related to a high ALT-803 concentration and to allow up to two additional courses of treatment.

Overall, 16 patients received IV dosing and 17 received subcutaneous dosing. The majority (85%) had acute myeloid leukemia (AML; n=22) or myelodysplastic syndromes (MDS; n=6), and the median time from alloHCT to first dose of ALT-803 was 292 days (range = 88-2,843 days). Similar numbers of patients received myeloablative (45%) and reduced-intensity (55%) conditioning.

“ALT-803 was well-tolerated in both IV and subcutaneous cohorts,” the authors wrote, with no dose-limiting toxicities (defined as any treatment-emergent, non-hematologic grade 3 adverse event [AE] lasting more than 48 hours; a grade 4-5 AE; or grade 3-4 acute GVHD within 6 weeks of first ALT-803 dose) observed in the dose-finding phase of the study.

The AEs occurring most frequently with the highest doses of ALT-803 included hypertension and injection-site reaction in the subcutaneous cohort (see TABLE). Each administration route had a “distinct AE profile,” the researchers reported, and “IV administration was uniformly associated with infusion-related fever and chills/rigors, [while] the subcutaneous cohort was uniquely associated with injection-site rash.”

Three patients experienced grade 4 AEs and two progressed to grade 5; this included two patients with neutropenia-associated sepsis from active acute leukemia. No patients met the criteria for severe cytokine release syndrome or capillary leak syndrome.

Twenty-seven of the 33 patients (82%) received at least three doses of ALT-803 and were evaluable for response. Five patients responded to treatment, including one who achieved a complete response (CR), one who achieved partial response, and three who achieved stable disease.

Four of these responses occurred in patients who were treated at the 6 mcg/kg dose, and three occurred in those receiving IV dosing. The researchers observed one cytogenetic CR, with resumption of normal hematopoiesis that lasted seven months. This finding suggests that ALT-803 “stimulated allogeneic immunity against diseased hematopoietic cells,” the authors reported. “While not a definitive clinical endpoint, the apparent clinical benefit in MDS/AML patients expected to progress without therapy supports the concept that stimulating immunity after allogeneic transplant can mediate activity against malignant hematopoietic cells.”

Results from pharmacokinetic analyses revealed that ALT-803 stimulated activation, proliferation, and expansion of NK cells and CD8-positive T cells without increasing regulatory T cells. Subcutaneous administration, but not IV administration, was associated with prolonged (>96 hours) serum concentrations, they reported.

“This study demonstrates the safety and immune-activating potential of subcutaneous ALT-803 dosing amenable to outpatient therapy, and a signal of efficacy when used to stimulate allogeneic immunity after HCT,” the researchers concluded. These findings “[provide] a clear rationale for testing ALT-803 in other clinical settings and in combination with complementary immunotherapy approaches.”

This early-phase trial is limited by its small patient population, limited data on duration of responses, and lack of a comparator arm.

The authors report financial relationships with Altor BioScience, which also provided funding for the clinical trial.


Romee R, Cooley S, Berrien-Elliott MM, et al. First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation. Blood. 2018 February 20. [Epub ahead of print]