First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia

Abstract

In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells. Escalating doses of rhIL-15 (0.3-1.0 μg/kg) were given on 12 consecutive days in a phase 1 trial. Of 26 patients, 36% had robust in vivo NK-cell expansion at day 14, and 32% achieved complete remission. Hypothesizing that SC dosing of rhIL-15 would be safer and better tolerated, 16 patients received 10 once per day doses of SC rhIL-15 at 2.0 μg/kg on a phase 2 trial. NK-cell expansion at day 14 was seen in 27% of the patients, and 40% achieved remission. rhIL-15 induced better rates of in vivo NK-cell expansion and remission compared with previous trials with IL-2, but it was associated with previously unreported cytokine release syndrome (CRS) after SC but not IV dosing. CRS was observed in 56% of patients given SC rhIL-15 (with concurrent neurologic toxicity in 5 of 9 patients) and was responsive to steroids and tocilizumab. SC administration was associated with slower pharmacokinetic clearance and higher levels of IL-6 than IV dosing. These novel trials testing the use of IL-15 to potentiate cell therapy suggest that dosing schedules based on pharmacokinetics and pharmacodynamics will preserve the therapeutic benefits of IL-15 and minimize CRS. These trials were registered at www.clinicaltrials.gov as #NCT01385423 and #NCT02395822.

Conflict of interest statement

Conflict-of-interest disclosure: S.C., who contributed to this work while on faculty at University of Minnesota, is now an employee of Fate Therapeutics. The remaining authors declare no competing financial interests.

Figures

Graphical abstract

Figure 1.

rhIL-15 promotes donor chimerism 14 days after haplo-NK-cell infusion with highly functional donor NK cells. (A) Percentages of peripheral blood NK-cell detectable donor chimerism at days 7 and 14 in the IV and SC rhIL-15 cohorts. (B) Cytotoxicity of K562 cells was measured using NK cells isolated from peripheral blood mononuclear cells at day 14 after haplo-NK-cell infusion from patients who successfully in vivo expanded donor NK cells vs nonexpanders. Cytotoxicity was similar in IV or SC IL-15–stimulated NK cells (not shown).

Figure 2.

rhIL-15 with haplo-NK-cell infusion is associated beneficial clinical outcomes. Kaplan-Meier curves of overall survival (A) and progression-free survival (B) of patients who received IV (n = 26) and SC (n = 16) rhIL-15 with haplo-NK-cell infusion.

Figure 3.

Pharmacokinetics of rhIL-15 and inflammatory cytokines. (A) Mean and serum IL-15 levels measured in IV and SC rhIL-15 cohorts at the specified time points are compared (standard error of the mean shown). Peak IL-15 levels were significantly higher 1 hour after dosing in the IV vs SC cohorts. Immediately before dose 2 (dashed box), patients in the SC cohort had significantly higher residual IL-15 levels than those in the IV cohort. Cytokine levels associated with IV rhIL-15 (B) and SC rhIL-15 (C). IL-6 levels are significantly increased at 4 hours after dose 6 in SC compared with IV dosing (P = .04).