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.

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).