A Pilot Study of MG4101, Allogeneic Natural Killer Cell, in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: Prognosis of relapsed or refractory acute myleoid leukemia (AML) is dismal. Several studies demonstrated that allogeneic natural killer (NK) cells have potent anti-tumor effect in AML. In this study, we aimed to investigate the safety and efficacy of allogeneic, ex vivo expanded killer-cell immunoglobulin-like receptor (KIR) B haplotype NK cells (MG4101) in refractory or relapsed AML and to elucidate the association between immunologic characteristics and clinical response.

Methods: Patients were scheduled to receive MG4101 for a total of 2 cycles for 28 days in each cycle. After lymphodepletion with fludarabine and cyclophosphamide, MG4101 derived from unrelated healthy donors was administered intravenously for 3 days during the first 3 weeks of the treatment cycle followed by IL-2 for 3 days. Throughout the entire treatment schedule, it was aimed to deliver a total of 2.0 - 5.0 x 10 ⁹ cells to each patient based on actual body weight. NK cell receptor ligand (NKRL) in AML blast and KIR typing of donors and recipients were evaluated and analyzed with the clinical response of the patients.

Results: Between Apr 2018 to Feb 2020, a total of 11 patients (male, n=5) with refractory or relapsed AML patients were conesecutively enrolled. 5 patients (45.5%) were intermediate risk group, and 6 patients (54.5%) were adverse risk group. Three patients had antecedent hematologic malignancies (atypical chronic myeloid leukemia [n=1], myelodysplastic syndrome [n=2]). Of 7 evaluable patients, 2 patients (28.6%) showed partial response (PR) and 2 patients (28.6%) showed stable disease (SD). Median overall survival of entire patients was 3.4 months (95% confidence interval, 2.5 - 4.3 months): 3.7 months in responders (PR or SD) and 1.0 months in nonresponders. There was only 1 grade 4 infusion-related hypersensitivity reaction, which resolved with supportive care, and there was no cytokine release syndrome, or any sign of graft-versus-host disease associated with MG4101 treatment.

NKRL expression varied widely among the patients treated with MG4101. In patients with favorable clinical outcome, ULBP3, activating NKRL for NKG2D receptor, was highly expressed or increased with treatment. PD-L1 expression, in contrast, was maintained relatively low until the end of the treatment. Besides, activating KIR and its cognate ligand interaction were associated with treatment response. Among the responders including PR and SD, the sum of activating KIR tended to be higher than non-responders.

Conclusions: MG4101 in refractory or relapsed AML was well tolerated without significant treatment-related toxicity. NKRL expression in AML blasts was heterogeneous, and treatment response with MG4101 was also highly variable. In our patient cohort, patients with high activating KIR responded favorably to MG4101 treatment. These findings suggests further investigation of MG4101 in patients in relapsed or refractory AML and highlights the importance of immunologic mechanism in treating myeloid neoplasm.

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