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ACUTE MYELOID LEUKEMIA

The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients—a randomized trial

Leukemia (2023)Cite this article

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Abstract

Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21–70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.

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Fig. 1: Treatment schema and random allocation of the patients.
Fig. 2: HCT outcomes in each treatment group determined by intention-to-treat analysis.
Fig. 3: Subgroup analysis for disease progression and NK and T cell recovery after haploidentical HCT with or without post-HCT DNKI infusion.
Fig. 4: Single cellular landscape of PBMCs after haploidentical hematopoietic cell transplantation (HCT) with or without post-transplantation donor natural killer cell infusion (DNKI).
Fig. 5: Donor natural killer cell infusion (DNKI) expands memory-like NK cells, which, in turn clonally expand CD8+ effector-memory T cells.

Data availability

For the patient-level data generated in the study, please contact Dr. Kyoo-Hyung Lee at haploset@gmail.com.

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Acknowledgements

The authors thank Drs. Koen van Besien (Weill Cornell Medicine) and Haesook Teresa Kim (Dana-Farber Cancer Institute) for their critical review of the manuscript and invaluable comments. This work was supported by grants from the following bodies: 1. Korean Health Technology R&D Project, Ministry of Health and Welfare (A121934, HI12C1788), Republic of Korea. 2. R&D Convergence Program of the National Research Council of Science & Technology (NST) (CRC-15-02-KRIBB), Republic of Korea. 3. National Research Foundation of Korea (NRF) (2019R1A2C3002034, 2019R1A2C1007906, 2020R1A2C2012467, 2020R1A2B5B03094920, and 2021M3A9I4024447), Republic of Korea. 4. Electronics and Telecommunications Research Institute (ETRI) grant (22RB1100, Exploratory and Strategic Research of ETRI-KAIST ICT Future Technology), Republic of Korea. 5. Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Program (KGM 5502221), Republic of Korea.

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  1. These authors contributed equally: Kyoo-Hyung Lee, Suk Ran Yoon, Jeong-Ryeol Gong.

Authors and Affiliations

  1. Hematology Section, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Kyoo-Hyung Lee, Eun-Ji Choi, Je-Hwan Lee, Jung-Hee Lee, Yunsuk Choi, Han-Seung Park, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Jimin Woo, Hyeran Kang, Seunghyun Baek & Su Mi Kim

  2. Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    Suk Ran Yoon, Soo-Yeon Park, Sol-Ji Jung, Hanna Kim, Soo Yun Lee, Haiyoung Jung, Jae-Eun Byun & Inpyo Choi

  3. Department of Functional Genomics, University of Science and Technology, Daejeon, Republic of Korea

    Suk Ran Yoon, Haiyoung Jung, Mirang Kim, Seon-Young Kim, Jeong-Hwan Kim & Inpyo Choi

  4. Department of Bio and Brain Engineering, Laboratory for Systems Biology and Bio-Inspired Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea

    Jeong-Ryeol Gong, Hoon-Min Kim & Kwang-Hyun Cho

  5. Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hun Sik Kim

  6. Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Chan-Jeoung Park

  7. Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Sung-Cheol Yun

  8. Department of Biochemistry, School of Life Sciences, Chungbuk National University, Cheongju, Republic of Korea

    Jae-Eun Byun

  9. Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea

    Mirang Kim, Seon-Young Kim & Jeong-Hwan Kim

  10. Ingenium Therapeutics, Daejeon, Republic of Korea

    Inpyo Choi

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Contributions

K-HL: Conceptualization, resources, study design, project administration, supervision, manuscript writing, and editing. SRY: NK cell production, analytical experiments, and data analysis. J-RG: Single-cell RNA analysis, manuscript writing and editing. E-JC: Study patient reenrollment and care, data analysis, statistical analysis, and manuscript editing. HSK: FACS data analysis. C-JP: FACS data analysis. S-CY: Statistical consultation and analysis. S-YP: NK cell production, analytical experiments, and data analysis. S-JJ: NK cell production, analytical experiments, and data analysis. HK: NK cell production, analytical experiments, and data analysis. SYL: NK cell production, analytical experiments, and data analysis. HJ: Single-cell RNA analysis and data interpretation. J-EB: Single-cell RNA analysis and data interpretation. MK: Single-cell RNA analysis and data interpretation. S-YK: Single-cell RNA analysis and data interpretation. J-HK: Single-cell RNA analysis and data interpretation. J-HL: Study patient enrollment and care, clinical data interpretation, and data analysis. J-HL: Clinical data analysis and interpretation. YC: Clinical data analysis and interpretation. H-SP: Patient management, clinical data interpretation, and data analysis. Y-SL: HCT management and clinical study data management. Y-AK: HCT management and clinical study data management. MJ: HCT management and clinical data management. JMW: HCT management and clinical data management. HK: HCT management and clinical data management. SB: HCT management and study data management. SMK: HCT management and study data management. H-MK: Single-cell RNA analysis, manuscript writing and editing. K-HC: Study design, resources, supervision, single-cell RNA analysis, manuscript writing and editing. IC: Conceptualization, resources, study design, project administration, supervision, manuscript writing, and editing.

Corresponding authors

Correspondence to Kyoo-Hyung Lee, Kwang-Hyun Cho or Inpyo Choi.

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Competing interests

K-HL, E-JC, J-HL, J-HL, and H-SP are recipients of royalty from Ingenium Therapeutics, Daejon, Korea. K-HL and E-JC are consultants for the same company and receive consultation fees. The other authors declare no competing conflict of interest.

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Lee, KH., Yoon, S.R., Gong, JR. et al. The infusion of ex vivo, interleukin-15 and -21-activated donor NK cells after haploidentical HCT in high-risk AML and MDS patients—a randomized trial. Leukemia (2023). https://doi.org/10.1038/s41375-023-01849-5

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