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A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation

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Abstract

Natural killer (NK) cell based immunotherapy is an emerging strategy in hematologic malignancies because allogeneic NK cells can provide potent antitumor immunity without inducing graft-versus-host disease. Thus, we expanded cord blood-derived NK (CB-NK) cells ex vivo from random (MHC mismatched and KIR mismatched) donors, and investigate the feasibility and efficacy of repeated infusions CB-NK cells as maintenance therapy after autologous hematopoietic stem cell transplantation (ASCT). Thirty-one patients with acute myeloid leukemia and high-risk lymphoma received ASCT and the adoptive CB-NK cell multiple infusions for maintenance therapy. Patients received a median dose of 5.98 × 107/kg (range, 1.87-17.69 × 107/kg) CB-NK cells and 23 patients completed four infusions, 8 patients received three infusions. Only mild infusion reactions occurred in 15.5% of 116 infusions. Compared to a contemporaneous cohort of 90 patients who did not receive NK cell therapy, the adoptive transfer of CB-NK cells as maintenance treatment showed a tendency of difference in decreasing the relapse rate between CB-NK group and control group (9.7% vs 24.4%). The patients who receiving NK cell infusions had a better PFS and OS than controls (4 year PFS, 84.4 ± 8.3% vs 73.5 ± 5.4%; and 4 year OS, 100% vs 78.1 ± 5.4%) . These findings demonstrate safety and validity of maintenance therapy using CB-NK cells multiple infusions after ASCT, and it is worthy of further clinical trial verification.

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Data availability

The datasets used and/or analyzed during the study are available from the corresponding author on reasonable request.

References

  1. Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ et al (2011) Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood 118(23):6037–6042

    Article  CAS  PubMed  Google Scholar 

  2. Venditti A, Piciocchi A, Candoni A, Melillo L, Calafiore V, Cairoli R et al (2019) GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood 134(12):935–945

    Article  CAS  PubMed  Google Scholar 

  3. Passweg JR, Labopin M, Christopeit M, Cornelissen J, Pabst T, Socié G et al (2020) Postremission Consolidation by Autologous Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia in First Complete Remission (CR) and Negative Implications for Subsequent Allogeneic HCT in Second CR: A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT). Biol Blood Marrow Transplant 26(4):659–664

    Article  CAS  PubMed  Google Scholar 

  4. Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA et al (2013) Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med 369(18):1681–1690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Dahi PB, Lazarus HM, Sauter CS, Giralt SA (2019) Strategies to improve outcomes of autologous hematopoietic cell transplant in lymphoma. Bone Marrow Transplant 54(7):943–960

    Article  PubMed  Google Scholar 

  6. Mizutani M, Hara M, Fujita H, Aoki J, Kanamori H, Ohashi K et al (2016) Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR. Bone Marrow Transplant 51(5):645–653

    Article  CAS  PubMed  Google Scholar 

  7. Schmitz N, Truemper L, Bouabdallah K, Ziepert M, Leclerc M, Cartron G et al (2021) A randomized phase 3 trial of autologous vs allogeneic transplantation as part of first-line therapy in poor-risk peripheral T-NHL. Blood 137(19):2646–2656

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang J, Duan X, Yang L, Liu X, Hao C, Dong H et al (2020) Comparison of Survival Between Autologous and Allogeneic Stem Cell Transplantation in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: A Meta-Analysis. Cell Transplant. 963689720975397

  9. Dunbar EM, Buzzeo MP, Levine JB, Schold JD, Meier-Kriesche HU, Reddy V (2008) The relationship between circulating natural killer cells after reduced intensity conditioning hematopoietic stem cell transplantation and relapse-free survival and graft-versus-host disease. Haematol 93(12):1852–1858

    Article  Google Scholar 

  10. Porrata LF, Inwards DJ, Ansell SM, Micallef IN, Johnston PB, Nevala W et al (2016) Sustained natural killer cell recovery post-autologous peripheral blood hematopoietic stem cell transplantation predicts survival in non-Hodgkin’s lymphoma. Blood 128:4641

    Article  Google Scholar 

  11. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al (2002) Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 295:2097–2100

    Article  CAS  PubMed  Google Scholar 

  12. Bednarski JJ, Zimmerman C, Berrien-Elliott MM, Foltz JA, Becker-Hapak M, Neal CC et al (2022) Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant. Blood 139(11):1670–1683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Choi I, Yoon SR, Park SY, Kim H, Jung SJ, Jang YJ et al (2014) Donor-derived natural killer cells infused after human leukocyte antigen-haploidentical hematopoietic cell transplantation: a dose-escalation study. Biol Blood Marrow Transplant 20(5):696–704

    Article  CAS  PubMed  Google Scholar 

  14. Devillier R, Calmels B, Guia S, Taha M, Fauriat C, Mfarrej B et al (2021) Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor. Cancers (Basel) 13(11)

  15. Tschan-Plessl A, Kalberer CP, Wieboldt R, Stern M, Siegler U, Wodnar-Filipowicz A et al (2021) Cellular immunotherapy with multiple infusions of in vitro-expanded haploidentical natural killer cells after autologous transplantation for patients with plasma cell myeloma. Cytotherapy 23(4):329–338

    Article  CAS  PubMed  Google Scholar 

  16. Shah N, Li L, McCarty J, Kaur I, Yvon E, Shaim H et al (2017) Phase I study of cord blood-derived natural killer cells combined with autologous stem cell transplantation in multiple myeloma. Br J Haematol 177(3):457–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T et al (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 129:424–447

    Article  PubMed  PubMed Central  Google Scholar 

  18. International Non-Hodgkin's Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329(14):987–994

    Article  Google Scholar 

  19. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR et al (2007) Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26(6):798–811

    Article  CAS  PubMed  Google Scholar 

  20. NCI National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), , 2021 Available from: http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

    Google Scholar 

  21. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E et al (2014) Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 32(27):3059–3068

    Article  PubMed  PubMed Central  Google Scholar 

  22. Nguyen R, Wu H, Pounds S, Inaba H, Ribeiro RC, Cullins D et al (2019) A phase II clinical trial of adoptive transfer of haploidentical natural killer cells for consolidation therapy of pediatric acute myeloid leukemia. J Immunother Cancer 7(1):81

    Article  PubMed  PubMed Central  Google Scholar 

  23. Dolstra H, Roeven MWH, Spanholtz J, Hangalapura BN, Tordoir M, Maas F et al (2017) Successful Transfer of Umbilical Cord Blood CD34(+) Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients. Clin Cancer Res 23(15):4107–4118

    Article  CAS  PubMed  Google Scholar 

  24. Vela M, Corral D, Carrasco P, Fernandez L, Valentin J, Gonzalez B et al (2018) Haploidentical IL-15/41BBL activated and expanded natural killer cell infusion therapy after salvage chemotherapy in children with relapsed and refractory leukemia. Cancer Lett 422:107–117

    Article  CAS  PubMed  Google Scholar 

  25. Björklund AT, Carlsten M, Sohlberg E, Liu LL, Clancy T, Karimi M et al (2018) Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML. Clin Cancer Res 24(8):1834–1844

    Article  PubMed  Google Scholar 

  26. Ciurea SO, Schafer JR, Bassett R, Denman CJ, Cao K, Willis D et al (2017) Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. Blood 130(16):1857–1868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luevano M, Daryouzeh M, Alnabhan R, Querol S, Khakoo S, Madrigal A et al (2012) The unique profile of cord blood natural killer cells balances incomplete maturation and effective killing function upon activation. Hum Immunol. 73:248–257

    Article  CAS  PubMed  Google Scholar 

  28. Dalle JH, Menezes J, Wagner E, Blagdon M, Champagne J, Champagne MA et al (2005) Characterization of cord blood natural killer cells: implications for transplantation and neonatal infections. Pediatr Res. 57:649–655

    Article  CAS  PubMed  Google Scholar 

  29. Berrien-Elliott MM, Foltz JA, Russler-Germain DA, Neal CC, Tran J, Gang M et al (2022) Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia. Sci Transl Med 14(633):eabm1375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Cooley S, He F, Bachanova V, Vercellotti GM, DeFor TE, Curtsinger JM et al (2019) First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia. Blood Adv 3(13):1970–1980

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank all of the participants in this study, include patients, nurses, and laboratory technicians for their contributions.

Author information

Authors and Affiliations

  1. Department of Hematology, Institute of Hematology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China

    Yuling Wu, Jie Ji, Pu Kuang, Xinchuan Chen, Zhigang Liu, Jian Li, Tian Dong & Ting Liu

  2. Sichuan Cord Blood Bank and Sichuan Neo-life Stem Cell Biotech Inc., Chengdu, Sichuan, China

    Yue Wang, Xuelian Li & Qiang Chen

Authors
  1. Yuling Wu
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  2. Yue Wang
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  3. Jie Ji
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  4. Pu Kuang
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  5. Xinchuan Chen
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  6. Zhigang Liu
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  7. Jian Li
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  8. Tian Dong
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  9. Xuelian Li
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  10. Qiang Chen
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  11. Ting Liu
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Contributions

T.L. designed and guild the clinical research. Q.C. guild the expansion of CB-NK cells products., YL.W., J.J.,Q.C., and T.L. interpreted the data. Y.W., X.L., expand CB-NK cells. P.K., X.C., J.J., Z.L., J.L, and T.D. treated patients. YL.W. and T.L. analyzed the data and wrote the paper. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Ting Liu.

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Ethics approval

The study was reviewed and approved by the Ethics Committees of West China Hospital, Sichuan University, and was registered on the Clinical Trial Registry (clinicaltrials.gov, NCT05250362). Written informed consent was obtained from all patients.

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The authors declare no competing interests.

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Wu, Y., Wang, Y., Ji, J. et al. A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation. Ann Hematol 102, 3229–3237 (2023). https://doi.org/10.1007/s00277-023-05471-4

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  • DOI: https://doi.org/10.1007/s00277-023-05471-4

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