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Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma

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Abstract

Liver transplantation (LT) is a viable treatment option for cirrhosis patients with hepatocellular carcinoma (HCC). However, recurrence is the rate-limiting factor of long-term survival. To prevent this, we conducted the phase I study of the adoptive transfer of deceased donor liver-derived natural killer (NK) cells. Liver NK cells were extracted from donor liver graft perfusate and were stimulated in vitro with IL-2. The patient received an intravenous infusion of NK cells 3–5 days after LT. Eighteen LT recipients were treated. There were no severe cell infusion-related adverse events or acute rejection episodes. One patient withdrew from the study because the pathological observation revealed sarcoma instead of HCC. All patients who received this immunotherapy completed the follow-up for at least 2 years without evidence of HCC recurrence (median follow-up, 96 months [range, 17–121 months]). Considering that 9 (52.9%) of the 17 patients pathologically exceeded the Milan criteria, liver NK cell infusion is likely to be useful for preventing HCC recurrence after LT. This is the first-in-human immunotherapy study using deceased donor liver-derived NK cells to prevent HCC recurrence after LT. This treatment was well tolerated and resulted in no HCC recurrence after LT.

Clinical trial registration www.clinicaltrials.gov; NCT01147380; registration date: June 17, 2010.

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Abbreviations

CIK:

Cytokine-induced killer

CTCAE:

Common Terminology Criteria for Adverse Events

DDLT:

Deceased donor liver transplantation

FCM:

Flow cytometry

GVHD:

Graft-versus-host disease

HCC:

Hepatocellular carcinoma

HLA:

Human leukocyte antigen

KIR:

Killer cell immunoglobulin-like receptor

LDLT:

Living donor liver transplantation

LMNCs:

Liver mononuclear cells

LT:

Liver transplantation

MELD:

The Model for End-Stage Liver Disease

NK:

Natural killer

PBMCs:

Peripheral blood mononuclear cells

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

UNOS:

The United Network for Organ Sharing

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Acknowledgements

We would like to thank Oliver Umland for supporting flow cytometry analysis, Drs. Ryosuke Misawa, Taizo Hibi, Koichiro Uchida, Takehiko Dohi, Izumi Carpenter, Ji Fan, David Grant, Panagiotis Tryphonopoulos, Bonnie Blomberg, and Gary Kleiner for study support, and Editage (www.editage.com) for English language editing.

Funding

This study was supported by the research funding the Grant No. 1BG-08 from the Florida Department of Health and the Bankhead-Coley Cancer Research Program (Seigo Nishida), AMED under Grant Number JP21fk0210051 (Hideki Ohdan), and JSPS KAKENHI Grant Number JP20K09104 (Masahiro Ohira).

Author information

Author notes

  1. Masahiro Ohira and Ryuichi Hotta contributed equally to this work and should be considered as first authors

Authors and Affiliations

  1. Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Masahiro Ohira, Ryuichi Hotta, Yuka Tanaka & Hideki Ohdan

  2. Department of Surgery, Division of Liver and Gastrointestinal Transplantation, University of Miami Miller School of Medicine, Miami, FL, USA

    Masahiro Ohira, Ryuichi Hotta, Toshiharu Matsuura, Akin Tekin, Gennaro Selvaggi, Rodrigo Vianna, Seigo Nishida & Andreas G. Tzakis

  3. Cell Transplant Center, Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA

    Camillo Ricordi

  4. Department of Pathology and Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Phillip Ruiz

  5. Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA

    Seigo Nishida

  6. Transplant Center, Cleveland Clinic, Cleveland, OH, USA

    Andreas G. Tzakis

  7. Transplant Center, Cleveland Clinic Florida, Weston, FL, USA

    Andreas G. Tzakis

  8. Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan

    Masahiro Ohira

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  1. Masahiro Ohira
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Corresponding authors

Correspondence to Andreas G. Tzakis or Hideki Ohdan.

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Conflict of interest

The authors of this manuscript have no conflict of interest to disclose as described by the Cancer Immunology, Immunotherapy.

Ethical approval

This phase I clinical trial was approved by the Institutional Review Board of the University of Miami Miller School of Medicine (IRB#20100344) and the Food and Drug Administration, and was registered with ClinicalTrials.gov (NCT01147380). The trial was designed and conducted according to the Declaration of Helsinki.

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All patients provided written informed consent before enrolling in the study.

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Ohira, M., Hotta, R., Tanaka, Y. et al. Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma. Cancer Immunol Immunother 71, 589–599 (2022). https://doi.org/10.1007/s00262-021-03005-3

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