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Novel adjuvant dendritic cell therapy with transfection of heat-shock protein 70 messenger RNA for patients with hepatocellular carcinoma: a phase I/II prospective randomized controlled clinical trial

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A Correction to this article was published on 05 January 2021

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Abstract

Introduction

A proteomic analysis of hepatocellular carcinoma (HCC) has revealed that Heat Shock Protein 70 (HSP70) is among the cancer antigen proteins of HCC. Moreover, we confirmed that HSP70 was highly expressed in HCC by immunohistochemical staining. Based on these results, we developed an HSP70 mRNA-transfected dendritic cell (DC) therapy for treating unresectable or recurrent HCC, and the phase I trial was completed successfully. Thus, we aimed to investigate the safety and efficacy of this therapy as a postoperative adjuvant treatment after curative resection for HCC to prevent recurrence by conducting a phase I/II randomized controlled clinical trial.

Methods

Patients (n = 45) with resectable HCC of stages II–IVa were registered and randomly assigned into two groups (DC group: 31 patients, control group: 14 patients) before surgery. The primary endpoint was disease-free survival (DFS), and the secondary endpoints were safety and overall survival. The DC therapy was initially administered at approximately 1 week after surgery, and twice every 3–4 weeks thereafter.

Results

No adverse events specific to the immunotherapy were observed in the DC group. There was no difference in DFS between the DC and control groups (p = 0.666). However, in the subgroup with HSP70-expressing HCC, DFS of the DC group tended to be better (p = 0.090) and OS of the DC group was significantly longer (p = 0.003) than those of the control group.

Conclusion

The HSP70 mRNA-transfected DC therapy was performed safely as an adjuvant therapy. The prognosis of HSP70-expressing HCC cases could be expected to improve with this therapy.

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Acknowledgments

The authors thank Ms. Akiko Sano and Mrs. Kaori Kaneyasu for their excellent technical assistance with this work. The authors also thank Dr. Kohei Sakai for the generation of HSP70 mRNA.

Funding

No relevant funding was used for this study.

Author information

Authors and Affiliations

  1. Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Hiroto Matsui Matsui, Shoichi Hazama, Masao Nakajima, Ming Xu, Satoshi Matsukuma, Yukio Tokumitsu, Yoshitaro Shindo, Shinobu Tomochika, Shin Yoshida, Michihisa Iida, Nobuaki Suzuki, Shigeru Takeda, Shigefumi Yoshino & Hiroaki Nagano

  2. Department of Translational Research and Developmental Therapeutics Against Cancer, Yamaguchi University School of Medicine, Ube, Yamaguchi, Japan

    Shoichi Hazama

  3. Yamaguchi University Hospital Cancer Center, Ube, Yamaguchi, Japan

    Shigefumi Yoshino

  4. Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama, Japan

    Tomio Ueno

  5. Yamaguchi University, Yamaguchi, Yamaguchi, Japan

    Masaaki Oka

Authors
  1. Hiroto Matsui Matsui
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  2. Shoichi Hazama
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  3. Masao Nakajima
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  4. Ming Xu
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  5. Satoshi Matsukuma
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  8. Shinobu Tomochika
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  9. Shin Yoshida
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  10. Michihisa Iida
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  13. Shigefumi Yoshino
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  16. Hiroaki Nagano
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Contributions

All authors contributed to the study design, data interpretation and review of the manuscript.

Corresponding author

Correspondence to Hiroaki Nagano.

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Conflicts of interest

The authors have no conflict of interest.

Ethics approval

The protocol was approved by the institutional review board of Yamaguchi University (IRB number: H24-40) and was registered with the UMIN Clinical Trials Registry (registration no. UMIN000010691). The study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki.

Informed consent

All patients provided written informed consent prior to undergoing any study-related procedure.

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Consent for publication was obtained from all patients. In addition, all authors agree with the publication of this manuscript.

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Immunotherapy targeting HSP70 as a tumor-associated antigen (TSA) using mRNA-transfected DC was safe and effective for curatively resected HSP70-expressing HCC. This study revealed HSP70 could be a TSA for the immunotherapy against HCC.

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Matsui, H.M., Hazama, S., Nakajima, M. et al. Novel adjuvant dendritic cell therapy with transfection of heat-shock protein 70 messenger RNA for patients with hepatocellular carcinoma: a phase I/II prospective randomized controlled clinical trial. Cancer Immunol Immunother 70, 945–957 (2021). https://doi.org/10.1007/s00262-020-02737-y

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