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Dendritic cells transfected with heat-shock protein 70 messenger RNA for patients with hepatitis C virus-related hepatocellular carcinoma: a phase 1 dose escalation clinical trial

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Abstract

Background

We previously reported overexpression of heat-shock protein (HSP) 70 in hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) using proteomic profiling and immunohistochemical staining (IHS). This suggested that HSP70 could be a molecular target for treatment of HCC.

Methods

Twelve patients with HCV-related HCC were enrolled in a phase 1 clinical trial. Dendritic cells (DCs) transfected with HSP70 mRNA (HSP70-DCs) induced by electroporation were injected intradermally. Patients were treated three times every 3 weeks. The number of HSP70-DCs injected was 1 × 107 as the lowest dose, then 2 × 107 as the medium dose, and then 3 × 107 as the highest dose. Immunological analyses were performed.

Findings

No adverse effects of grade III/IV, except one grade III liver abscess at the 3 × 107 dose, were observed. Thus, we added three more patients to confirm whether 3 × 107 is an appropriate dose. Eventually, we chose 3 × 107 as the recommended dose of DCs. Complete response (CR) without any recurrence occurred in two patients, stable disease in five, and progression of disease in five. The two patients with CR have had no recurrence for 44 and 33 months, respectively. IHS in one patient who underwent partial hepatectomy showed infiltration of CD8+ T cells and granzyme B in tumors, indicating that the dominant immune effector cells were cytotoxic T lymphocytes with tumor-killing activity.

Interpretation

This study demonstrated that HSP70-DCs therapy is both safe and feasible in patients with HCV-related HCC. Further clinical trials should be considered.

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Abbreviations

AFP:

α-Fetoprotein

CR:

Complete response

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events version 3.0

CTL:

Cytotoxic T cell

DCs:

Dendritic cells

ECOG PS:

Eastern Cooperative Oncology Group Performance Status

ELISPOT:

Enzyme-linked immunospot

FITC:

Fluorescein isothiocyanate

GM-CFS:

Granulocyte–macrophage colony-stimulating factor

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

HSP:

Heat-shock protein

HSP70-DCs:

HSP70 mRNA-transfected DCs

IFN-γ:

Interferon gamma

IHS:

Immunohistochemical staining

IL-4:

Interleukin-4

IM-DCs:

Immature DCs

mAb:

Monoclonal antibodies

M-DCs:

Mature DCs

MRI:

Magnetic resonance imaging

PBMCs:

Peripheral blood mononuclear cells

PD:

Progression of disease

PIVKA-II:

Vitamin K absence or antagonist II

RECIST:

Response Evaluation Criteria in Solid Tumors guideline version 1.1

RFA:

Radiofrequency ablation

SD:

Stable disease

SE:

Standard error

TAA:

Tumor-associated antigens

TACE:

Transcatheter arterial chemoembolization

TNF-α:

Tumor necrosis factor-α

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Acknowledgments

This study was funded by KAKEN 20591612. We thank Ms. Akiko Sano, Ms. Kaori Kaneyasu, and Ms. Yuko Yanai for their excellent technical assistance.

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Yoshinari Maeda, Kiyoshi Yoshimura, Hiroto Matsui, Yoshitaro Shindo, Takao Tamesa, Yukio Tokumitsu, Noriaki Hashimoto, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Shigefumi Yoshino, Shoichi Hazama & Masaaki Oka

  2. Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Kouhei Sakai, Yutaka Suehiro & Yuji Hinoda

  3. Department of Immunology and Cell Signaling Analysis, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi, 755-8505, Japan

    Koji Tamada

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  1. Yoshinari Maeda
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Correspondence to Yoshinari Maeda.

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Maeda, Y., Yoshimura, K., Matsui, H. et al. Dendritic cells transfected with heat-shock protein 70 messenger RNA for patients with hepatitis C virus-related hepatocellular carcinoma: a phase 1 dose escalation clinical trial. Cancer Immunol Immunother 64, 1047–1056 (2015). https://doi.org/10.1007/s00262-015-1709-1

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