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

Yoshinari Maeda, Kiyoshi Yoshimura, Hiroto Matsui, Yoshitaro Shindo, Takao Tamesa, Yukio Tokumitsu, Noriaki Hashimoto, Yoshihiro Tokuhisa, Kazuhiko Sakamoto, Kouhei Sakai, Yutaka Suehiro, Yuji Hinoda, Koji Tamada, Shigefumi Yoshino, Shoichi Hazama, Masaaki Oka

Research output: Contribution to journalArticle

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 3Âweeks. The number of HSP70-DCs injected was 1Â×Â107 as the lowest dose, then 2Â×Â107 as the medium dose, and then 3Â×Â107 as the highest dose. Immunological analyses were performed. Findings: No adverse effects of grade III/IV, except one grade III liver abscess at the 3Â×Â107 dose, were observed. Thus, we added three more patients to confirm whether 3Â×Â107 is an appropriate dose. Eventually, we chose 3Â×Â107 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 33Âmonths, 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.

Original languageEnglish (US)
Pages (from-to)1047-1056
Number of pages10
JournalCancer Immunology Immunotherapy
Volume64
Issue number8
DOIs
StatePublished - May 16 2015
Externally publishedYes

Fingerprint

HSP70 Heat-Shock Proteins
Hepacivirus
Dendritic Cells
Hepatocellular Carcinoma
Clinical Trials
Messenger RNA
Staining and Labeling
Recurrence
Granzymes
Liver Abscess
Clinical Trials, Phase I
Electroporation
Hepatectomy
Cytotoxic T-Lymphocytes
Cell- and Tissue-Based Therapy
Proteomics
Disease Progression
Neoplasms
T-Lymphocytes

Keywords

  • Dendritic cell
  • Electroporation
  • Heat-shock protein 70
  • Hepatocellular carcinoma
  • Immunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

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. / Maeda, Yoshinari; Yoshimura, Kiyoshi; Matsui, Hiroto; Shindo, Yoshitaro; Tamesa, Takao; Tokumitsu, Yukio; Hashimoto, Noriaki; Tokuhisa, Yoshihiro; Sakamoto, Kazuhiko; Sakai, Kouhei; Suehiro, Yutaka; Hinoda, Yuji; Tamada, Koji; Yoshino, Shigefumi; Hazama, Shoichi; Oka, Masaaki.

In: Cancer Immunology Immunotherapy, Vol. 64, No. 8, 16.05.2015, p. 1047-1056.

Research output: Contribution to journalArticle

Maeda, Y, Yoshimura, K, Matsui, H, Shindo, Y, Tamesa, T, Tokumitsu, Y, Hashimoto, N, Tokuhisa, Y, Sakamoto, K, Sakai, K, Suehiro, Y, Hinoda, Y, Tamada, K, Yoshino, S, Hazama, S & Oka, M 2015, '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 Immunology Immunotherapy, vol. 64, no. 8, pp. 1047-1056. https://doi.org/10.1007/s00262-015-1709-1
Maeda, Yoshinari ; Yoshimura, Kiyoshi ; Matsui, Hiroto ; Shindo, Yoshitaro ; Tamesa, Takao ; Tokumitsu, Yukio ; Hashimoto, Noriaki ; Tokuhisa, Yoshihiro ; Sakamoto, Kazuhiko ; Sakai, Kouhei ; Suehiro, Yutaka ; Hinoda, Yuji ; Tamada, Koji ; Yoshino, Shigefumi ; Hazama, Shoichi ; Oka, Masaaki. / 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. In: Cancer Immunology Immunotherapy. 2015 ; Vol. 64, No. 8. pp. 1047-1056.
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T2 - A phase 1 dose escalation clinical trial

AU - Maeda, Yoshinari

AU - Yoshimura, Kiyoshi

AU - Matsui, Hiroto

AU - Shindo, Yoshitaro

AU - Tamesa, Takao

AU - Tokumitsu, Yukio

AU - Hashimoto, Noriaki

AU - Tokuhisa, Yoshihiro

AU - Sakamoto, Kazuhiko

AU - Sakai, Kouhei

AU - Suehiro, Yutaka

AU - Hinoda, Yuji

AU - Tamada, Koji

AU - Yoshino, Shigefumi

AU - Hazama, Shoichi

AU - Oka, Masaaki

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N2 - 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 3Âweeks. The number of HSP70-DCs injected was 1Â×Â107 as the lowest dose, then 2Â×Â107 as the medium dose, and then 3Â×Â107 as the highest dose. Immunological analyses were performed. Findings: No adverse effects of grade III/IV, except one grade III liver abscess at the 3Â×Â107 dose, were observed. Thus, we added three more patients to confirm whether 3Â×Â107 is an appropriate dose. Eventually, we chose 3Â×Â107 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 33Âmonths, 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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