Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer

Shuhei Mayanagi, Minoru Kitago, Toshiharu Sakurai, Tatsuo Matsuda, Tomonobu Fujita, Hajime Higuchi, Junichi Taguchi, Hiroya Takeuchi, Osamu Itano, Koichi Aiura, Yasuo Hamamoto, Hiromasa Takaishi, Masato Okamoto, Makoto Sunamura, Yutaka Kawakami, Yuukou Kitagawa

Research output: Contribution to journalArticle

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Abstract

This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 10<sup>7</sup> cells) on days 8 and 22 and gemcitabine (1000 mg/m<sup>2</sup>) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

Original languageEnglish
Pages (from-to)397-406
Number of pages10
JournalCancer Science
Volume106
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1

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gemcitabine
Wilms' Tumor Genes
Wilms Tumor
Pancreatic Neoplasms
Dendritic Cells
Vaccination
Peptides
Information Services
Delayed Hypersensitivity
Neoplasm Metastasis
HLA-A Antigens
Immunologic Factors
Skin Tests
Interleukin-8
C-Reactive Protein
Interferons
Registries
Neutrophils
Clinical Trials
Lymphocytes

Keywords

  • Delayed-type hypersensitivity
  • Dendritic cell vaccination
  • First-line therapy
  • Immunotherapy
  • Neutrophil lymphocyte ratio

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer. / Mayanagi, Shuhei; Kitago, Minoru; Sakurai, Toshiharu; Matsuda, Tatsuo; Fujita, Tomonobu; Higuchi, Hajime; Taguchi, Junichi; Takeuchi, Hiroya; Itano, Osamu; Aiura, Koichi; Hamamoto, Yasuo; Takaishi, Hiromasa; Okamoto, Masato; Sunamura, Makoto; Kawakami, Yutaka; Kitagawa, Yuukou.

In: Cancer Science, Vol. 106, No. 4, 01.04.2015, p. 397-406.

Research output: Contribution to journalArticle

Mayanagi, S, Kitago, M, Sakurai, T, Matsuda, T, Fujita, T, Higuchi, H, Taguchi, J, Takeuchi, H, Itano, O, Aiura, K, Hamamoto, Y, Takaishi, H, Okamoto, M, Sunamura, M, Kawakami, Y & Kitagawa, Y 2015, 'Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer', Cancer Science, vol. 106, no. 4, pp. 397-406. https://doi.org/10.1111/cas.12621
Mayanagi, Shuhei ; Kitago, Minoru ; Sakurai, Toshiharu ; Matsuda, Tatsuo ; Fujita, Tomonobu ; Higuchi, Hajime ; Taguchi, Junichi ; Takeuchi, Hiroya ; Itano, Osamu ; Aiura, Koichi ; Hamamoto, Yasuo ; Takaishi, Hiromasa ; Okamoto, Masato ; Sunamura, Makoto ; Kawakami, Yutaka ; Kitagawa, Yuukou. / Phase I pilot study of Wilms tumor gene 1 peptide-pulsed dendritic cell vaccination combined with gemcitabine in pancreatic cancer. In: Cancer Science. 2015 ; Vol. 106, No. 4. pp. 397-406.
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N2 - This study aimed to evaluate the feasibility of and immune response to Wilms tumor gene 1 (WT1) peptide-pulsed dendritic cell vaccination combined with gemcitabine (DCGEM) as a first-line therapy among patients with advanced pancreatic cancer. Ten HLA-A*2402 patients were treated with WT1 peptide-pulsed DC vaccination (1 × 107 cells) on days 8 and 22 and gemcitabine (1000 mg/m2) on days 1, 8 and 15. Induction of a WT1-specific immune response was evaluated using the delayed-type hypersensitivity (DTH) skin test, interferon-γ enzyme-linked immunospot and HLA tetramer assays, along with assays for various immunological factors. DCGEM was well-tolerated, and the relative dose intensity of gemcitabine was 87%. Disease control associated with a low neutrophil/lymphocyte ratio was observed in all three patients with DTH positivity; it was also correlated with a low percentage of granulocytic myeloid derived suppressor cells in the pretreatment peripheral blood (P = 0.017). Patients with liver metastases and high levels of inflammatory markers such as C-reactive protein and interleukin-8 (IL-8) showed poor survival even though a WT1-specific immune response was induced in them. WT1 peptide-pulsed DCGEM is feasible and effective for inducing anti-tumor T-cell responses. Our results support future investigations for pancreatic cancer patients with non-liver metastases and favorable immunological conditions. This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trials Registry (http://www.umin.ac.jp/ctr/ number: UMIN-000004855).

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