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Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma

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Abstract

Background

This trial was designed to evaluate the safety and clinical responses to a combination of temozolomide (TMZ) chemotherapy and immunotherapy with fusions of DCs and glioma cells in patients with glioblastoma (GBM).

Method

GBM patients were assigned to two groups: a group of recurrent GBMs after failing TMZ-chemotherapy against the initially diagnosed glioma (Group-R) or a group of newly diagnosed GBMs (Group-N). Autologous cultured glioma cells obtained from surgical specimens were fused with autologous DCs using polyethylene glycol. The fusion cells (FC) were inoculated intradermally in the cervical region. Toxicity, progression-free survival (PFS), and overall survival (OS) of this trial were evaluated. Expressions of WT-1, gp-100, and MAGE-A3, recognized as chemoresistance-associated peptides (CAP), were confirmed by immunohistochemistry of paraffin-embedded tumor samples. Patient’s PBMCs of pre- and post-vaccination were evaluated by tetramer and ELISPOT assays.

Results

FC-immunotherapy was well tolerated in all patients. Medians of PFS and OS of Group-R (n = 10) were 10.3 and 18.0 months, and those of Group-N (n = 22) were 18.3 and 30.5 months, respectively. Up-regulation and/or cytoplasmic accumulation of CAPs was observed in the recurrent tumors of Group-R patients compared with their initially excised tumors. Specific immune responses against CAPs were observed in the tetramer and ELISPOT assays.

Conclusions

The combination of TMZ-treatment leading to up-regulation and/or cytoplasmic accumulation of CAPs, with FC-immunotherapy as a means of producing specific immunity against CAPs, may safely induce anti-tumor effects in patients with GBM.

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Abbreviations

AA:

Anaplastic astrocytoma

AO:

Anaplastic oligodendroglioma

CAP:

Chemoresistance-associated peptide

CI:

Confidence intervals

FC:

Fusion cell

GBM:

Glioblastoma multiforme

gp-100:

Glycoprotein-100

IR:

Injection site reaction

KPS:

Karnofsky performance status

LL:

Leukopenia/lymphopenia

MAGE:

Melanoma-associated antigen gene

PFS:

Progression-free survival

siRNA:

Small interference RNA

TMZ:

Temozolomide

TRP:

Tyrosinase-related protein

WT-1:

Wilms’ Tumor 1

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Acknowledgments

The authors thank Dr. Masako Nishikawa for her advice on statistical analyses, Dr. Kostadin L. Karagiozov for editing the manuscript, and Ms. Yukiko Kobayashi and Ms. Akiko Kuhara for their technical assistance.

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Authors and Affiliations

  1. Department of Neurosurgery, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Yasuharu Akasaki, Nobuyuki Watanabe, Yuta Suzuki, Yohei Yamamoto, Ryosuke Mori, Takao Arai, Toshihide Tanaka, Tatsuhiro Joki, Takaaki Yanagisawa & Yuichi Murayama

  2. Division of Oncology, Research Center for Medical Science, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Tetsuro Kikuchi, Sadamu Homma, Kazumi Hayashi & Hideo Komita

  3. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Shigeo Koido & Toshifumi Ohkusa

  4. Division of Blood Transfusion, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461, Japan

    Tetsunori Tasaki

Authors
  1. Yasuharu Akasaki
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  2. Tetsuro Kikuchi
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Corresponding author

Correspondence to Yasuharu Akasaki.

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Akasaki, Y., Kikuchi, T., Homma, S. et al. Phase I/II trial of combination of temozolomide chemotherapy and immunotherapy with fusions of dendritic and glioma cells in patients with glioblastoma. Cancer Immunol Immunother 65, 1499–1509 (2016). https://doi.org/10.1007/s00262-016-1905-7

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  • DOI: https://doi.org/10.1007/s00262-016-1905-7

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