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Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response

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Abstract

To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks from the first administration of maintenance temozolomide. All patients showed good tolerability during the observation period. Skin disorders, such as grade 1/2 injection-site reactions, were observed in all seven patients. Although grade 3 lymphocytopenia potentially due to concurrent radio/temozolomide therapy was observed in five patients (71.4 %), no other grade 3/4 hematological or neurological toxicities were observed. No autoimmune reactions were observed. All patients are still alive, and six are on Wilms tumor 1 peptide vaccination without progression, yielding a progression-free survival from histological diagnosis of 5.2–49.1 months. Wilms tumor 1 peptide vaccination was stopped in one patient after 12 injections by the patient’s request. The safety profile of the combined Wilms tumor 1 peptide vaccination and temozolomide therapy approach for treating glioblastoma was confirmed.

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Abbreviations

CR:

Complete response

CTCAE:

Common Terminology Criteria for Adverse Events

DSMC:

Data Safety Monitoring Committee

DTH:

Delayed-type hypersensitivity

EORTC/NCIC:

European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada

FACS:

Fluorescence-activated cell sorting

GBM:

Glioblastoma

GTR:

Gross total resection

mAbs:

Monoclonal antibodies

NR:

No recurrence

PR:

Partial resection

Gy:

Gray

IDH1:

Isocitrate dehydrogenase 1

ORR:

Objective response rate

OS:

Overall survival

PBMCs:

Peripheral blood mononuclear cells

PD:

Progressive disease

PFS:

Progression-free survival

PS:

Performance status

RECIST:

Response Evaluation Criteria in Solid Tumors

RT:

Radiotherapy

RPA:

Recursive partitioning analysis

TMZ:

Temozolmide

TPS:

Total prognostic score

WT1:

Wilms tumor 1

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Acknowledgments

The authors would like to thank Ms. Tomoe Umeda, Department of Cancer Immunotherapy, for her technical assistance. They would also thank Ms. Mariko Kakinoki and Ms. Yuko Komiyama, Department of Neurosurgery, for their secretarial assistance. This work was supported in part by Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (No. 23592123 to Naoya Hashimoto and No. 22591609 to Akihiro Tsuboi).

Conflict of interest

The funding source has no involvement in the study design, the collection, analysis, and interpretation of data, and in the writing of the report.

Ethical standards

This study was conducted according to the principles expressed in the Declaration of Helsinki and approved by the ethics review boards of the Osaka University Faculty of Medicine. Written informed consents were obtained from all patients enrolled.

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    Authors and Affiliations

    1. Department of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Naoya Hashimoto, Naoki Kagawa, Yasuyoshi Chiba, Manabu Kinoshita, Noriyuki Kijima & Toshiki Yoshimine

    2. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Akihiro Tsuboi

    3. Department of Cancer Immunology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Yoshihiro Oka, Soyoko Morimoto & Hiroko Nakajima

    4. Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Yoshihiro Oka & Sumiyuki Nishida

    5. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Haruo Sugiyama

    6. Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, 1-7 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Naoki Hosen & Yusuke Oji

    7. Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka, 565-0871, Japan

      Yoshihiro Oka

    8. Department of Neurosurgery, Hyogo College of Medicine, 1-1 Mukogawacho, Nishinomiya, Hyogo, 663-8501, Japan

      Shuichi Izumoto & Norio Arita

    9. Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

      Satoshi Morita

    10. Tokai Central Hospital, 4-6-2 Sohara Higashijima-cho, Kakamigahara, Gifu, 504-8601, Japan

      Junichi Sakamoto

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    1. Naoya Hashimoto
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    Corresponding author

    Correspondence to Naoya Hashimoto.

    Additional information

    Naoya Hashimoto and Akihiro Tsuboi have contributed equally to this work.

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    Hashimoto, N., Tsuboi, A., Kagawa, N. et al. Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response. Cancer Immunol Immunother 64, 707–716 (2015). https://doi.org/10.1007/s00262-015-1674-8

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    • DOI: https://doi.org/10.1007/s00262-015-1674-8

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