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Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression

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Abstract

The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.

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Abbreviations

CR:

Complete response

CRPC:

Castration-resistant prostate cancer

CTL:

Cytotoxic T lymphocytes

CTLA-4:

Cytotoxic T lymphocyte antigen 4

ECOG:

Eastern Cooperative Oncology Group

EGF-R:

Epidermal growth factor receptor

HLA:

Human leukocyte antigen

HNRPL:

Heterogeneous nuclear ribonucleoprotein L

IgG:

Immunoglobulin G

MDSC:

Myeloid-derived suppressor cells

MRP3:

Multidrug resistance-associated protein 3

PAP:

Prostatic acid phosphatase

PBMC:

Peripheral blood mononuclear cells

PD:

Progressive disease

PFS:

Progression-free survival

PPV:

Personalized peptide vaccine

PR:

Partial response

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

PTHrP:

Parathyroid hormone-related peptide

SART3:

Squamous cell carcinoma antigens 3

TAA:

Tumor-associated antigen

Treg :

Regulatory T cells

UBE2 V:

Ubiquitin-conjugated enzyme variant Kua

WHSC2:

Wolf–Hirschhorn syndrome critical region 2

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Acknowledgments

This study was supported by grants from the Ministry of Health, Labor and Welfare of Japan (M. Noguchi), and Sendai Kousei Hospital (K. Itoh).

Conflict of interest

K Itoh is a consultant/advisory board member in Green Peptide Co. A.Yamada is a part-time executive of Green Peptide Co. No potential conflict of interest is disclosed by other authors.

Author information

Authors and Affiliations

  1. Division of Clinical Research, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan

    Masanori Noguchi

  2. Department of Urology, Kurume University School of Medicine, Kurume, Japan

    Masanori Noguchi & Shigetaka Suekane

  3. Department of Urology, Dokkyo Medical University Koshigaya Hospital, Koshigaya, Japan

    Gaku Arai

  4. Department of Urology, Kitasato University School of Medicine, Kanagawa, Japan

    Kazumasa Matsumoto

  5. Department of Urology, Kyushu University Faculty of Medicine, Fukuoka, Japan

    Seiji Naito

  6. Department of Pathology, Kurume University School of Medicine, Kurume, Japan

    Fukuko Moriya

  7. Department of Immunology, Kurume University School of Medicine, Kurume, Japan

    Nobukazu Komatsu & Tetsuro Sasada

  8. Cancer Vaccine Center, Kurume University School of Medicine, Kurume, Japan

    Satoko Matsueda & Kyogo Itoh

  9. Division of Cancer Vaccines, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan

    Akira Yamada

  10. Bio-Statistics Center, Kurume University School of Medicine, Kurume, Japan

    Tatsuyuki Kakuma

Authors
  1. Masanori Noguchi
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  2. Gaku Arai
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  3. Kazumasa Matsumoto
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  4. Seiji Naito
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  5. Fukuko Moriya
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  6. Shigetaka Suekane
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  7. Nobukazu Komatsu
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  8. Satoko Matsueda
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  9. Tetsuro Sasada
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  10. Akira Yamada
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  11. Tatsuyuki Kakuma
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  12. Kyogo Itoh
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Corresponding author

Correspondence to Masanori Noguchi.

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Noguchi, M., Arai, G., Matsumoto, K. et al. Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression. Cancer Immunol Immunother 64, 493–505 (2015). https://doi.org/10.1007/s00262-015-1660-1

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  • DOI: https://doi.org/10.1007/s00262-015-1660-1

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