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A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients

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Abstract

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II–IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

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Abbreviations

α-GalCer:

α-Galactosylceramide

AE:

Adverse event

AJCC:

American Joint Committee on Cancer

CDR3:

Complementary determining region 3

CTCAE:

Common terminology criteria for adverse events

DCV:

Dendritic cell vaccine

ECOG:

Eastern Cooperative Oncology Group performance status

FGF2:

Fibroblast growth factor 2

FWER:

Family wise error rate

IP-10:

IFN-γ-inducible protein-10

M1:

Influenza virus matrix protein 1

MCP-1:

Monocyte chemoattractant protein-1

MIP:

Macrophage inflammatory protein

NKT cell:

Natural killer T cell

NP:

Influenza virus nucleoprotein

NY-ESO-1:

New York esophageal squamous cell carcinoma-1

PB-1:

Influenza virus protein basic-1

PDGF-BB:

Platelet-derived growth factor BB

PGE2 :

Prostaglandin E2

RANTES:

Regulated on activation, normal T cell expressed and secreted

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Acknowledgements

The authors wish to thank the Hugh Green Cytometry Core for flow cytometry support.

Funding

This work was funded by Health Research Council programme Grant 10/667 and the Health Research Council of New Zealand IROF fund 14/1003.

Author information

Author notes

  1. Olivier Gasser, Katrina J. Sharples, and Catherine Barrow have contributed equally to this study.

Authors and Affiliations

  1. Malaghan Institute of Medical Research, PO Box 7060, Wellington, 6242, New Zealand

    Olivier Gasser, Evelyn Bauer, Catherine E. Wood, Brigitta Mester, Robert Weinkove & Ian F. Hermans

  2. Dunedin School of Medicine, University of Otago, PO Box 56, Dunedin, 9054, New Zealand

    Katrina J. Sharples

  3. Cancer Trials New Zealand, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand

    Katrina J. Sharples, Victoria A. Hinder, Jerome Macapagal, Monica McCusker & Michael P. Findlay

  4. Capital and Coast District Health Board, Private Bag 7902, Wellington, 6242, New Zealand

    Catherine Barrow, Catherine E. Wood, Marina Dzhelali & Robert Weinkove

  5. Maurice Wilkins Centre for Molecular Biodiscovery, Private Bag 92019, Auckland, 1142, New Zealand

    Geoffrey M. Williams, Margaret A. Brimble, P. Rod Dunbar & Ian F. Hermans

  6. GlycoSyn, PO Box 31 310, Lower Hutt, 5040, New Zealand

    Graham Caygill & Jeremy Jones

  7. The Ferrier Research Institute, Victoria University of Wellington, PO Box 33436, Lower Hutt, 5046, New Zealand

    Colin M. Hayman & Gavin F. Painter

  8. School of Biological Sciences, University of Auckland, PO Box 92019, Auckland, New Zealand

    P. Rod Dunbar

  9. School of Biological Sciences, Victoria University of Wellington, PO Box 600, Wellington, 6140, New Zealand

    Ian F. Hermans

Authors
  1. Olivier Gasser
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  2. Katrina J. Sharples
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  3. Catherine Barrow
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  4. Geoffrey M. Williams
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  5. Evelyn Bauer
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  6. Catherine E. Wood
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  7. Brigitta Mester
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  8. Marina Dzhelali
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  9. Graham Caygill
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  10. Jeremy Jones
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  11. Colin M. Hayman
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  12. Victoria A. Hinder
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  13. Jerome Macapagal
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  14. Monica McCusker
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  15. Robert Weinkove
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  16. Gavin F. Painter
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  17. Margaret A. Brimble
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  18. Michael P. Findlay
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  19. P. Rod Dunbar
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  20. Ian F. Hermans
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Contributions

Olivier Gasser developed the cellular methodology and performed the immunogenicity analyses. Katrina J. Sharples prepared the statistical plan and performed the analysis. Catherine Barrow chaired the trial management committee, oversaw patient recruitment and treated patients. Geoffrey M. Williams, P. Rod Dunbar, and Margaret A. Brimble developed the synthetic methodology and manufactured GMP grade peptides. Evelyn Bauer and Brigitta Mester developed the methodology and manufactured the cellular vaccine to GMP standards. Graham Caygill, Jeremy Jones, Colin M. Hayman, and Gavin F. Painter developed the synthetic methodology and manufactured α-GalCer to GMP standards. Catherine E. Wood, Marina Dzhelali, and Robert Weinkove provided local clinical support. Victoria A. Hinder, Jerome Macapagal, Monica McCusker, Catherine E. Wood, Marina Dzhelali, Catherine Barrow, Katrina J. Sharples, and Michael P. Findlay undertook clinical project development, management, analysis and reporting. Olivier Gasser, Katrina J. Sharples, P. Rod Dunbar, and Ian F. Hermans analyzed the immunological data and wrote the manuscript, with input from the other authors. Catherine Barrow, Katrina J. Sharples, Michael P. Findlay, P. Rod Dunbar, and Ian F. Hermans conceived and designed the study.

Corresponding author

Correspondence to Ian F. Hermans.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval and ethical standards

The study was approved by the Northern B Health and Disability Ethics Committee (Ref 13/NTB/5) and registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12612001101875). The study was monitored by an independent Data Monitoring Committee appointed by the Health Research Council of New Zealand.

Informed consent

All patients gave written informed consent.

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Gasser, O., Sharples, K.J., Barrow, C. et al. A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients. Cancer Immunol Immunother 67, 285–298 (2018). https://doi.org/10.1007/s00262-017-2085-9

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  • DOI: https://doi.org/10.1007/s00262-017-2085-9

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