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Low-dose cyclophosphamide enhances antigen-specific CD4+ T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma

Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4+ T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.

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Abbreviations

i.m.:

Intramuscularly

i.v.:

Intravenously

ICS:

Intracellular cytokine staining

IHC:

Immunohistochemistry

MDSC:

Myeloid-derived suppressor cells

nTregs:

Natural regulatory T cells

PBMC:

Peripheral blood mononuclear cells

RECIST:

Response evaluation criteria in solid tumours

RT-PCR:

Reverse transcription polymerase chain reaction

Tregs:

Regulatory T cells

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Conflict of interest

I. D. Davis, W. Chen and J. Cebon are patent holders of ISCOMATRIX™ vaccine, CSL Limited. E. Maraskovsky is an employee of CSL Limited. All other authors have no conflict of interest to disclose.

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Correspondence to Oliver Klein.

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Klein, O., Davis, I.D., McArthur, G.A. et al. Low-dose cyclophosphamide enhances antigen-specific CD4+ T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma. Cancer Immunol Immunother 64, 507–518 (2015). https://doi.org/10.1007/s00262-015-1656-x

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