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.
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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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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DOI: https://doi.org/10.1007/s00262-015-1656-x