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Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination

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Abstract

We have previously reported two trials in non-small cell lung cancer (NSCLC) evaluating vaccine therapy with the telomerase peptide GV1001. The studies demonstrated considerable differences in survival among immune responders, highlighting that an immune response is not necessarily beneficial. In the present study, we conducted long-term clinical follow-up and investigated immunological factors hypothesized to influence clinical efficacy. Peripheral blood mononuclear cells from 33 NSCLC trial patients and 15 healthy donors were analyzed by flow cytometry for T regulatory cells (Tregs, CD4+CD25+CD127low/−FOXP3+) and two types of myeloid-derived suppressor cells (MDSCs, HLA-DR low CD14 + or Lin /lo HLA-DR CD33 + CD11b +). T cell cultures were analyzed for 17 cytokines. The results demonstrated that immune responders had increased overall survival (OS, p < 0.001) and progression-free survival (p = 0.003), compared to subjects without immunological response. The mean OS advantage was 54 versus 13 months. Six patients were still alive at the last clinical update, all belonging to the immune responders. No serious toxicity had developed (maximum observation 13 years). Most patients developed a polyfunctional cytokine profile, with high IFNγ/IL-4 and IFNγ/IL-10 ratios. Low Treg levels were associated with improved OS (p = 0.037) and a favorable cytokine profile, including higher IFNγ/IL-10 ratios. High CD33+ MDSC levels were associated with poorer immune response rate (p = 0.005). The levels of CD14+ MDSC were significantly higher in patients than in healthy controls (p = 0.012). We conclude that a randomized GV1001 trial in NSCLC is warranted. The findings suggest that Tregs and MDSCs are associated with a tolerogenic cytokine milieu and impaired clinical efficacy of vaccine responses.

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Abbreviations

MCP:

Monocyte chemoattractant protein

MDSC:

Myeloid-derived suppressor cell

MIP:

Macrophage inflammatory protein

NSCLC:

Non-small cell lung cancer

OS:

Overall survival

PFS:

Progression-free survival

Th:

T helper

Treg:

T regulatory cell

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Acknowledgments

The work was supported by the Norwegian Health Region South-East and the Faculty of Medicine, University of Oslo. Pharmexa (Denmark) supplied GV1001 free of charge. The authors thank Sissel Trachsel and Mira Roness for valuable technical assistance. We also thank doctors and nurses at the study hospitals for excellent clinical follow-up and patient care. Special thanks to Steinar Aamdal, Christian Kersten, Stein Sundstrøm, Else Marit Suso, Svein Dueland, Odd Terje Brustugun, Kristin Øwre, and Ingun Sve.

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Correspondence to Jon Amund Kyte.

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J.A. Kyte has received research support (≈10,000 Euro) from Kael-Gemvax. G. Gaudernack is a member of Kael-Gemvax advisory board. The other authors declare that they have no conflict of interest.

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Hansen, G.L., Gaudernack, G., Brunsvig, P.F. et al. Immunological factors influencing clinical outcome in lung cancer patients after telomerase peptide vaccination. Cancer Immunol Immunother 64, 1609–1621 (2015). https://doi.org/10.1007/s00262-015-1766-5

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