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T cell responses in melanoma patients after vaccination with tumor-mRNA transfected dendritic cells

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Abstract

We have developed an individualized melanoma vaccine based on autologous dendritic cells (DCs) transfected with autologous tumor-mRNA. The vaccine targets the unique spectrum of tumor antigens in each patient and may recruit multiple T cell clones. In a recent phase I/II trial, we demonstrated T cell responses against vaccine antigens in 9/19 patients evaluable by T cell assays. Here, we report a follow-up study that was conducted to characterize interesting T cell responses and to investigate the effects of long-term booster vaccination. Two patients were selected for continued vaccine therapy. The clinical follow-up suggested a favorable clinical development in both patients. The immunological data (T cell proliferation/IFNγ ELISPOT/Bioplex cytokine assays) indicated sustained T cell responses and suggested an enhancing effect of booster vaccinations. Both CD4+ and CD8+ T cell responses were demonstrated. From post-vaccination samples, we generated 39 T cell clones that responded specifically to stimulation by mRNA-transfected DCs and 12 clones that responded to mock-transfected DCs. These data clearly indicate a two-component vaccine response, against transfected and non-transfected antigens. T cell receptor (TCR) clonotype mapping, performed on 11 tDC-specific clones, demonstrated that 10/11 clones had different TCRs. The results thus indicate a broad spectrum T cell response against antigens encoded by the transfected tumor-mRNA. We generally observed mixed Th1/Th2 cytokine profiles, even in T cell clones that were confirmed to be derived from a single cell. This finding suggests that cytokine patterns after cancer vaccination may be more complex than indicated by the classic Th1/Th2 dichotomy.

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Abbreviations

DC:

Dendritic cell

PBMC:

Peripheral blood mononuclear cell

TCR:

T cell receptor

DTH:

Delayed-type hypersensitivity

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Acknowledgment

This work was supported by the Norwegian Ministry of Health (Gene Therapy Grant), the Norwegian Cancer Society and ENACT.

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Authors and Affiliations

  1. Section for Immunotherapy, Department of Immunology, Cancer Research Institute, The Norwegian Radium Hospital, University of Oslo, 0310, Oslo, Norway

    Jon Amund Kyte, Kari Lislerud & Gustav Gaudernack

  2. Laboratory for Cellular Therapy, The Norwegian Radium Hospital, Oslo, Norway

    Gunnar Kvalheim

  3. Tumor Immunology Group, Institute of Cancer Biology, Danish Cancer Society, Copenhagen, Denmark

    Per thor Straten

  4. Department of Clinical Cancer Research, The Norwegian Radium Hospital, Oslo, Norway

    Svein Dueland & Steinar Aamdal

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  1. Jon Amund Kyte
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  2. Gunnar Kvalheim
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  3. Kari Lislerud
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  4. Per thor Straten
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Correspondence to Jon Amund Kyte.

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Kyte, J.A., Kvalheim, G., Lislerud, K. et al. T cell responses in melanoma patients after vaccination with tumor-mRNA transfected dendritic cells. Cancer Immunol Immunother 56, 659–675 (2007). https://doi.org/10.1007/s00262-006-0222-y

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