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Myeloma

DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma

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Abstract

We previously described PASD1 as a new cancer testis antigen in multiple myeloma (MM) that is retained post-therapy, suggesting the use of vaccination strategies to induce anti-PASD1 immunity in a setting of minimal residual disease. We have focused on DNA fusion gene vaccines, coupling fragment C domain (DOM) of tetanus toxin with PASD1 sequence, and examined efficacy in Human Leukocyte Antigen (HLA)-A2 (HHD) transgenic mice using a human MM cell line expressing PASD1 protein and chimeric HLA-A2 class I molecules as target. DNA vaccines encoded two HLA-A2-restricted epitopes (p.DOM-PASD1(1), p.DOM-PASD1(2)) and full-length PASD1 (p.DOM-PASD1FL). p.DOM-PASD1(1) proved superior to p.DOM-PASD1(2) in generating T-cell responses in HHD mice, able to lyse the chimeric murine RMA-HHD cells. Boosting by electroporation significantly enhanced p.DOM-PASD1(1). Only p.DOM-PASD1(1) induced cytotoxic T-lymphocytes (CTLs) were able to lyse human MM target cells expressing endogenous antigen. The p.DOM-PASD1FL vaccine predominantly induced strong PASD1(1) over PASD1(2) T-cell immune responses, indicative of immunodominance. Importantly, p.DOM-PASD1FL generated immune-mediating killing of native chimeric MM cells, in the absence of exogenous added peptide, implicating PASD1(1) specific CTLs. These data demonstrate that PASD1-derived epitopes are both efficiently and selectively processed and presented by native human MM cells. Notably, they permit the use of PASD1-encoding DNA vaccine therapy in a clinical setting.

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Acknowledgements

Funding: Leukaemia & Lymphoma Research (UK), EU FP6 Grant 037602 (MSCNET).

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Author notes

  1. N Savelyeva and S S Sahota: Joint Senior Authors.

Authors and Affiliations

  1. Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK

    D Joseph-Pietras, Y Gao, N Zojer, J Rice, N Savelyeva & S S Sahota

  2. Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, UK

    K Ait-Tahar, A H Banham & K Pulford

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  1. D Joseph-Pietras
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  2. Y Gao
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  4. K Ait-Tahar
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  5. A H Banham
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  6. K Pulford
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  7. J Rice
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Correspondence to S S Sahota.

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Joseph-Pietras, D., Gao, Y., Zojer, N. et al. DNA vaccines to target the cancer testis antigen PASD1 in human multiple myeloma. Leukemia 24, 1951–1959 (2010). https://doi.org/10.1038/leu.2010.196

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  • DOI: https://doi.org/10.1038/leu.2010.196

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