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Myeloma

A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients

Leukemia volume 29, pages 218–229 (2015)Cite this article

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Abstract

We evaluated a cocktail of HLA-A2-specific peptides including heteroclitic XBP1 US184–192 (YISPWILAV), heteroclitic XBP1 SP367–375 (YLFPQLISV), native CD138260–268 (GLVGLIFAV) and native CS1239–247 (SLFVLGLFL), for their ability to elicit multipeptide-specific cytotoxic T lymphocytes (MP-CTLs) using T cells from smoldering multiple myeloma (SMM) patients. Our results demonstrate that MP-CTLs generated from SMM patients’ T cells show effective anti-MM responses including CD137 (4-1BB) upregulation, CTL proliferation, interferon-γ production and degranulation (CD107a) in an HLA-A2-restricted and peptide-specific manner. Phenotypically, we observed increased total CD3+CD8+ T cells (>80%) and cellular activation (CD69+) within the memory SMM MP-CTL (CD45RO+/CD3+CD8+) subset after repeated multipeptide stimulation. Importantly, SMM patients could be categorized into distinct groups by their level of MP-CTL expansion and antitumor activity. In high responders, the effector memory (CCR7−CD45RO+/CD3+CD8+) T-cell subset was enriched, whereas the remaining responders’ CTL contained a higher frequency of the terminal effector (CCR7−CD45RO−/CD3+CD8+) subset. These results suggest that this multipeptide cocktail has the potential to induce effective and durable memory MP-CTL in SMM patients. Therefore, our findings provide the rationale for clinical evaluation of a therapeutic vaccine to prevent or delay progression of SMM to active disease.

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Acknowledgements

We acknowledge the generous gift of K562-A*0201 cells from Dr P Cresswell (Yale University, New Haven, CT, USA). We also thank Mr J Daley and Ms S Lazo-Kallanian from the Flow Cytometry facility at Dana-Farber Cancer Institute for providing flow cytometry assistance. This work was supported in part by grants from the National Institutes of Health Grants RO1-124929 to Dr NC Munshi, P50-100007, PO1-78378 and PO1155258 to Drs KC Anderson and NC Munshi, and RO1-50947 to Dr KC Anderson. This research was also supported in part by a kind donation from Mr and Mrs Stewart Nagler. Dr KC Anderson is an American Cancer Society Clinical Research Professor.

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    J Bae, R Prabhala, A Brown, P Richardson, G Dranoff, K C Anderson & N C Munshi

  2. Harvard Medical School, Boston, MA, USA

    J Bae, R Prabhala, A Brown, P Richardson, G Dranoff, K C Anderson & N C Munshi

  3. VA Boston Healthcare System, Boston, MA, USA

    R Prabhala & N C Munshi

  4. Johns Hopkins School of Public Health, Baltimore, MD, USA

    A Voskertchian

  5. Tufts University School of Medicine, Boston, MA, USA

    C Maguire

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Correspondence to J Bae.

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Competing interests

KC Anderson is an advisory board for Celgene, Millennium, Gilead, Sanofi-Aventis and Onyx. NC Munshi serves on the advisory boards of Celgene, Onyx and Johnson & Johnson, and PG Richardson serves on the advisory boards of Celgene, Millennium and Johnson & Johnson. NC Munshi, KC Anderson and J Bae have ownership interest and are advisory board members in OncoPep Inc. The remaining authors declare no conflict of interest.

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Bae, J., Prabhala, R., Voskertchian, A. et al. A multiepitope of XBP1, CD138 and CS1 peptides induces myeloma-specific cytotoxic T lymphocytes in T cells of smoldering myeloma patients. Leukemia 29, 218–229 (2015). https://doi.org/10.1038/leu.2014.159

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