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Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation

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Abstract

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4+ and CD8+ T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8+ T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM.

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Abbreviations

4-1BBL:

4-1BB ligand

ASCT:

Autologous stem cell transplantation

caTLR4:

Constitutively active Toll-like receptor 4

CD40L:

CD40 ligand

CM-DC:

Cytokine cocktail matured dendritic cell

CR:

Complete response

DC:

Dendritic cell

Flu-NP:

Influenza nuclear protein

iDC:

Immature dendritic cell

IDO:

Indoleamine 2,3-dioxygenase

IMiD:

Immunomodulatory drug

MDSC:

Myeloid-derived suppressor cell

MM:

Multiple myeloma

NAC:

Non-adherent cell

NK:

Natural killer

PBMC:

Peripheral blood mononuclear cell

Teff:

Effector T cell

Treg:

Regulatory T cell

VGPR:

Very good partial remission

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Acknowledgments

The authors would like to thank Bilal Khan, Chiraz Mahmoud, Steven Heynderickx, Angelo Willems, Elsy Vaeremans, Petra Roman and Xavier Debaere for excellent technical assistance and Sarah Maenhout for her advice regarding the MDSC suppression assays. This study was supported by the Stichting Tegen Kanker, the International Myeloma Foundation (Brian D Novis junior research award), the King Baudouin Foundation (Fund Catharina Weekers) and the Wetenschappelijk Fonds Willy Gepts (Universitair Ziekenhuis Brussel). Parts of this work were realized with a research grant Emmanuel van de Schueren of the Vlaamse Liga Tegen Kanker.

Conflict of interest

TriMix DCs are the topic of a current patent application (WO2009/034172). Kris Thielemans is mentioned as inventor of this application. None of the authors involved in this study receives any form of support or remuneration related to this platform.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Therapy, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090, Brussels, Belgium

    Brenda De Keersmaecker, Jurgen Corthals, Sofie Wilgenhof, Carlo Heirman, Joeri L. Aerts & Kris Thielemans

  2. Department of Clinical Hematology, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium

    Karel Fostier & Rik Schots

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  1. Brenda De Keersmaecker
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  2. Karel Fostier
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Correspondence to Brenda De Keersmaecker.

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De Keersmaecker, B., Fostier, K., Corthals, J. et al. Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation. Cancer Immunol Immunother 63, 1023–1036 (2014). https://doi.org/10.1007/s00262-014-1571-6

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