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Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation

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Abstract

Revlimid® (Lenalidomide, CC-5013) and CC-4047 are IMiDs® immunomodulatory drugs that have been described as having immunomodulatory properties and anti-tumor activity. Here we report proapoptotic effects of CC-5013 and CC-4047 on tumor cells in a co-culture model of PBMC and tumor cells. CC-5013 and CC-4047 enhanced PBMC activity leading to tumor cell apoptosis in K562/PBMC co-culture model. We also demonstrate that the natural killer (NK) cell population of PBMC was essential in inducing K562 apoptosis. Increases of NK and natural killer T (NKT) cell populations by CC-5013 and CC-4047 was observed along with modulation of NK cell CD56 adhesion marker. In addition, our data indicate that NK activation by CC-4047 was dependent on other cell types of PBMC. We expanded the application of K562/PBMC co-culture model to other hematological and solid tumors. In Raji/PBMC co-culture model, CC-5013 and CC-4047 dose-dependently augmented tumor cell apoptosis. Pre-treatment of Raji cells with Rituximab further enhanced apoptosis induced by CC-5013 or CC-4047-treated PBMC. Moreover, CC-5013 and CC-4047 significantly increased PC-3 prostate cancer cell apoptosis in PC-3/PBMC co-culture, either as single agent or in combination with Docetaxel. Together, the results reveal that co-culture models are suitable cellular systems to assess anti-tumor activities of these compounds. Our findings support clinical evaluation of CC-5013 and CC-4047 in relapsed NHL with Rituximab and in prostate cancer with Docetaxel.

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Abbreviations

ADCC:

Antibody-dependent cell-mediated cytotoxicity

BrdU:

Bromodeoxyuridine

CD56:

NCAM1, Neural cell adhesion molecule 1

DMSO:

Dimethyl sulfoxide

FBS:

Fetal bovine serum

IL-2:

Interleukin-2 protein

IL-2R:

Interleukin-2 receptor

LLT1:

Lectin-like transcript 1

mAb:

Monoclonal antibody

NK:

Natural killer cell

NKSF:

NK cell stimulatory factor

NKT:

Natural killer T cell

PBMC:

Peripheral blood mononuclear cells

SD:

Standard deviation

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Authors and Affiliations

  1. Celgene Corporation, 4550 Towne Centre Court, San Diego, CA, 92121, USA

    Dan Zhu, Laura G. Corral, Yuedi W. Fleming & Bernd Stein

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  1. Dan Zhu
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  2. Laura G. Corral
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  3. Yuedi W. Fleming
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  4. Bernd Stein
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Corresponding author

Correspondence to Dan Zhu.

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D. Zhu and L. G. Corral contributed equally to this study.

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Zhu, D., Corral, L.G., Fleming, Y.W. et al. Immunomodulatory drugs Revlimid® (lenalidomide) and CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. Cancer Immunol Immunother 57, 1849–1859 (2008). https://doi.org/10.1007/s00262-008-0512-7

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