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Cancer Immunology, Immunotherapy

, Volume 57, Issue 12, pp 1849–1859 | Cite as

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

  • Dan Zhu
  • Laura G. Corral
  • Yuedi W. Fleming
  • Bernd Stein
Original Article

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.

Keywords

Tumor cell apoptosis Co-culture model IMiDs® immunomodulatory drugs 

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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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Dan Zhu
    • 1
  • Laura G. Corral
    • 1
  • Yuedi W. Fleming
    • 1
  • Bernd Stein
    • 1
  1. 1.Celgene CorporationSan DiegoUSA

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