Immunomodulatory Drug CC-5013 or CC-4047 and Rituximab Enhance Antitumor Activity in a Severe Combined Immunodeficient Mouse Lymphoma Model

New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T...

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Bibliographic Details
Published in:Clinical cancer research 2005-08, Vol.11 (16), p.5984-5992
Main Authors: Hernandez-Ilizaliturri, Francisco J., Reddy, Nishitha, Holkova, Beata, Ottman, Edris, Czuczman, Myron S.
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal - therapeutic use
Antibodies, Monoclonal, Murine-Derived
Antigens, CD20 - analysis
Antineoplastic agents
Apoptosis - drug effects
Biological and medical sciences
CC-4047
CC-5013
Cell Line, Tumor
Cell Proliferation - drug effects
DNA - biosynthesis
Drug Therapy, Combination
Female
Flow Cytometry
Hematologic and hematopoietic diseases
Humans
Immunologic Factors - pharmacology
Immunologic Factors - therapeutic use
Killer Cells, Natural - drug effects
Killer Cells, Natural - metabolism
Killer Cells, Natural - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
lymphoma
Lymphoma, Non-Hodgkin - drug therapy
Lymphoma, Non-Hodgkin - metabolism
Lymphoma, Non-Hodgkin - pathology
Male
Medical sciences
Mice
Mice, SCID
Pharmacology. Drug treatments
Rituximab
SCID mouse
Survival Analysis
Thalidomide - analogs & derivatives
Thalidomide - pharmacology
Thalidomide - therapeutic use
Treatment Outcome
Xenograft Model Antitumor Assays - methods
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Summary:New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c) inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkin's lymphoma cells with CC-5013 resulted in a 40% to 70% growth inhibition when compared with controls ( P < 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013) plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days ( P = 0.0012) compared with 58 days ( P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy–treated animals. The synergistic effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab against B-cell lymphomas and warrants further exploration in the context of a clinical trial.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-05-0577