Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells.
Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cellular cytotoxicity (ADCC), is currently being investigated as a therapy for chronic lymphocytic leukemia (CLL). The anti-CD20 antibody rituximab is active in CLL and represents a rational agent to combine with lenalidomide. We therefore examined whether lenalidomide combined with rituximab enhances direct apoptosis and ADCC in CLL cells. In contrast to previous reports using CD20-positive lymphoma cell lines, lenalidomide down-regulated CD20 surface antigen expression in CLL patient cells via enhanced internalization, without influencing transcription. The CD20 surface antigen internalization enhanced delivery of an oligonucleotide incorporated into anti-CD20 immunoliposomes. In addition, CD20 surface antigen down-modulation by lenalidomide in CLL was accompanied by diminished rituximab-mediated apoptosis and ADCC. These observations suggest a need for alternative sequencing strategies to avoid antagonism between lenalidomide and rituximab therapy in CLL. In addition, they suggest that lenalidomide therapy might be useful to enhance targeted delivery of RNAi-based therapies using CD20 immunoliposomes in B-cell malignancies.
Lapalombella
Rosa
R
Division of Hematology-Oncology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, USA.
Yu
Bo
B
Triantafillou
Georgia
G
Liu
Qing
Q
Butchar
Jonathan P
JP
Lozanski
Gerard
G
Ramanunni
Asha
A
Smith
Lisa L
LL
Blum
William
W
Andritsos
Leslie
L
Wang
Da-Sheng
DS
Lehman
Amy
A
Chen
Ching-Shih
CS
Johnson
Amy J
AJ
Marcucci
Guido
G
Lee
Robert J
RJ
Lee
L James
LJ
Tridandapani
Susheela
S
Muthusamy
Natarajan
N
Byrd
John C
JC
D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D018951:Antigens, CD20 / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004336:Drug Antagonism; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D000077269:Lenalidomide; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008081:Liposomes; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D008081:Liposomes; D000069283:Rituximab; D013792:Thalidomide; D000077269:Lenalidomide
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