Abstract
AbstractLenalidomide, 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.
Highlights
The anti-CD20 antibody rituximab represents a major therapeutic advance for B-cell malignancies, including chronic lymphocytic leukemia (CLL).1 Rituximab has several potential mechanisms of action, including antibody-dependent cellular cytotoxicity (ADCC),2 complement-dependent cytotoxicity (CDC),3 and apoptosis with cross-linking.4 The importance of ADCC in rituximab efficacy is supported by 4 non-Hodgkin lymphoma (NHL) trials in which patients bearing the Fc␥RIIA-H131R and Fc␥RIIIA-V158F highaffinity Fc␥R polymorphisms exhibited improved response to rituximab therapy.5-9 Whereas in vitro studies demonstrate rituximab can mediate ADCC against primary CLL cells,2,10 one preliminary study did not identify correlation of response with high-affinity Fc␥R polymorphisms.11 This has prompted investigation of innate immune enhancing agents to improve both ADCC and rituximab efficacy.Lenalidomide is one such agent attractive for combination with rituximab
Given the importance of antibody therapy for CLL, we explored the effects of lenalidomide on CD20 antigen expression as well as rituximabmediated direct apoptosis and ADCC of CLL cells in vitro
Given that previous studies in lymphoma cell lines showed modest apoptosis and cell-cycle arrest with lenalinomide, we assessed the ability of lenalidomide to promote apoptosis in CLL patient cells
Summary
The anti-CD20 antibody rituximab represents a major therapeutic advance for B-cell malignancies, including chronic lymphocytic leukemia (CLL). Rituximab has several potential mechanisms of action, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis with cross-linking. The importance of ADCC in rituximab efficacy is supported by 4 non-Hodgkin lymphoma (NHL) trials in which patients bearing the Fc␥RIIA-H131R and Fc␥RIIIA-V158F highaffinity Fc␥R polymorphisms exhibited improved response to rituximab therapy. Whereas in vitro studies demonstrate rituximab can mediate ADCC against primary CLL cells, one preliminary study did not identify correlation of response with high-affinity Fc␥R polymorphisms. This has prompted investigation of innate immune enhancing agents to improve both ADCC and rituximab efficacy.Lenalidomide is one such agent attractive for combination with rituximab. The importance of ADCC in rituximab efficacy is supported by 4 non-Hodgkin lymphoma (NHL) trials in which patients bearing the Fc␥RIIA-H131R and Fc␥RIIIA-V158F highaffinity Fc␥R polymorphisms exhibited improved response to rituximab therapy.. Whereas in vitro studies demonstrate rituximab can mediate ADCC against primary CLL cells, one preliminary study did not identify correlation of response with high-affinity Fc␥R polymorphisms.. Whereas in vitro studies demonstrate rituximab can mediate ADCC against primary CLL cells, one preliminary study did not identify correlation of response with high-affinity Fc␥R polymorphisms.11 This has prompted investigation of innate immune enhancing agents to improve both ADCC and rituximab efficacy. Given the importance of antibody therapy for CLL, we explored the effects of lenalidomide on CD20 antigen expression as well as rituximabmediated direct apoptosis and ADCC of CLL cells in vitro. Our results are in contrast to these earlier cell line experiments, and have important implications for the therapeutic combination of lenalinomide with rituximab
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