scholarly journals Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 5180-5189 ◽  
Author(s):  
Rosa Lapalombella ◽  
Bo Yu ◽  
Georgia Triantafillou ◽  
Qing Liu ◽  
Jonathan P. Butchar ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Surface Antigen ◽  
Targeted Delivery ◽  
Antigen Expression ◽  
Lymphocytic Leukemia ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Surface Antigen Expression ◽  
Primary Chronic Lymphocytic Leukemia ◽  
Anti Cd20

Abstract 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.

scholarly journals IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4723-4730 ◽  
Author(s):  
Aruna Gowda ◽  
Julie Roda ◽  
Syed-Rehan A. Hussain ◽  
Asha Ramanunni ◽  
Trupti Joshi ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Family Member ◽  
Lymphocytic Leukemia ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Bh3 Domain ◽  
Induced Apoptosis ◽  
Primary Chronic Lymphocytic Leukemia

Abstract Interleukin-21 (IL-21) is a recently identified γ-chain receptor cytokine family member that promotes B-cell apoptosis as well as activation of innate immune system. Based on this, we hypothesized that IL-21 might enhance the apoptosis induced by fludarabine and rituximab and also play a role in augmenting immune-mediated clearance of the chronic lymphocytic leukemia (CLL) cells. Our studies demonstrate that the majority of CLL patients have surface IL-21 receptor-α, and its expression correlates with apoptosis, tyrosine phosphorylation of STAT1, and up-regulation of the proapoptotic BH3 domain protein BIM. IL-21–induced BIM up-regulation is critical for apoptosis because inhibition of BIM expression using small interfering RNA prevented IL-21–induced apoptosis. IL-21 treatment of CLL cells but not normal T cells with fludarabine or rituximab additively enhanced the direct cytotoxic effect of these therapies. In addition to its proapoptotic effect, IL-21 promoted STAT1 and STAT5 phosphorylation in natural killer cells with concurrent enhanced antibody-dependent cellular cytotoxicity against rituximab-coated CLL cells in vitro. These data provide justification for combination studies of IL-21 with fludarabine and rituximab in CLL and suggest that BIM up-regulation might serve as relevant pharmacodynamic end point to measure biologic effect of this cytokine in vivo.

Gene and surface-antigen expression profilings concordantly identify alpha4-integrin/CD49d as a marker for unmutated (UM) bad prognosis B-cell chronic lymphocytic leukemia (B-CLL)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10076-10076
Author(s):  
V. Gattei ◽  
D. Benedetti ◽  
D. Marconi ◽  
M. Dal Bo ◽  
A. Zucchetto ◽  
...  
Keyword(s):  
Surface Antigen ◽  
Survival Data ◽  
Gene Mutations ◽  
Antigen Expression ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Common Reference ◽  
Surface Antigen Expression ◽  
Log Ratio ◽  
Ratio Range

10076 Background: The highly heterogeneous clinical courses of B-CLL can be foreseen by investigating IgVH gene mutations or expression of specific prognosticators. Gene and surface-antigen expression profilings (GEP and SEP) have been both employed for identifying molecules of prognostic relevance in B-CLL. Methods: i) GEP - Purified B-CLL cells from 19 UM and 38 mutated (M) cases were investigated for differential GEP by using a two-color Operon Human Genome Oligo Set 2.1 platform with normal B cells as common reference and by applying, after data pre-processing, the LIMMA (Linear Model for MicroArray) package with two combined cutoffs (Bayesian log-odds>1; adjusted p value for false discovery rate <10e−4); ii) SEP - B-CLL cells from 60 UM and 101 M cases were investigated for the expression of 36 surface markers by flow cytometry. Results: i) GEP - 77 probes (32 duplicates) were overexpressed in M B-CLLs (UM/M log-ratio range −0.79/−3.62; p range 6.72e−5/3.6e−10) and 81 probes (46 duplicates) in UM B-CLLs (UM/M log-ratio range 0.87/4.57; p range 9.49e−5/3.01e−12); the CD49d gene was overexpressed in UM cases with UM/M log-ratio of 3.21 (p=8.3e-10). ii) SEP - Six markers significantly discriminated UM to M B-CLLs (t-test, p<10ed-3) and separated most UM (49/60) from M B-CLLs by hierarchical clustering; among them, CD49d was significantly overexpressed in UM cases (median % positive cells 71.2±36 vs. 10.0±31; p=2.1e−10). By applying standardized log-rank statistics in 95 pts, all with CD49d expression and survival data, 30% of positive cells was judged optimal cutoff for identifying two groups with different survivals, 41 CD49dhigh pts showing worse prognosis than 54 CD49dlow cases (p=7.4×10e−5). Similarly, 46 UM B-CLLs had shorter survival than 77 M cases (p=1.4×10e−5). By combining IgVH mutations and CD49d expression, 42 concordant M/CD49dlow pts had better prognosis than 25 concordant UM/CD49dhigh cases (p=1.8×10e−5); noteworthy, among 28 discordant cases, 16 with a M/CD49dhigh phenotype had survival similar to bad prognosis cases. Conclusions: CD49d is a novel prognosticator for B-CLL. Given its high expression level in bad prognosis subsets, CD49d may be a promising therapeutic target. No significant financial relationships to disclose.

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