Statins Impair Antitumor Effects of CD20 mAb by Inducing Conformational Changes of CD20.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2341-2341
Author(s):  
Jakub Golab ◽  
Magdalena Winiarska ◽  
Jacek Bil ◽  
Ewa Wilczek ◽  
Grzegorz Wilczynski ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
B Cell ◽  
Conformational Changes ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
T Test ◽  
Phase Iii ◽  
Antitumor Effects ◽  
Anti Cd20

Abstract A number of monoclonal antibodies (mAb) are presently in development or approved for CD20-directed immunotherapy. Ofatumumab, a human IgG1 anti-CD20 mAb, is currently being evaluated in phase III clinical trials for B-CLL and FL, and in phase II clinical trials for rheumatoid arthritis (RA). Rituximab, a chimeric IgG1 anti-CD20 mAb, has been approved for 1st line treatment of CD20-positive B cell lymphomas alone or in combination with chemotherapy, and in RA. Virtually all rituximab-treated patients relapse after single-agent treatment. The clinical efficacy of rituximab might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising anti-lymphoma effects. We studied the influence of statins on ofatumumab- and rituximab-mediated cytotoxicity. Surprisingly, B cells incubated with statins showed decreased rather than increased CD20 mAb-mediated complement-dependent cytotoxicity (CDC) in cell viability assays. However, cell lysis of statin-treated B cells remained higher when using ofatumumab in comparison to rituximab. Statins decreased CD20 immunostaining in flow cytometry but did not affect total cellular CD20 levels when compared to non-treated cells. Incubation of B cells with other cholesterol depleting agents (methyl-β-cyclodextrin (MβCD) and berberine) established that the presence of plasma membrane cholesterol and not lipid rafts may be required for CD20 mAb-mediated CDC. Cholesterol restitution reversed ofatumumab- and rituximab-mediated CDC and CD20 mAb staining. Statin incubation resulted in conformational changes of CD20 and impaired binding of CD20 mAb to the CD20 molecule as observed by atomic force microscopy. Freshly isolated cells of 4 B cell lymphoma patients were treated with the cholesterol-depleting agent MβCD, and CD20 mAb (B9E9) binding and rituximab-mediated CDC were significantly decreased (P<0.05 t-test, versus control) In addition, 5 hypercholesterolemia patients were treated with atorvastatin. Ofatumumab binding to freshly isolated B cells was found decreased in all patients upon statin treatment (P<0.01, paired t-test). Based on these data, statins may interfere with CD20 detection and anti-lymphoma activity of CD20 mAb and may have significant clinical implications as impaired mAb binding to CD20 conformational epitopes elicited by statins may delay diagnosis, postpone treatment or impair anti-lymphoma activity of CD20 mAb. MAb which are less sensitive to such changes may minimize possible effects of statins on mAb-mediated immunotherapy in these patients.

scholarly journals B-cell–targeted therapies in relapsing forms of MS

2017 ◽  
Vol 4 (6) ◽  
pp. e405 ◽  
Author(s):  
Divyanshu Dubey ◽  
Thomas Forsthuber ◽  
Eoin P. Flanagan ◽  
Sean J. Pittock ◽  
Olaf Stüve
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
B Cell ◽  
Therapeutic Strategies ◽  
Phase Iii ◽  
B Cell Depletion ◽  
Pathogenic Role ◽  
Phase Iii Clinical Trials ◽  
Anti Cd20

In recent years, there has been a significant increase in the therapeutic options available for the management of relapsing forms of MS. Therapies primarily targeting B cells, including therapeutic anti-CD20 monoclonal antibodies, have been evaluated in phase I, phase II, and phase III clinical trials. Results of these trials have shown their efficacy and relatively tolerable adverse effect profiles, suggesting a favorable benefit-to-risk ratio. In this review, we discuss the pathogenic role of B cells in MS and the rationale behind the utilization of B-cell depletion as a therapeutic cellular option. We also discuss the data of clinical trials for anti-CD20 antibodies in relapsing forms of MS and existing evidence for other B-cell–directed therapeutic strategies.

scholarly journals Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5191-5201 ◽  
Author(s):  
Stephen A. Beers ◽  
Ruth R. French ◽  
H. T. Claude Chan ◽  
Sean H. Lim ◽  
Timothy C. Jarrett ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Type I ◽  
Type Ii ◽  
Antigenic Modulation ◽  
Lymphatic Leukemia ◽  
Human B Cells ◽  
Anti Cd20

Abstract Rituximab, a monoclonal antibody that targets CD20 on B cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success, a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 monoclonal antibodies (mAbs) are continuously being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAbs are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B cells, despite both operating exclusively via activatory Fcγ receptor–expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B cells, leading to reduced macrophage recruitment and the degradation of CD20/mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors and most cases of chronic lymphatic leukemia and mantle cell lymphoma, showed rapid CD20 internalization that paralleled that seen in the Tg mouse B cells, whereas most follicular lymphoma and diffuse large B-cell lymphoma cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic.

Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4977-4977
Author(s):  
Jennifer Wayne ◽  
Kristen N. Ganjoo ◽  
Andres Forero ◽  
Brad Pohlman ◽  
Sven de Vos ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Evaluable Population ◽  
Anti Cd20

Abstract Abstract 4977 Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma J Wayne,1 K Ganjoo,2 A Forero,3 B Pohlman,4 S de Vos,5 S Carpenter,6 J Wooldridge,6 S Marulappa,1 V Jain11Mentrik Biotech, LLC, Dallas, TX, 2Standford University Medical Center, Stanford, CA, 3Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL,4Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 5David Geffen School of Medicine at University of California, Los Angeles, CA, 6Eli Lilly and Company, Indianapolis, Indiana Introduction AME-133v is a humanized anti-CD20 monoclonal antibody that has a 13 to 20-fold increase in binding affinity and approximately 6-fold more potent effector function in antibody-dependent cell-mediated cytotoxicity (ADCC) compared to rituximab. Phase I/II clinical trials of AME-133v in patients with relapsed follicular lymphoma have demonstrated an overall response rate of greater than 30% with a complete response rate of 16%. The extent and duration of depletion of CD19+ B-cells in peripheral blood was used as a surrogate of therapeutic levels of AME-133v. Analysis from the Phase I/II clinical trials is presented in this report. Methods CD-19 positive B-cells in peripheral blood were measured in 77 patients with relapsed follicular lymphoma enrolled in two phase I/II clinical trials of AME-133v. These studies assessed five different doses of AME-133v (from 2 mg/m2 to 375 mg/m2). AME-133v was administered intravenously four times at weekly intervals in both trials. Blood samples were taken at multiple time points throughout the trial and a central lab measured levels of circulating CD19+ B-cells using fluorescence-activated cell sorting (FACS). Results Excluding the four patients enrolled in the 2 mg/m2 dose cohort, depletion of peripheral B-cells occurred in all patients and was sustained over time (Table 1). Baseline levels of B-cell counts ranged from 4 × 103 to 1,187 × 103 cells/μL, with an average of 102 × 103 cells/μL and a median of 60 × 103 cells/μL. Within 24 hours of the first infusion, all patients had depletion of circulating B-cells; ninety-six percent of patients had less than 10 × 103 cells/μL and two patients had less than 20 × 103 cells/μL. Interestingly, AME-133v was effective at depleting B-cells even at doses as low as 7.5 mg/m2. To assess sustainability of B-cell depletion after four doses of AME-133v, CD19+ cell counts were evaluated at nine weeks after the fourth infusion and every three months thereafter. Complete depletion of CD19+ lymphocytes was sustained for nine weeks. At five months after the last infusion of AME-133v, nearly two-thirds of patients had no detectable circulating B-cells. Sustained B-cell depletion lasted for at least eight months following the last infusion in 63% of patients. Table 1. B-cell counts for all patients in 7.5, 30, 100 and 375 mg/m2 cohorts. Percentages are cumulative Time Point Cell Count (x 103 cells/μL) 0 < 1 2 to 10 11 to 30 31 to 50 < 100 Day 1 (24 hours after last infusion) 62 % 66 % 96 % 100 % 100% 100% Day 7 (day of infusion 2) 75% 80% 95% 97% 97% 98% Day 28 (1 week after last infusion) 78 % 87% 95% 98% 98% 100% Day 84 (9 weeks after last infusion) 78% 87% 91% 96% 96% 98% Day 174 (5 months after last infusion) 60% 60% 70% 86% 93% 100% Day 264 (8 months after last infusion) 26% 26% 41% 63% 81% 89% Day 354 (11 months after last infusion) 0% 0% 15% 40% 55% 80% DEMOGRAPHIC CHARACTERISTICS (EVALUABLE POPULATION) “\f C \l 1 Demographic and Disease Characteristics on evaluable population (N=30) Conclusion The rapid and sustained effect of AME-133v on B-cell depletion, even in low-affinity FcγRIIIa patients, indicates a potentially relevant biological activity of the antibody in treating B-cell non-Hodgkin lymphoma. Notably, this depletion occurred even at very low doses of drug administration and persisted over time. This may be related to its higher affinity for CD20, increased ADCC, or both. The sustained B-cell depletion may result in prolonged clinical response and might mitigate the need for maintenance therapy. A randomized trial is being planned to compare efficacy of AME-133v vs. rituximab. Disclosures: No relevant conflicts of interest to declare.

Epigenomic Evolution In Diffuse Large B-Cell Lymphomas

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 634-634 ◽  
Author(s):  
Heng Pan ◽  
Yanwen Jiang ◽  
David Redmond ◽  
Kui Nie ◽  
Leandro Cerchietti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
B Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Test ◽  
Normal Tissues ◽  
Epigenetic Diversity ◽  
Allele Specific ◽  
Allele Specific Methylation

Abstract Diffuse Large B-cell Lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. It is a heterogeneous disease in which one third of patients either do not respond to treatment or relapse within five years after chemotherapy. It is unclear whether epigenetic alterations are responsible for B cell lymphomas relapse phenotypes, such as increased aggressiveness and chemoresistance. To investigate how the B cell lymphoma epigenome evolves upon chemotherapy, we used Enhanced Reduced Representation Bisulfite Sequencing (ERRBS) to profile DNA methylation genome-wide in primary matched diagnosis-relapse DLBCL samples. We interrogated 13 pairs of DLBCL diagnosis tumors and their matched relapse samples. In addition, we performed methylation profiling of normal tonsilar B cell subsets (Naïve and germinal center B cells) from two healthy human individuals. ERRBS provided DNA methylation levels at 3-4M CpG sites. When combining methylation levels from all interrogated CpG sites, we observed increased DNA methylation levels at CpG-islands (CGIs; p=3.5e-9, t-test) in DLBCLs compared to normal B cells, and stable or slightly decreasing methylation levels outside of CGIs (>10 kb away from known CGIs; p=0.057, t-test). There was no significant change in average DNA methylation levels from diagnosis to relapse either at CGIs or outside of CGIs. However, when we investigated DNA methylation changes at gene promoters, we identified 107 consistently differentially methylated promoters between diagnosis and relapse (> 10% DNA methylation alteration and p < 0.05, paired t-test). Pathway analysis of the corresponding genes using iPAGE identified several pathways and processes associated with either hyper or hypo-methylated genes in relapse, demonstrating that methylation changes associated with relapse are functionally coherent. For example, several genes with TGF-beta receptor activity displayed lower DNA methylation in relapse. Taking advantage of single CpG resolution and high coverage provided by ERRBS, we then sought to investigate the extent of allele-specific methylation (ASM) levels in normal tissues and DLBCL patients. We found increased ASM levels in DLBCLs compared to normal tissues (p=0.0011, t-test) confirming observations in solid tumors. There was no significant change in ASM levels from diagnosis to relapse (p=0.24, t-test). These results suggest that methylation changes associated with lymphomagenesis might frequently involve one allele only, perhaps due to differential nuclear localization of individual chromosomes. However allele-specific methylation may not play a key role in lymphoma progression. Finally, we investigated whether intra-tumor methylation heterogeneity at diagnosis would predict whether a DLBCL patient would relapse. We quantified intra-tumor methylation heterogeneity using a statistical approach based on the probability that two randomly sampled DNA molecules from the tumor cell populations differ from each other in their methylation pattern. We found decreased intra-sample methylation heterogeneity in DLBCLs compared to normal germinal center B cells (p=1.9e-4, t-test), consistent with the clonal origin of tumors. 12 out of 13 pairs also displayed decreased methylation heterogeneity from diagnosis to relapse, which is also consistent with clonal selection upon chemotherapy treatment. We then performed ERRBS on primary tumors from 8 DLBCL patients who have not relapsed five years after treatment. We found that non-relapse patients displayed significantly lower intra-tumor methylation heterogeneity as compared to that of the relapsed patients (p=0.047, t-test), which suggests that increased epigenetic diversity within a population of tumor cells at diagnosis might fuel the Darwinian evolutionary process underlying relapse. We also looked at genetic clonal heterogeneity based on next-generation sequencing of somatic hypermutation profiles in IGH VDJ sequences, but found no differences between relapsed and not relapsed patients (p=0.22, Wilcoxon test). This suggests that epigenetic heterogeneity plays a more substantial role than clonal heterogeneity in fueling the relapse phenotype. In summary, this study provides the first comprehensive characterization of aberrations in DNA methylation in relapse DLBCLs and identified epigenetic diversity in DLBCLs as a potential predictor of relapse. Disclosures: No relevant conflicts of interest to declare.

In vivo activity of rituximab-CpG oligodeoxynucleotide conjugate against rituximab-resistant human CD20+ B-cell lymphoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8529-8529
Author(s):  
J. Timmerman ◽  
D. Betting ◽  
R. Yamada ◽  
S. Hurvitz ◽  
K. Steward ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cpg Oligodeoxynucleotides ◽  
Cell Immunity ◽  
Cpg Oligodeoxynucleotide ◽  
Immunocompetent Mice ◽  
Anti Cd20

8529 Background: The anti-CD20 monoclonal antibody rituximab (R) is a mainstay in the treatment of B cell non-Hodgkin's lymphoma (NHL), exerting anti-tumor effects via antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity, and apoptosis induction. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) are potent activators of ADCC and T cell immunity, and have been studied for anti-NHL effects when administered by systemic or intratumoral routes. We sought to optimize the delivery of CpG to sites of NHL to improve R efficacy. Methods: We utilized an aggressive syngeneic human CD20-expressing murine B cell lymphoma (38C13-huCD20) to study the in vivo augmentation of R efficacy by CpG. Established tumors in immunocompetent mice were treated with R plus CpG given systemically, intratumorally, or chemically linked to antibody using maleimide-sulfhydryl chemistry (D. Betting et al, J. Immunol. 2008; 181: 4131). Results: 5- to 7-day established tumors were completely resistant to single agent R. Combining intratumoral, but not systemic administration of CpG with R resulted in tumor eradication from up to 42% of mice (p < 0.0003 vs. R alone, CpG alone, R + systemic CpG). Mechanistic studies indicated that both natural killer cells and complement participated in the cure of tumors by intratumoral CpG + R, by increasing tumor cell sensitivity to complement and ADCC lysis, and by augmenting the cytotoxicity of ADCC effectors. To overcome the need for repeated direct intratumoral injections and allow precise targeting of CpG to tumor cells, we chemically linked CpG to R using a cleavable linker. A single i.v. injection of this R-CpG conjugate achieved eradication of established tumors from 100% of mice. In contrast, equivalent doses of unlinked i.v. R + CpG, CpG alone, or R alone cured only 8% of mice. Thus, combining CpG with R was most effective using direct conjugation to the antibody. Conclusions: In conclusion, enhancement of R efficacy required sustained intratumoral delivery of CpG to maximize anti-tumor responses. R-CpG conjugate efficiently eradicated an established B cell lymphoma that is fully resistant to single-agent R. Clinical testing of anti-CD20-CpG conjugates against B cell NHL is thus warranted. [Table: see text]

scholarly journals Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2457-2466 ◽  
Author(s):  
DG Maloney ◽  
TM Liles ◽  
DK Czerwinski ◽  
C Waldichuk ◽  
J Rosenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chimeric Antibody ◽  
Cd20 Antibody ◽  
Anti Cd20

The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC- 2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment- related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.

scholarly journals Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma

Blood ◽  
1994 ◽  
Vol 84 (8) ◽  
pp. 2457-2466 ◽  
Author(s):  
DG Maloney ◽  
TM Liles ◽  
DK Czerwinski ◽  
C Waldichuk ◽  
J Rosenberg ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
B Cells ◽  
Phase I ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chimeric Antibody ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract The B-cell antigen CD20 is expressed on normal B cells and by nearly all B-cell lymphomas. This nonmodulating antigen provides an excellent target for antibody-directed therapies. A chimeric anti-CD20 antibody (IDEC-C2B8), consisting of human IgG1-kappa constant regions and variable regions from the murine monoclonal anti-CD20 antibody IDEC- 2B8, has been produced for clinical trials. It lyses CD20+ cells in vitro via complement and antibody-dependent cell-mediated lysis. Preclinical studies have shown that the chimeric antibody selectively depletes B cells in blood and lymph nodes in macaque monkeys. In this phase I clinical trial, 15 patients (3 per dose level) with relapsed low-grade B-cell lymphoma were treated with a single dose (10, 50, 100, 250, or 500 mg/m2) of antibody administered intravenously. Treatment- related symptoms correlated with the number of circulating CD20 cells and grade II events consisted of fever (5 patients); nausea (2), rigor (2), orthostatic hypotension (2), bronchospasm (1), and thrombocytopenia (1). No significant toxicities were observed during the 3 months of follow-up. Serum C3, IgG, and IgM levels, neutrophils, and T cells were largely unchanged. At the three higher dose levels, pharmacokinetics of the free antibody showed a serum half-life of 4.4 days (range, 1.6 to 10.5). Levels greater than 10 micrograms/mL persisted in 6 of 9 patients for more than 14 days. No quantifiable immune responses to the infused antibody have been detected. CD20+ B cells were rapidly and specifically depleted in the peripheral blood at 24 to 72 hours and remained depleted for at least 2 to 3 months in most patients. Two-week postinfusion tumor biopsies showed the chimeric antibody bound to tumor cells and a decrease in the percentage of B cells. Tumor regressions occurred in 6 of 15 patients (2 partial and 4 minor responses). The results of this single-dose trial have been used to design a multiple-dose phase I/II study.

Ironclad: A randomized phase III study of ibrutinib (Ibr) or no consolidation following autologous hematopoietic stem cell transplantation (AutoHCT) for relapsed/refractory activated-B-cell (ABC) subtype diffuse large B-cell lymphoma (DLBCL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS7566-TPS7566
Author(s):  
Charalambos Andreadis ◽  
Timothy S Fenske ◽  
Brian Thomas Hill ◽  
Patrick J. Stiff ◽  
David L. Grinblatt ◽  
...  
Keyword(s):  
B Cell ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Phase Iii ◽  
High Dose ◽  
Eligibility Criteria ◽  
Hematopoietic Stem ◽  
Phase Iii Study

TPS7566 Background: Relapsed DLBCL in the rituximab era portends a poor prognosis with only about 25% of patients achieving long-term disease control following 2ndline therapy and AutoHCT. Patients with the ABC subtype have an inferior prognosis at diagnosis than those with GC and are overrepresented at relapse. In order to improve outcomes in ABC-DLBCL, we designed a study targeting disease pathobiology at the time of AutoHCT. Ibr has a safety profile allowing combination with cytotoxic chemotherapy and has single-agent activity with a 37% response rate in patients with relapsed/refractory ABC-DLBCL. Methods: This is an intergroup, randomized, placebo-controlled phase III study combining Ibr or placebo with high-dose chemotherapy during conditioning with AutoHCT and for 12 months following AutoHCT. Pts with relapsed or refractory DLBCL have tissue submitted centrally for real-time review and subtype assignment by GEP (Frederick Laboratory). Key eligibility criteria include no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no progression on prior Ibr. Pts with chemosensitive ABC-DLBCL are randomized to Ibr 560 mg or placebo with BEAM or CBV chemotherapy until day 0. After engraftment, pts receive Ibr 560 mg daily or placebo for 12 additional cycles. Pts with progressive disease on placebo can cross over to Ibr monotherapy. An initial safety cohort of 6 pts is being enrolled to evaluate the tolerability of Ibr with concurrent BEAM and CBV therapy. The primary endpoint is superior 2-year PFS (Ha/H0: 67% vs 50%). Secondary endpoints include time to count recovery, post-transplant response rates, OS, PFS, and incidence of 2arymalignancies. In correlative studies, we will assess the prognostic and predictive role of pre-transplant FDG-PET in the setting of Ibr or placebo therapy, the role of emergent BCR pathway mutations, double hit genetics, and pharmacogenetic determinants on treatment outcome and toxicities. We expect to accrue 296 patients over 4 years. An Alliance/BMT-CTN study: NCT02443077 Clinical trial information: NCT02443077.

The Novel Triterpenoid 2-cyano-3,12-dioxooleana-1,9-dien-28-oic Acid (CDDO) Induces Apoptosis of Human Diffuse Large B-Cell Lymphoma Cells (DLCL) through a Peroxisome Proliferator-Activated Receptor γ (PPARγ) Independent Pathway Which Is Enhanced by NFκB Inhibition.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2425-2425
Author(s):  
Denise Ray ◽  
Kimberly Morse ◽  
Shannon Hilchey ◽  
Tatiana Garcia ◽  
Raymond Felgar ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Death ◽  
B Cell ◽  
Transcriptional Activity ◽  
Nuclear Translocation ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Cell Phenotype ◽  
Clinical Activity ◽  
Peroxisome Proliferator

Abstract Ligands for the transcription factor PPARγ are emerging as a new class of anti-tumor agents. Herein we report that the synthetic triterpenoid CDDO, a PPARγ ligand that induces PPARγ transcriptional activity in human DLCL OCI-Ly-19 cells, also induces cell death in human DLCL of both germinal center (OCI-Ly19) and activated B-cell phenotype (OCI-Ly10), cells which express the PPARγ protein. This effect of CDDO appears to be independent of PPARγ stimulated pathways since the functional antagonist of PPARγ, GW9662, which completely inhibits CDDO induced PPARγ transcriptional activity was unable to prevent CDDO induced cell death. Similar findings were seen using the additional PPARγ antagonists T0070907 and BADGE. CDDO induces cell death by inhibiting cell proliferation and inducing apoptosis as shown by Annexin-V and propidium iodide staining. As we have previously shown that PPARγ ligands inhibit NF-κB activity in B lymphocytes (J. Immunol2005; 174(7): 4060–9), we next examined the effect of CDDO on NF-κB in DLCL cells. Surprisingly, exposure of Ly19 cells to CDDO resulted in a dose-, and time-dependent increase in the activity of both the p50 and p65 subunits of NF-κB as determined by ELISA, by direct visualization of the nuclear translocation of p65 using indirect immunofluorescence assays, and by EMSA. The nuclear translocation of both the p50 and p65 NF-κB subunits was also confirmed by performing immunoblot analyses using nuclear fractions of CDDO-treated Ly19 cells. NF-κB activation was also observed in Ly10 cells exposed to CDDO. Follow-up experiments revealed that the activation of NF-κB in Ly19 cells by CDDO was due to proteolysis of inhibitory IκBα molecules. To determine whether the CDDO-induced NF-κB activation was a pro- survival mechanism, Ly19 and Ly10 cells were pre-treated with the NF-κB inhibitors SN50, helenalin or BAY 11-7082 and then exposed to CDDO for 24 hrs. In all cases, the NF-κB inhibitors significantly enhanced CDDO induced cell death suggesting that NF-κB activation is an anti-apoptotic mechanism elicited to protect the cell against CDDO cytotoxicity. Collectively, these studies suggest that; (a) CDDO (which will shortly be entering clinical trials for patients with acute myeloid leukemia) as a single agent may have significant clinical activity in patients with DLCL and; (b) the combination of CDDO with pharmacological inhibitors of NF-κB would be a rationale combination of novel agents to test in the context of clinical trials for patients with DLCL.

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