LFB-R603, a Third-Generation Monoclonal Anti-CD20 Antibody Displays An Additive Antitumor Activity with Antileukemic Chemotherapeutic Agents in Mouse Xenograft Models

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1660-1660 ◽  
Author(s):  
Isabel Tourais Esteves ◽  
Charles Dumontet ◽  
Stéphanie Herveau ◽  
Lina Reslan ◽  
Frédérique Brune ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Mantle Cell Lymphoma ◽  
Subcutaneous Injection ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Mantle Cell ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 1660 LFB-R603, a next generation anti-CD20 antibody currently in clinical development, is characterized by a specific glycosylation pattern containing a high percentage of non fucosylated antibodies molecules at the Fc site. This pattern of glycosylation increases the affinity of antibodies for human FcγRIIIa, resulting in an increased antibody dependent cell-mediated cytotoxicity (ADCC) by human FcγRIIIa-expressing effector cells. This antibody is currently in a phase I clinical trial in B-CLL patients and its use is planned to be expanded to other non-hodgkin's lymphomas (NHL) such as follicular and mantle cell lymphoma, as a single agent and in combination with chemotherapeutic agents. The antitumor efficacy of LFB-R603 was studied in comparison with rituximab in combination with conventional chemotherapeutic agents in two models of NHL developed in immuno-deficient mice. The RL cell line, derived from a patient with follicular lymphoma (FL), was xenografted in mice by subcutaneous injection. Tumor-bearing mice were treated intravenously during 4 weeks with the anti-CD20 antibodies used alone or in combination with suboptimal doses of cyclophosphamide 50 mg/kg or bendamustine 30 mg/kg. LFB-R603 and rituximab displayed a dose-related antitumor activity. The tumor growth inhibition (TGI) was at day 30, 64% at 10 mg/kg, 84% at 30 mg/kg and 100% at 100 mg/kg for LFB-R603 compared with the untreated-group. For rituximab, the TGI was 84% at 30 mg/kg and 99% at 100 mg/kg. More interestingly, LFB-R603 at 100 mg/kg dose showed a significantly superior antitumor activity as a delay of 21 days in tumor growth was observed compared to rituximab (p=0.00001). The combination of LFB-R603 or rituximab at 60 mg/kg with cyclophosphamide enhanced the effect observed with the antileukemic agent only and the additive effect was similar for the two antibodies as a delay of 13 days in tumor growth was observed for both combination-treated groups compared with the cyclophosphamide-treated group (p=0.00001). However, LFB-R603 displayed a significant higher antitumor activity against RL xenografts than rituximab when combined with bendamustine as a tumor growth delay of 7 days was observed between the two treated-groups (p=0.00001). The NCEB cell line, derived from a patient with mantle cell lymphoma (MCL), was xenografted in mice by subcutaneous injection. In this model, LFB-R603 and rituximab injected once weekly up to 3 weeks displayed a dose-related TGI activity. A higher activity of LFB-R603 compared to rituximab was observed at all tested doses (3, 10, 30 and 60 mg/kg). TGI values at day 51 were 91% for LFB-R603 at 3 mg/kg versus 40% for rituximab, 88% for LFB-R603 at 10 mg/kg versus 57 % for rituximab and 100% for LFB-R603 at 30 and 60 mg/kg versus 66% for rituximab when compared with untreated-group. In conclusion, LFB-R603 displayed a greater antitumor activity as compared to rituximab in two different non-clinical in vivo models of NHL, namely follicular and mantle cell lymphoma. Moreover, additive effects were obtained when LFB-R603 was combined with chemotherapeutic agents such as cyclophosphamide and bendamustine in the FL model. Disclosures: Tourais Esteves: LFB Biotechnologies: Employment. Dumontet:LFB Biotechnologies: Research Funding. Herveau:LFB Biotechnologies: Research Funding. Reslan:LFB Biotechnologies: Research Funding. Brune:LFB Biotechnologies: Employment. Van Overtvelt:LFB Biotechnologies: Employment. Salcedo:LFB Biotechnologies: Employment. Fournès:LFB Biotechnologies: Employment.

Anti-CD20 Antibody GA101 Shows Higher Cytotoxicity but Is Competitively Displaced by Rituximab in Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2704-2704
Author(s):  
Daniel A. Heinrich ◽  
Christian Klein ◽  
Kristina Decheva ◽  
Marc Weinkauf ◽  
Grit Hutter ◽  
...  
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Deutschland Gmbh ◽  
Mantle Cell ◽  
Cd20 Antibody ◽  
Anti Cd20

Abstract Abstract 2704 Poster Board II-680 Background: Mantle cell lymphoma (MCL) is characterized by a poor long-term prognosis with a median survival of 3–5 years. Type I anti-CD20 antibody rituximab has demonstrated a clear anti-proliferative effect in MCL and achieves increased response rates in combination with chemotherapy. GA101, a third-generation IgG1 anti-CD20 antibody displays improved ADCC and superior direct cell death induction by virtue of glycoengineering compared to rituximab and its targeting a type II epitope on CD20, respectively. Methods: Using a panel of MCL cell lines (Rec-1, HBL-2, Jeko-1, Granta-519, JVM-2 and Z-138) we determined the effect of GA101 alone as well as in combination with rituximab on cell viability and proliferation. Karpas-422 (Diffuse Large B-Cell Lymphoma) was used as a control cell line. MCL and Karpas-422 cells were treated with GA101 or rituximab at concentrations of 1 – 20μg/ml and rituximab. Cell viability was analyzed by trypan-blue exclusion tests at 0h, 24h, 48h and 72h. The panel of MCL cell lines and Karpas-422 were then treated with GA101 and rituximab each at 1 and 10 μg/ml to determine potential synergism of antibody combinations. Accordingly, a fractional product calculation was performed: synergism > 0,1; antagonism < −0,1. In addition, Western-blot and RNA-array-analyses were performed to elucidate potential intra-cellular downstream pathway mechanisms. Results: After mono-exposure with GA101 (1 μg/ml), Granta-519 and Rec-1 showed the highest sensitivity (65–75% cell reduction in Granta-519 and 35–40% in Rec-1). Intermediate results were gained for Z-138, HBL-2, Jeko-1 and JVM-2 and Karpas-422 (15–20%). rituximab mono-exposure at 12,5 μg/ml showed a 25% reduction of cell count in Granta-519, 20% in HBL-2 and < 5% in Rec-1, Jeko-1 and Z-138. Combination experiments suggested the competitive binding of the two antibodies. Thus, GA101 plus rituximab combination experiments resulted in a lower cytotoxicity than GA101 alone, according to fractional product calculations. Conclusions: Although GA101 is competitively displaced by rituximab, GA101 demonstrates higher efficacy in MCL cell lines than rituximab, even at a more than 10-fold lower concentration. Currently RNA-array- and Western blot analysis are being performed to identify the critical pathways responsible for the superior cytotoxicity of GA101. Disclosures: Klein: Discovery Oncology, Roche Diagnostics GmbH: Employment. Weinkauf:Lilly Deutschland GmbH: Research Funding. Hutter:Lilly Deutschland GmbH: Research Funding. Zimmermann:Lilly Deutschland GmbH: Research Funding. Dreyling:Roche: Honoraria, Research Funding.

Ublituximab (TG-1101), a Novel Glycoengineered Anti-CD20 Monoclonal Antibody, in Combination with Ibrutinib Is Highly Active in Patients with Relapsed and/or Refractory Mantle Cell Lymphoma; Results of a Phase II Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3980-3980 ◽  
Author(s):  
Kathryn Kolibaba ◽  
John M. Burke ◽  
Heather D. Brooks ◽  
Daruka Mahadevan ◽  
Jason Melear ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Monoclonal Antibody ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Employment Equity ◽  
Highly Active ◽  
Mantle Cell ◽  
Equity Ownership ◽  
Anti Cd20

Abstract Introduction: Ublituximab (UTX) is a novel, chimeric monoclonal antibody (mAb) which targets a unique epitope on the CD20 antigen and has been glycoengineered to enhance affinity for all variants of FcγRIIIa receptors, demonstrating greater ADCC than rituximab and ofatumumab. In patients (pts) with rel/ref CLL, the combination of UTX with ibrutinib was well-tolerated and highly active demonstrating an 88% ORR (95% ORR in high-risk CLL) with responses attained rapidly (median time to iwCLL response of 8 weeks). Ibrutinib has demonstrated single agent activity in Mantle Cell Lymphoma (MCL), achieving a 68% ORR (21% CR) in a single arm trial in relapsed or refractory patients (Wang et al, NEJM 2013). Herein we report on the first combination of ibrutinib with a glycoengineered anti-CD20 mAb, UTX, in patients with Mantle Cell Lymphoma (MCL). Methods: Eligible patients had rel/ref MCL with an ECOG PS < 3. Prior ibrutinib treatment was permitted. UTX (900 mg) was administered on Days 1, 8, and 15 in Cycle 1 followed by Day 1 of Cycles 2 - 6. Ibrutinib was started on Day 1 and continued daily at 560 mg. Following Cycle 6, patients came off study but could remain on ibrutinib. Primary endpoints were safety and ORR with an emphasis on early activity with response assessments by CT scan scheduled prior to cycles 3 and 6 only (criteria per Cheson 2007). Results: 15 patients were enrolled: 13 M/2 F, median age 71 yr (range 55-80), ECOG 0/1: 9/6, median prior Tx = 3 (range 1-8), 53% with ≥ 2 prior anti-CD20 therapies, 40% prior bortezomib. Gr 3/4 AE's occurring in at least 5% of patients and at least possibly related to UTX and/or ibrutinib included: neutropenia (13%), fatigue (7%), rash (7%) and atrial fibrillation (7%). Ibrutinib was dose reduced due to an AE in 1 patient (rash) and discontinued in 1 patient due to atrial fibrillation. No UTX dose reductions occurred. All 15 pts are evaluable for response with best response to treatment as follows: 87% (13/15) ORR with 33% (5/15) Complete Response. Three of the CR's occurred at week 8. Of the two patients not achieving an objective response, one patient was stable at first scan and came off treatment prior to second efficacy assessment (ibrutinib related A-Fib) and one patient progressed at first assessment. Responses generally improved from first to second assessment with median tumor reduction of 64% by week 8 and 82% by week 20. Conclusions: Ublituximab, a glycoengineered anti-CD20 mAb, in combination with ibrutinib is both well-tolerated and highly active in pts with rel/ref MCL. Response rate, depth of response, and time to response compare favorably to historical data with ibrutinib alone. A randomized phase 3 trial with ibrutinib +/- ublituximab is currently ongoing in high-risk CLL pts and future studies using this combination in MCL are being evaluated. Disclosures Kolibaba: Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; GSK: Research Funding; Genentech: Research Funding; Cell Therapeutics: Research Funding; Celgene: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Acerta: Research Funding. Burke:Gilead: Consultancy; Millenium/Takeda: Consultancy; Seattle Genetics, Inc.: Research Funding; Incyte: Consultancy; Janssen: Consultancy; TG Therapeutics: Other: Travel expenses. Farber:TG Therapeutics, Inc.: Research Funding. Fanning:Celgene and Millennium/Takeda: Speakers Bureau. Schreeder:TG Therapeutics, Inc: Research Funding. Boccia:Incyte Corporation: Honoraria. Sportelli:TG Therapeutics, Inc.: Employment, Equity Ownership. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Weiss:TG Therapeutics, Inc.: Employment, Equity Ownership. Sharman:Roche: Research Funding; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Research Funding; Calistoga: Honoraria; Janssen: Research Funding; TG Therapeutics, Inc.: Research Funding; Celgene Corporation: Consultancy, Research Funding.

Targeting Oxphos Pathway Against Ibrutinib Resistance to Mantle Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 290-290 ◽  
Author(s):  
Yang Liu ◽  
Taylor Bell ◽  
Hui Zhang ◽  
Yuting Sun ◽  
Carrie J Li ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Gene Set Enrichment Analysis ◽  
Pdx Model ◽  
Mantle Cell ◽  
Ibrutinib Resistance

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses to frontline therapy. Ibrutinib, a first-in-class, once-daily, oral covalent inhibitor of Bruton's tyrosine kinase (BTK) has achieved 68% of overall response rate in relapsed/refractory mantle cell lymphoma (MCL) patients. However, the vast majority of MCL patients experience disease progression, demonstrating that standard-of-care approaches are failing and that a means for targeting ibrutinib resistant MCL is clinically needed. Our hypothesis is that the ibrutinib-resistant MCL may rely on the mitochondrial oxidative phosphorylation (OXPHOS) pathway to produce energy for tumor growth. In this study, we investigated the effects of IACS-010759, a small molecule mitochondrial complex I inhibitor discovered in MD Anderson Cancer Center which can block the OXPHOS pathway, to overcome ibrutinib resistance in MCL in vitro and in a patient-derived xenograft (PDX) model. Methods: The OXPHOS metabolic pathways were investigated by RNASeq in a panel of ibrutinib-sensitive and -resistant MCL samples. Cell growth inhibition assays were tested after 72-hour treatment with IACS-010759 in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, and ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, by CellTiter-Glo luminescent cell viability assay (Promega). Furthermore, an IBN-resistant MCL PDX model was established and the therapeutic effects and tolerability of IACS-010759 were investigated in the primary MCL-bearing PDX model. Results: We have done RNA sequencing (RNASeq) in 7 primary ibrutinib-resistant and 16 ibrutinib-sensitive MCL patient samples, and analyzed the data using Gene Set Enrichment Analysis (GSEA) software. The results demonstrated that the OXPHOS pathway was activated in the primary ibrutinib-resistant MCL cells but not ibrutinib-sensitive MCL cells. Based on the RNASeq data, we selected an OXPHOS inhibitor IACS-010759 to investigate its effects on both primary ibrutinib-resistant and ibrutinib-sensitive MCL cells in vitroand in PDX mice. IACS-010759 significantly inhibited cell proliferation in ibrutinib-resistant MCL cell lines, Z-138 and Maver-1, but not in ibrutinib-sensitive MCL cell lines, Rec-1, Mino, and Jeko-1, during a 72-hour incubation. Furthermore, the primary ibrutinib-resistant MCL PDX mice were administrated with 10 mg/kg IACS-10759 by oral gavage, for 28 days using a 5 on/2 off dosing schedule. Our data showed that IACS-010759 completely eradicated tumor growth in ibrutinib-resistant MCL PDX mice (n=5, p=0.045). All mice tolerated the treatment dose and no toxicity was found during 28 days of IACS-010759 treatment. Conclusions: The OXPHOS inhibitor IACS-010759 overcomes ibrutinib resistance both in vitro and in the PDX mouse model. The investigation of its mechanism-of-action is ongoing. IACS-010759 could have the potential for clinical use in ibrutinib-resistant relapsed/refractory MCL patients. Disclosures Wang: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Asana BioSciences: Research Funding; Kite Pharma: Research Funding; Juno Therapeutics: Research Funding; Asana biosciences, Beigene, Celgene, Juno, Kite, Onyx, Pharmacyclics: Research Funding; Dava Oncology: Honoraria; BeiGene: Research Funding; Acerta: Consultancy, Research Funding.

scholarly journals A Phase 1 Multicenter Open-Label Study of Escalating Doses of the Novel Anti-CD20-Targeting Engineered Toxin Body MT-3724 in Subjects with Relapsed or Refractory Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 34-34
Author(s):  
Michael Wang ◽  
Preetesh Jain ◽  
Lei Feng ◽  
Maria Badillo ◽  
Vivian Graham ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Phase 2 ◽  
Open Label ◽  
Mantle Cell ◽  
Cell Kill ◽  
Anti Cd20

Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation by SLT-A of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A, is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. In a Phase 1/1b dose escalation/expansion study of MT-3724 monotherapy in subjects with heavily pretreated (including CD20 monoclonal antibodies) relapsed or refractory B-cell non-Hodgkin lymphoma (r/rNHL) the most common grade ≥3 treatment-related adverse events were myalgia and neutropenia (n=3 each). Dose-limiting toxicities (DLTs) were indicative of innate immune response. In subjects with negative rituximab serum concentrations there was a 38% objective response rate (Hamlin et al. ASH 2019). MT-3724 is currently being studied in five ongoing (three actively recruiting, two in development) Phase 2 studies for r/rNHL. This study will evaluate the safety, tolerability, recommended phase 2 dose (RP2D), efficacy, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of MT-3724 in two cohorts of subjects with r/r mantle cell lymphoma (r/rMCL). Study Design and Methods: This phase 1, multicenter, open-label, single arm study will include adults ≥18 yrs with histologically confirmed r/rMCL (histology plus expression of Cyclin D1 in association with CD20 and CD5 or evidence of t(11:14)) who have received ≥2 prior systemic therapies (including anti-CD20 antibody alone or in combination with other agents) and have ≥1 measurable lesion (Lugano criteria). Subjects with CNS involvement or recent treatment with rituximab (within 84 days of study initiation; if received within 12-37 weeks of start of treatment, serum rituximab level must be confirmed to be negative [&lt;500 ng/mL]), obinutuzumab (within 184 days), or ofatumumab (within 88 days) will be excluded. The washout period for these anti-CD20 antibodies, based on published half-life data for these agents, is required due to direct binding competition with MT-3724 for the same CD20 epitope. The primary objective is to evaluate safety and determine the RP2D of MT-3724 in subjects with r/rMCL. Secondary objectives include overall response rate based on the Lugano criteria as determined by the investigators, duration of response, disease control rate, progression-free survival, overall survival, PK, PD, and immunogenicity. An exploratory endpoint will assess if responders become eligible for potentially curative therapy (rate of bridge-to-hematopoietic stem cell transplantation or bridge-to-chimeric antigen receptor T-cell therapy). Subjects will receive escalating doses of MT-3724 as a one hr IV infusion in cycle (C) 1 on Days 1, 4, 8, 11, 18, and 25. In C2+, subjects will receive the highest MT-3724 dose on Days 1, 8, 15, and 22 of a 28-day cycle. Two sequential cohorts will be studied. The study will be initiated with Cohort 1 to evaluate DLTs during the first 42 days of therapy. Subjects will have a dose increase only if they do not experience DLTs and dose reductions will be permitted for treatment-related toxicities. If Cohort 1 is deemed tolerable, Cohort 2 (higher doses) will begin; if Cohort 1 dosing is not tolerable, Cohort 0 (lower doses) will begin (Table 1). A Bayesian optimal interval design will be used to identify the RP2D more accurately (target toxicity rate φ=0.3). Enrollment is anticipated to begin in December 2020. Disclosures Wang: Juno:Consultancy, Research Funding;Dava Oncology:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;MoreHealth:Consultancy;Targeted Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Oncternal:Consultancy, Research Funding;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;OncLive:Honoraria;Verastem:Research Funding;Acerta Pharma:Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;BioInvent:Research Funding;Guidepoint Global:Consultancy;VelosBio:Research Funding;Loxo Oncology:Consultancy, Research Funding;Lu Daopei Medical Group:Honoraria;Nobel Insights:Consultancy;Beijing Medical Award Foundation:Honoraria.Burnett:Molecular Templates, Inc.:Current Employment.Strack:Molecular Templates, Inc.:Current Employment.

scholarly journals Treatment of mantle-cell lymphoma with Rituximab (chimeric monoclonal anti-CD20 antibody): Analysis of factors associated with response

2000 ◽  
Vol 11 ◽  
pp. S117-S121 ◽  
Author(s):  
J.M. Foran ◽  
D. Cunningham ◽  
B. Coiffier ◽  
P. Solal-Celigny ◽  
F. Reyes ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Factors Associated ◽  
Mantle Cell ◽  
Cd20 Antibody ◽  
Anti Cd20

Anti-CD20 Antibody GA101 in Combination with Chemotherapy or Flavopiridol in Mantle Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4781-4781
Author(s):  
Daniel A. Heinrich ◽  
Christian Klein ◽  
Kristina Decheva ◽  
Marc Weinkauf ◽  
Grit Hutter ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Cdk Inhibitor ◽  
Type Ii ◽  
Deutschland Gmbh ◽  
Mantle Cell ◽  
Anti Cd20

Abstract Abstract 4781 Background Mantle cell lymphoma (MCL) responds only transiently to conventional chemotherapy resulting in a dismal long-term prognosis. At a molecular level it is characterised by the chromosomal translocation t(11;14)(q13;q32), which leads to constitutive over-expression of the cell cycle regulatory protein cyclin D1. GA101 is a third generation, glycoengineered type II IgG1 anti-CD20 monoclonal antibody with superior direct cell death induction by targeting a type II epitope and enhanced antibody dependent cellular cytotoxicity (ADCC). High efficacy in lymphoma cell lines has led to combination experiments with various chemotherapeutic compounds or the CDK-inhibitor Flavopiridol. Methods Using a MCL cell line panel (Granta-519, HBL-2, Jeko-1, Rec-1 and Z-138) and a Diffuse Large B-Cell Lymphoma cell line (Karpas-422) we determined the effect of GA101 (1 μg/ml) monotherapy as well as in combination with Fludarabine (0,25 μg/ml), Bendamustine (5 μg/ml), Mitoxantrone (0,25 and 0,5 μg/ml) and Flavopiridol (100nM) on cell proliferation and viability. Trypan-blue exclusion tests were used to analyze cell viability at 0h, 24h, 48h and 72h. The panel of MCL cell lines was treated to determine potential synergism of agent combinations. Accordingly, fractional product was calculated: synergism > 0,1; additive effect -0,1<x<0,1; antagonism < -0,1. Results After mono-exposure with GA101 (1 μg/ml), Granta-519 and Rec-1 showed the highest sensitivity (Granta: 65-75% cell reduction, Rec-1: 30-45%). Intermediate results were achieved for HBL-2 (20-30%), Z-138 and Karpas-422 (10-15%), Jeko-1 (5%). Fludarabine alone resulted in a 20-40% cell reduction. Bendamustine showed a higher efficacy in Jeko-1, Rec-1 and Z-138 (40-90%) than in Granta-519, Karpas-422 and HBL-2 (10%). Mitoxantrone treatment demonstrated a high impact on all cell lines (80-95% cell reduction). Flavopiridol induced a 65-85% cell reduction in Jeko-1, Rec-1 and Karpas-422in comparison to 30-45% in Granta-519, HBL-2 and Z-138. Additional experiments showed additive effects of all GA101 combinations resulting in 40-80% cell reduction (Fludarabine), 30-90% (Bendamustine), 85-95% (Mitoxantrone) and 60-80% (Flavopiridol). Conclusions These in vitro results demonstrate that the anti-CD20 monoclonal antibody GA101 alone or in combination with various chemotherapeutical compounds or the CDK-inhibitor (Flavopiridol) show a promising efficacy in MCL cell lines (additive in combination), supporting the clinical evaluation of such an innovative immuno-chemotherapy in mantle cell lymphoma. Disclosures: Klein: Roche (Glycart): Employment, Equity Ownership, Patents & Royalties. Weinkauf:Lilly Deutschland GmbH: Research Funding. Hutter:Lilly Deutschland GmbH: Research Funding. Zimmermann:Lilly Deutschland GmbH: Research Funding. Dreyling:Roche: Honoraria, Research Funding.

scholarly journals Radioimmunotherapy for Mantle Cell Lymphoma: 5-Year Follow-up of 90 Patients from the International RIT-Registry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5263-5263
Author(s):  
Karin Hohloch ◽  
Christine Windemuth-Kieselbach ◽  
Pier Luigi Zinzani ◽  
Roberto E. Cacchione ◽  
Wojciech Jurczak ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Mantle Cell Lymphoma ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Primary Therapy ◽  
First Line ◽  
Advisory Committees ◽  
Mantle Cell

To assess the efficacy of radioimmunotherapy (RIT) with 90yttrium-ibrutinib-tiuxetan (90Y-IT) in mantle cell lymphoma, data from 90 patients registered in the RIT Network with a median follow-up (FU) of 5.5 years after RIT were evaluated. 90Y-IT was given as first-line therapy in 45 (50%) (consolidation 44 pts., primary therapy 1 pt.) and at relapse in 45 (50%) patients (consolidation 24 pts., recurrence 12 pts., therapy refractory 3 pts., conditioning 2 pts., other 4 pts.). As a first-line treatment, 30 patients (pts.) (67%) achieved CR, 10 pts. (22%) PR%., 1 pt. (2%) PD, and for 4 pts. (9%) no response data was available. At relapse, CR was achieved in 17 pts. (38%), PR in 6 pts. (13%), SD in 2 pts. (4%), and 6 pts. (13%) had PD, while the response was not documented for 14 pts. (31%). After a median FU of 5.5 years, median PFS for all patients was 2.11 (95%CI: 1.03-2.32) years, and median OS was 4.05 (95%CI 2.79-7.21) years. Eleven pts. (12.2%) developed second malignancy. In conclusion, this is the largest report of MCL pts. treated with 90Y-IT to date. 90Y-IT was most often used as consolidation after first- and second-line chemotherapy and may improve the results achieved using chemoimmunotherapy alone. However, the results are less encouraging compared to treatment with small molecules such as ibrutinib. Disclosures Zinzani: TG Therapeutics: Honoraria, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy. Jurczak:Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Roche: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bayer: Research Funding; Gilead: Research Funding; MorphoSys: Research Funding; Incyte: Research Funding; Novo Nordisk: Research Funding; Servier: Research Funding; TG Therapeutics: Research Funding; Celtrion: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Truemper:Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding; Roche: Research Funding; Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy. Scholz:Janssen-Cilag: Consultancy; Hexal: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Pfizer: Speakers Bureau; Roche: Consultancy; GILEAD: Consultancy, Speakers Bureau; Daiichi Sankio: Consultancy. OffLabel Disclosure: Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin) is approved for treatment of patients with relapsed follicular lymphoma and as consolidation therapy after chemo(immuno)therapy of patients with follicular lymphoma.

scholarly journals Targeting Antibody Checkpoint Fcgriib Using Monoclonal Antibody BI-1206 to Overcome Therapeutic Resistance in Mantle Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-35
Author(s):  
Alexa A Jordan ◽  
Joseph McIntosh ◽  
Yang Liu ◽  
Angela Leeming ◽  
William Lee ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Tumor Growth ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Publicly Traded ◽  
In Vivo Efficacy ◽  
Mantle Cell ◽  
Xenograft Models

Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.

scholarly journals Ibrutinib-Lenalidomide-Rituximab in Patients with Relapsed/Refractory Mantle Cell Lymphoma: Final Results from the Nordic Lymphoma Group MCL6 (PHILEMON) Phase II Trial

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 36-36
Author(s):  
Mats Jerkeman ◽  
Martin Hutchings ◽  
Riikka Räty ◽  
Karin Fahl Wader ◽  
Anna Laurell ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mantle Cell Lymphoma ◽  
Research Funding ◽  
Tp53 Mutation ◽  
Phase Ii Trial ◽  
Cell Lymphoma ◽  
Molecular Remission ◽  
Mantle Cell ◽  
Grade 3

Introduction: In spite of improvements in treatment of mantle cell lymphoma (MCL), this is still considered an incurable lymphoma entity, and the majority of patients eventually relapse. Ibrutinib is a very active agent in MCL, but in vitro has been shown to partially antagonize the activity of rituximab, by suppression of NK cell activity and subsequent ADCC. Lenalidomide, on the other hand, improves rituximab-induced ADCC. In this multi-centre open-label phase II trial, we evaluated safety and efficacy of this triplet combination in patients with relapsed or refractory MCL. Methods: Patients with MCL, relapsing after or refractory to at least one rituximab-containing chemotherapy regimen, WHO PS 0-3, and measurable disease were eligible. The primary endpoint was maximal overall response rate (ORR) measured with CT and PET/CT. Minimal residual disease (MRD) monitoring by PCR was performed during follow-up, according to EuroMRD criteria. Ion Torrent sequencing of the most frequently mutated genes in MCL was performed on frozen tumor cells from bone marrow at time of relapse. Health-related quality of life was assessed by the EORTC-QLQ C30 questionnaire before and during treatment. Treatment schedule: Induction phase: Up to twelve 28-day cycles with: Lenalidomide 15 mg p o daily, days 1-21, Ibrutinib 560 mg p o days 1-28, Rituximab 375 mg/m2 i v day 1 in cycle 1, then 1400 mg s c (or 375 mg/m2i v) days 8, 15 and 22 in cycle 1, then day 1 in cycles 3, 5, 7, 9 and 11. Maintenance phase: For patients in CR, PR or SD, not in need of other treatment, given until progression, cycle duration 56 days. Ibrutinib: 560 mg p o days 1-56, 2. Rituximab 1400 mg s c (or 375 mg/m2i v) day 1 of each cycle. Results: Accrual of 50 pts was completed in June 2016, at 10 centres in Sweden, Norway, Denmark and Finland. The median age was 69.5 years, with a median MIPI score of 6.2. Patients had received a median of two previous regimens, four had progressed after single agent ibrutinib, and three had received prior allo-SCT. A TP53 mutation was detected in 11 of 49 evaluable cases (22%), 8 cases were of blastoid/pleomorphic histology, and 22 of 40 evaluable cases had a Ki67 &gt;30%. Treatment emergent-AEs of any grade in ≥20% of patients were rash (24%) and fatigue (20%). Five pts (10%) experienced rash grade 3, mainly during cycle 1. Hematological toxicity was generally of low grade, apart from grade 3-4 neutropenia in 5 patients. One patient died due to possible treatment-related toxicity (septic shock). In total, 27 patients achieved CR (54%) and 10 PR (20%). Among evaluable patients with a TP53 mutation, blastoid/pleomorphic histology or Ki67 &gt;30%, the CR rates were 7/11 (64%), 15/8 (62%) and 11/22 (50%), respectively. After a median follow-up of 40 months, the median PFS is 18 months (95% CI 6.5-28), and median OS 47 months (95% CI 30-64). Patients with a detectable TP53 mutation at relapse (n=11) had a median PFS of 13 months (95% CI 4.2-21), whereas pts without a TP53 mutation had a median PFS of 34 months (95% CI 8.3-60). Of the 28 patients evaluable for MRD at 6 months, 15/27 (56%) patients achieved molecular remission in blood and 12/28 (43%) in bone marrow. After 12 months, MRD-negativity in BM was 68% (13/19). Out of 4 patients with TP53-mutated MCL, 2 were MRD-negative in BM after 12 months, as well as 2 out of 4 patients with blastoid/pleomorphic histology. By self-reported HRQOL, a lower level of emotional functioning (EF), as well as a higher level of pain (PA) at baseline, was associated with inferior PFS. In addition, low EF was associated with inferior OS. By a Cox regression multivariable analysis, including MIPI, TP53, histology, Ki67, EF and PA, only MIPI was prognostic for PFS or OS with this regimen. Conclusions: The combination of ibrutinib, lenalidomide and rituximab has been shown to be an active and well tolerated regimen in this cohort of high risk R/R MCL, associated with a high rate of molecular remission. The activity in TP53 mutated MCL is lower than in unmutated disease, but this regimen may still serve as an option for a bridge to an allogeneic transplantation or CAR-T therapy in this category of patients. Disclosures Jerkeman: Roche: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Gilead: Research Funding. Hutchings:Genmab: Honoraria; Genmab: Consultancy; Takeda: Consultancy; Roche: Research Funding; Celgene: Research Funding; Daiichi: Research Funding; Sankyo: Research Funding; Genmab: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; Roche: Honoraria; Roche: Consultancy; Takeda: Honoraria.

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