Ofatumumab, a Fully Human Monoclonal Antibody Targeting CD20, Demonstrates Activity Against and Potentiates the Anti-Tumor Activity of Chemotherapy Agents In Rituximab-Sensitive Cell Lines (RSCL), Rituximab-Resistant Cell Lines (RRCL), Lymphoma Xenografts, and Primary Tumor Cells Derived From Patients with B-Cell Non-Hodgkin Lymphoma (NHL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3917-3917 ◽  
Author(s):  
Matthew Barth ◽  
Francisco J. Hernandez-Ilizaliturri ◽  
Cory Mavis ◽  
Ping-Chiao Tsai ◽  
John Gibbs ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Primary Tumor ◽  
Research Funding ◽  
Non Hodgkin Lymphoma ◽  
Cd20 Expression ◽  
Chemotherapy Agents ◽  
Anti Tumor Activity

Abstract Abstract 3917 Treatment with the anti-CD20 monoclonal antibody rituximab (RTX) has become the standard-of-care for the treatment of B-cell non-Hodgkin lymphoma (NHL). Despite revolutionizing NHL therapy, many patients demonstrate resistance de novo or develop resistance to RTX following treatment with RTX-containing regimens and/or RTX-based maintenance schedules. Ofatumumab (OFA) is a new 2nd-generation CD20 mAb targeting a novel membrane-proximal epitope on the CD20 antigen. OFA has been FDA-approved for the treatment of fludarabine- and alemtuzumab-refractory CLL and is being evaluated in several clinical trials in NHL. To better define OFA's activity, we conducted pre-clinical studies comparing OFA vs. RTX in a panel of RSCL, RRCL, primary lymphoma cells (n=10), and in a lymphoma xenograft model. Antibody-dependant cellular cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) assays were performed to evaluate differences in activity between RTX and OFA. Lymphoma cells were labeled with 51Cr prior to incubation with RTX or OFA (1 or 10 mg/ml) plus effector cells or human serum respectively. 51Cr-release was measured and the percentage of lysis was calculated. In addition, we evaluated the effect of OFA in the cytotoxic effects of chemotherapy agents (doxorubicin, cisplatin and vincristine) and correlated OFA anti-tumor activity to biomarkers known to affect RTX activity (i.e. CD20, CD55, and CD59 surface expression) using qualitative and quantitative flow cytometry. Competitive binding assays were performed using fluorescent-labeled RTX or OFA. OFA was more potent than RTX in elucidating effective CDC at the doses tested not only in RSCL, but also in all RRCL and in primary tumor cells derived from patients with B-cell lymphoma. OFA and RTX were equally effective in ADCC assays. In RSCL and RRCL, there was a linear decrease in sensitivity to RTX (as evaluated by CDC) with decreasing CD20 expression; in contrast, OFA maintained activity even at the lowest levels of CD20 expression. Furthermore, OFA was active despite high levels of CD59 and CD55. OFA had a higher affinity for CD20 than RTX in RSCL. Pre-incubation of RSCL and RRCL with OFA enhanced the anti-tumor activity of chemotherapy agents as determined by alamar blue reduction. Severe combined immunodeficiency (SCID) mice were inoculated via tail vein with Raji cells (day 0) and assigned to observation versus 4 doses of either OFA or RTX (1 or 10mg/kg/dose). The end point of the study was overall survival. Statistical analysis was performed with Kaplan-Meier survival curves and P values calculated by log-rank test. OFA was more effective in controlling in vivo lymphoma growth than RTX. The median survival for animals treated with OFA (1 or 10mg/kg/dose) [73 days and 78 days] was longer than those treated with RTX [56 days and 61 days] (P=0.04 and P=0.04 respectively). Our data suggest that OFA is more potent than RTX not only in RTX-sensitive but also in RTX-resistant models and potentiates the anti-tumor activity of chemotherapy agents commonly used in the treatment of B-cell NHL. We are continuing our research into defining the mechanisms by which OFA increases the lymphoma cell sensitivity threshold to chemotherapy agents and to novel target-specific small molecule inhibitors. Disclosures: Barth: Genmab: Research Funding. Hernandez-Ilizaliturri:Genmab: Research Funding. Mavis:Genmab: Research Funding. Gibbs:Genmab: Research Funding. Deeb:Genmab: Research Funding. Czuczman:Genmab: Research Funding.

The DAC Inhibitor, LBH589, Is Highly Effective in Both Rituximab-Sensitive and Rituximab-Resistant Lymphomas and Enhances the Anti-Tumor Activity of Bortezomib, Other Chemotherapy Agents, and Anti-CD20 Monoclonal Antibodies.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2715-2715
Author(s):  
Francisco J Hernandez-Ilizaliturri ◽  
Cory Marvis ◽  
Ilir Maraj ◽  
Mohammad M Chisti ◽  
John Gibbs ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Tumor Cells ◽  
Cell Lines ◽  
Primary Tumor ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Anti Cd20 ◽  
Chemotherapy Agents ◽  
Anti Tumor Activity

Abstract Abstract 2715 Poster Board II-691 Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins [histones (class I) and non-histones (class II)], leading to regulation of gene transcription and other cellular processes. LBH589 is a novel and potent DAC class I and II inhibitor undergoing pre-clinical and clinical testing. In order to better characterize the role of DAC inhibitors in the treatment of refractory/resistant B-cell lymphomas we studied the anti-tumor effect that LBH589 had when used with chemotherapy agents and anti-CD20 monoclonal antibodies against a panel of rituximab-[chemotherapy]-sensitive cell lines (RSCL), rituximab-[chemotherapy]-resistant cell lines (RRCL), and primary lymphoma cells isolated from patients with treatment-naïve or refractory/relapsed B-cell lymphoma. Non-Hodgkin's lymphoma (NHL) cell lines were exposed to the following chemotherapy agents or monoclonal antibodies: CDDP, doxorubicin, vincristine, bortezomib versus rituximab or veltuzumab (or isotype control), alone or in combination with LBH589. In dose-sequence studies the treatment with LBH589 preceded or followed in vitro exposure to the chemotherapy agent or the monoclonal antibody by 24 hrs. Changes in mitochondrial potential were determined by alamar blue reduction using a kinetic assay. Patient-derived primary tumor cells (N=25) were exposed to either LBH589 (2-25uM), bortezomib (1 to 10nM) or both. Changes in ATP content were determined by cell titer glow assay. RNA was isolated from NHL cell lines exposed to LBH859 or bortezomib and changes in gene expression of the Bcl-2 family members were determined by qualitative polymerase chain reaction (PCR). LBH589 was active as a single agent against RSCL, RRCL or patient-derived primary tumor cells. In addition, Bcl-XL gene down-regulation was observed following exposure to LBH859. On the other hand, upregulation of Bak and downregulation of Mcl-1 were observed following proteasome inhibition. Synergistic activity was observed by combining LBH589 and chemotherapy agents, bortezomib or either of the two anti-CD20 mAbs studied. In tumor-derived primary cells from lymphoma patients, the combination of LBH589 and bortezomib resulted in significant anti-tumor activity in follicular, Hodgkin and diffuse large B-cell lymphoma. The sequence of administration impacted the degree of antitumor activity observed (ie in general, exposure of tumors cells initially to LBH589, followed by exposure to chemo/mAbs was associated with the greatest degree of anti-tumor activity). Our data suggests that LBH589 is active against various RSCL, RRCL and patient-derived primary tumor cells. Our findings strongly suggest that LBH589 added to anti-CD20 and/or chemotherapy results in a novel and potent treatment strategy against B-cell lymphoma. Research, in part, supported as part of a subproject on NIH PO1 grant CA103985-1 awarded to the Garden State Cancer Center, Belleville, NJ and NHI R-01 grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute Disclosures: No relevant conflicts of interest to declare.

Evaluation of MLN4924, an investigational NEDD8-activating enzyme (NAE) inhibitor, as a novel targeted agent with single-agent antitumor activity in mantle cell lymphoma (MCL) and Hodgkin lymphoma preclinical models.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18539-e18539
Author(s):  
Richa Dawar ◽  
Matthew John Barth ◽  
Cory Mavis ◽  
Jospeh J. Skitzki ◽  
Myron Stefan Czuczman ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Cells ◽  
Cell Lines ◽  
Primary Tumor ◽  
Cell Lymphoma ◽  
Resistant Cell ◽  
Chemotherapeutic Agents ◽  
Lymphoma Cell ◽  
Anti Tumor Activity

e18539 Background: MLN4924 is a novel, potent, and selective inhibitor of NAE, an essential component of the ubiquitin-proteosome system (UPS). We have previously demonstrated that the UPS plays a pivotal role in the development of rituximab and chemotherapy resistance in B-cell lymphomas. There is a scientific need to target the UPS more efficiently in an attempt to reverse acquired resistance to biological and chemotherapeutic agents in relapsed/refractory aggressive lymphoma. To this end, we studied the anti-tumor activity of MLN4924 in rituximab-chemotherapy sensitive and resistant pre-clinical models. Methods: A panel of Burkitt (BL), diffuse large B-cell (DLBCL), MCL and HL lymphoma cell lines and primary tumor cells isolated from patients with non-Hodgkin lymphoma (NHL) (N=10) were exposed to escalating doses of MLN4924 alone or in combination with a panel of chemotherapeutic agents for up to 72 hrs. Cell viability was determined by alamar Blue reduction or CellTiter-glo assay. Apoptosis was determined by Western blotting. Cell cycle analysis was performed by flow cytometry. Results: MLN4924 demonstrated activity in all cell lines in a time-and dose-dependent manner, including the rituximab/chemotherapy-resistant cell lines. The most potent activity was noted in MCL and HL cell lines (IC50 doses were tenfold lower as compared to DLBCL or BL cell lines). A variable degree of anti-tumor activity was observed in primary tumor cells isolated from NHL patients. Induction of apoptosis was observed in rituximab-resistant cell lines. MLN4924 exhibited synergistic anti-tumor activity when combined with bortezomib, bendamustine, and cytarabine in MCL cell lines. Conclusions: MLN4924 exhibits potent in vitro cytotoxic activity against a variety of human B-cell lymphoma cell lines and primary tumor cells isolated from NHL patients. Significant activity was observed in MCL cell lines. Experiments investigating the in vivo activity of MLN4924 are ongoing. MLN4924 is a highly promising agent for the treatment of relapsed/refractory MCL or HL.

scholarly journals ANTI-TUMOR ACTIVITY OF DARATUMUMAB, A NOVEL HUMAN ANTI CD38 MONOCLONAL ANTIBODY, IN IN VITRO AND IN VIVO MODELS OF B-CELL NON-HODGKIN LYMPHOMA

2017 ◽  
Vol 35 ◽  
pp. 46-47 ◽  
Author(s):  
P. Pérez-Galán ◽  
A. Vidal-Crespo ◽  
A. Matas-Céspedes ◽  
V. Rodriguez ◽  
C. Rossi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
In Vivo Models ◽  
Non Hodgkin Lymphoma ◽  
Anti Tumor Activity

scholarly journals Incidence and Characteristics of CD20 Monoclonal Antibody-Induced Interstitial Pneumonitis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4567-4567
Author(s):  
Jacob Newton Stein ◽  
Natalie S Grover ◽  
Janhvi Rabadey ◽  
Christopher Dittus
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Interstitial Pneumonitis ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Antibody Therapy ◽  
B Cell Lymphoma ◽  
Monoclonal Antibody Therapy ◽  
Non Hodgkin Lymphoma

Abstract Background: CD20 monoclonal antibody therapy is the backbone of treatment for B-cell non-Hodgkin lymphoma. Several studies have described an association between the use of rituximab and non-infectious interstitial pneumonitis, with estimates ranging from 3.9% to 8.4%. 1-3 However, several novel CD20 monoclonal antibodies have been introduced in the past decade, with obinutuzumab gaining FDA approval in 2013, ofatumumab first approved in 2014, and rituximab/hyaluronidase human approved as a subcutaneous route of rituximab in 2017. While the use of these agents has rapidly increased in clinical practice, the incidence of pneumonitis with these agents is not well known. Thus, we have performed a retrospective review of patients with B cell lymphoma treated with CD20 monoclonal antibody therapy to determine the incidence and characteristics of pneumonitis with these novel agents. Methods: We evaluated all patients at the University of North Carolina at Chapel Hill with B-cell lymphoma who were treated with CD20 monoclonal antibody therapy from 2014 to 2020. We performed individual chart review to verify the presence of interstitial pneumonitis, as defined by presence of respiratory symptoms (cough, dyspnea, fever, chest pain) in addition to imaging findings (pulmonary opacity on chest X-ray and/or ground glass opacities on chest computed tomography (CT)) without alternative cause (CHF with pulmonary edema, COPD flare, infectious cause including bacterial, fungal or viral pneumonia/bronchitis). We extracted demographic data, comorbid conditions, tobacco use history, and timing of pneumonitis related to CD20 monoclonal antibody exposure. We determined rates of pneumonitis based on agent and chemotherapy backbone. Results: We identified 18 cases of chart-confirmed interstitial pneumonitis over a six-year period, out of 2,207 patients treated with CD20-monoclonal antibody therapy. Seven (39%) were current or former smokers, with a median of 30 pack-years smoked. Five (29%) had a history of hypersensitivity reaction to rituximab infusion. Pneumonitis developed after a median of 4 cycles, and 16 days from the most recent CD20 monoclonal antibody infusion. Ten (56%) had diffuse large B-cell lymphoma, 4 (22%) had mantle cell lymphoma, and 1 (6%) each had follicular lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and Waldenstrom's macroglobulinemia. Eight cases (44%) occurred among patients being treated with R-CHOP, 2 (11%) were treated with BR, 2 (11%) were receiving single agent rituximab, although several other regimens were represented. Most cases occurred in patients being treated with infusional rituximab, but the rate remained quite low (14/1654, 0.8%). Four occurred in patients receiving subcutaneous rituximab hycela out of 167 treated patients (2.4%), less than prior estimates of pneumonitis with monoclonal antibody therapy. Most cases of pneumonitis were treated with steroids (n=15, 83%), although none required infliximab or anti-TNF agents, and no cases of pneumonitis were fatal. Most notably, we did not identify any cases of pneumonitis among patients treated with ofatumumab (n=51) or obinutuzumab (n=58). Conclusion: This retrospective review reinforced the safety of novel anti-CD20 agents, with low rates of interstitial pneumonitis among patients treated with infusional or subcutaneous rituximab. Cases that did occur were effectively treated with steroids, and there were no fatalities associated with pneumonitis. Ofatumumab and obinutuzumab were not associated with any cases of interstitial pneumonitis. Bibliography 1. Katsuya H, Suzumiya J, Sasaki H, et al. Addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy has a high risk of developing interstitial pneumonia in patients with non-Hodgkin lymphoma. Leuk Lymphoma. 2009;50(11):1818-1823. doi:10.3109/10428190903258780 2. Salmasi G, Li M, Sivabalasundaram V, et al. Incidence of pneumonitis in patients with non-Hodgkin lymphoma receiving chemoimmunotherapy with rituximab. Leuk Lymphoma. 2015;56(6):1659-1664. doi:10.3109/10428194.2014.963075 3. Liu X, Hong X-N, Gu Y-J, Wang B-Y, Luo Z-G, Cao J. Interstitial pneumonitis during rituximab-containing chemotherapy for non-Hodgkin lymphoma. Leuk Lymphoma. 2008;49(9):1778-1783. doi:10.1080/10428190802270886 Figure 1 Figure 1. Disclosures Grover: Novartis: Consultancy; Genentech: Research Funding; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Dittus: BeiGene: Other: Advisory Board; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Genentech: Research Funding.

scholarly journals Ixazomib in Previously Untreated Indolent B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5326-5326
Author(s):  
Solomon A. Graf ◽  
Ryan C. Lynch ◽  
David G. Coffey ◽  
Mazyar Shadman ◽  
Sandra Kanan ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Research Funding ◽  
Response Assessment ◽  
Clinical Indication ◽  
Non Hodgkin Lymphoma ◽  
Tumor Reduction ◽  
Frontline Treatment ◽  
Grade 3 ◽  
Indication For Treatment

Abstract Background: Frontline treatment of indolent B-cell non-Hodgkin lymphoma (iB-NHL) typically involves intravenously administered anti-CD20 monoclonal antibodies with or without cytotoxic chemotherapy. Effective and low-toxicity therapies with improved convenience of administration are sought. We hypothesized that ixazomib (Ix) could safely and conveniently induce remissions in patients with untreated iB-NHL. Here we present the first data on frontline use of Ix in untreated iB-NHL. Methods: This single-arm, open-label phase II "window" trial for patients with untreated iB-NHL (NCT02339922) opened to enrollment in May 2016. Eligibility included histopathologically confirmed iB-NHL, measurable disease, a clinical indication for treatment based on NCCN guidelines, and no prior systemic treatment. Ix was administered at 4 mg orally once a week on consecutive 28-day cycles until disease progression or unacceptable toxicity and four doses of weekly rituximab (R) were added during the 7th cycle, after the initial window period. The primary endpoint was investigator-assessed response rate after independent radiology review. Response assessment occurred at every 2 cycles and using standard (Lugano) criteria. Tumor tissue was collected for gene expression profiling and immunohistochemical evaluation of molecular pathways associated with proteasome inhibition. Results: As of July 1, 2018, 15 patients were treated. The median age was 64 years (range, 47 to 81) and 53% were men. Disease histologies included follicular lymphoma (FL, n = 10), mantle cell lymphoma (MCL, n = 2), marginal zone lymphoma (MZL, n = 2), and small lymphocytic lymphoma (SLL, n = 1). At the start of therapy, all had stage III/IV disease and B-symptoms were present in 40%. For patients with FL, 80% had poor risk by FLIPI. Overall, the indication for treatment included symptoms due to disease (40%), steady progression of disease (33%), and cytopenia due to disease (27%). To date, 14 patients were evaluable for response and 13 experienced tumor burden reduction during the Ix-only window (Figure 1). Of patients with FL, 6 completed the Ix-only window phase and, of these, 5 achieved PR. An additional 4 patients with FL have not completed all 6 cycles of Ix monotherapy. Of these, 1 patient achieved a PR after 4 cycles and continues on treatment, 1 patient came off study with stable disease after 4 cycles, and 2 patients have experienced tumor reduction without meeting formal response criteria and continue on treatment (after 2 and 4 cycles, respectively). Of those patients with FL that received R, all achieved formal remission (3 CR, 3 PR). Median progression free survival has not been reached with a median follow up of 7.4 months. No patient with non-FL histology had yet achieved a PR during the Ix-only window or had undergone response assessment after receiving R at the time of the data cut. The most common adverse events (AEs) for all pts were grade 1-2 and included nausea (53%), diarrhea (53%), rash (40%), and fatigue (33%). Peripheral neuropathy occurred in 20% patients (grade 2 in 7%). A single grade ≥ 3 AE occurred (syncope, grade 3). Conclusions: Data from this interim analysis suggest that Ix monotherapy is well tolerated and highly active in the frontline treatment of FL with all patients demonstrating tumor reduction to date and augmented responses following the addition of R. Non-FL histologies of B-NHL appear less responsive to Ix, but numbers are small. Accrual on study continues. Correlative analyses are underway to determine if Ix or Ix-R may represent a viable frontline option for some patients with iB-NHL. Figure 1. Waterfall plot of response. Number of cycles of treatment received to date indicated for each subject. Four weekly doses of rituximab are added, per protocol, with the 7th cycle of ixazomib. Asterisk indicates treatment on study ongoing. Disclosures Graf: Acerta: Research Funding; TG Therapeutics: Research Funding; Beigene: Research Funding. Lynch:T.G. Therapeutics: Research Funding; Takeda Pharmaceuticals: Research Funding; Rhizen Pharmaceuticals S.A.: Research Funding; Incyte Corporation: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Shadman:Genentech: Consultancy; Genentech: Research Funding; Verastem: Consultancy; AbbVie: Consultancy; Gilead Sciences: Research Funding; Beigene: Research Funding; Qilu Puget Sound Biotherapeutics: Consultancy; AstraZeneca: Consultancy; TG Therapeutics: Research Funding; Mustang Biopharma: Research Funding; Pharmacyclics: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Gopal:Pfizer: Research Funding; Aptevo: Consultancy; BMS: Research Funding; Brim: Consultancy; Asana: Consultancy; Seattle Genetics: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Incyte: Consultancy; Teva: Research Funding.

scholarly journals Daratumumab displays in vitro and in vivo anti-tumor activity in models of B-cell non-Hodgkin lymphoma and improves responses to standard chemo-immunotherapy regimens

Haematologica ◽  
2019 ◽  
Vol 105 (4) ◽  
pp. 1032-1041 ◽  
Author(s):  
Anna Vidal-Crespo ◽  
Alba Matas-Céspedes ◽  
Vanina Rodriguez ◽  
Cédric Rossi ◽  
Juan G. Valero ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Anti Tumor Activity

scholarly journals CD20 antibodies: type II to tango?

Blood ◽  
2012 ◽  
Vol 119 (22) ◽  
pp. 5061-5063 ◽  
Author(s):  
Marinus H. J. van Oers
Keyword(s):  
Monoclonal Antibody ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Type Ii ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20 ◽  
Intense Research ◽  
Cd20 Antibodies

Although the chimeric anti-CD20 monoclonal antibody (mAb) rituximab has revolutionized the treatment of B-cell non-Hodgkin lymphoma (NHL), still many patients relapse and an increasing number become refractory to rituximab-containing therapy. This has initiated intense research to develop more potent anti-CD20 antibodies.

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