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Rituximab resistance

Kosuke Iwane, Takahisa Kayahara, Hiroyuki Takabatake, Yoichi Morimoto, Akiko Iseki, Motowo Mizuno, Kenji Notohara
A Japanese male in his 70s with chronic hepatitis C was diagnosed with diffuse large B-cell lymphoma and achieved and maintained complete remission following treatment with eight cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone). Seven years later, he received the direct-acting antivirals (DAAs) sofosbuvir/ledipasvir for hepatitis C virus (HCV) genotype 1b. Although the patient achieved sustained virological response immediately after the initial treatment period, laboratory data showed elevation of LD and soluble IL-2R...
2019: Nihon Shokakibyo Gakkai Zasshi, the Japanese Journal of Gastro-enterology
Ziju Xu-Monette, Min Xiao, Qingyan Au, Raghav Padmanabhan, Bing Xu, Nicholas Hoe, Sandra Rodriguez-Perales, Raul Torres-Ruiz, Ganiraju Manyam, Carlo Visco, Yi Miao, Xiaohong Tan, Hongwei Zhang, Alexandar Tzankov, Jing Wang, Karen Dybkaer, Wayne Tam, Hua You, Govind Bhagat, Eric D Hsi, Maurilio Ponzoni, Andrés J M Ferreri, Michael B Møller, Miguel A Piris, J Han van Krieken, Jane N Winter, Jason R Westin, Lan V Pham, L Jeffrey Medeiros, George Z Rassidakis, Yong Li, Gordon J Freeman, Ken H Young
PD-1/L1 and CTLA-4 blockade immunotherapies have been approved for twelve types of cancer and are being studied in diffuse large B-cell lymphoma (DLBCL), the most common aggressive B-cell lymphoma. However, whether both PD-1 and CTLA-4 checkpoints are active and clinically significant in DLBCL is unknown. Whether PD-1 ligands expressed by tumor cells or by the microenvironment of DLBCL are critical for immune checkpoint is unclear. We performed immunophenotypic profiling for 405 patients with de novo DLBCL using a MultiOmyx immunofluorescence platform and simultaneously quantitated expression/coexpression of 13 immune markers to identify prognostic determinants...
February 11, 2019: Cancer Immunology Research
Kenneth W Locke, Daniel C Maneval, Michael J LaBarre
ENHANZE® drug delivery technology is based on the proprietary recombinant human hyaluronidase PH20 enzyme (rHuPH20; Halozyme Therapeutics, Inc.) that facilitates the subcutaneous (SC) delivery of co-administered therapeutics. rHuPH20 works by degrading the glycosaminoglycan hyaluronan (HA), which plays a role in resistance to bulk fluid flow in the SC space, limiting large volume SC drug delivery, dispersion, and absorption. Co-administration of rHuPH20 with partner therapies can overcome administration time and volume barriers associated with existing SC therapeutic formulations, and has been shown to reduce the burden on patients and healthcare providers compared with intravenous formulations...
December 2019: Drug Delivery
Charlotte Lees, Colm Keane, Maher K Gandhi, Jay Gunawardana
Primary mediastinal B-cell lymphoma (PMBCL) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B-cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B (NF-κB) and Janus kinase/signal transducers and activators of transcription (JAK-STAT) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion...
February 10, 2019: British Journal of Haematology
Anna Felberg, Aleksandra Urban, Anna Borowska, Grzegorz Stasiłojć, Michał Taszner, Andrzej Hellmann, Anna Maria Blom, Marcin Okrój
Anti-CD20 monoclonal antibodies (mAbs) rituximab and ofatumumab are potent activators of the classical complement pathway, and have been approved for the treatment of B-cell malignancies. However, complement exhaustion and overexpression of complement inhibitors by cancer cells diminish their therapeutic potential. The strategies of targeting membrane complement inhibitors by function-blocking antibodies and the supplementation with fresh frozen plasma have been proposed to overcome tumour cell resistance. We present a novel approach, which utilizes gain-of-function variants of complement factor B (FB), a component of alternative C3/C5 convertases, which augment mAb-activated reactions through a positive feedback mechanism called an amplification loop...
February 6, 2019: Cancer Immunology, Immunotherapy: CII
Cristina Bagacean, Adrian Tempescul, David Ternant, Anne Banet, Nathalie Douet-Guilbert, Anne Bordron, Boutahar Bendaoud, Hussam Saad, Mihnea Zdrenghea, Christian Berthou, Gilles Paintaud, Yves Renaudineau
Chronic lymphocytic leukemia (CLL) is the most common type of leukemia and the anti-CD20 monoclonal antibody, rituximab, represents the therapeutic gold standard for more than 2 decades in this pathology, when used in combination with chemotherapy. However, some patients experience treatment resistance or rapid relapses, and in particular, those harboring a 17p/TP53 deletion (del(17p)). This resistance could be explained by a chemo-resistance, but it could also result from the direct impact of del(17p) on the pharmacokinetics of rituximab, which represents the aim of the present study...
January 29, 2019: Journal for Immunotherapy of Cancer
Milena Tocut, Ziv Rozman, Alexander Biro, Asher Winder, Amir Tanay, Gisele Zandman-Goddard
Type I cryoglobulinemia is associated with B cell proliferative diseases, whereas essential mixed cryoglobulinemia is classically associated with infections, malignancy, and autoimmune diseases, but may be idiopathic. Prognosis in patients with grave manifestations and renal involvement is often poor. We report a case of a 40-year-old woman, 2 weeks post-partum for pre-eclampsia who was hospitalized with nephritic syndrome and acute renal failure. The patient harbored type I and type II cryoglobulinemia. Renal and cutaneous biopsies confirmed the diagnosis; however, an underlying etiology was not established...
January 10, 2019: Clinical Rheumatology
Madeline Neiveyans, Rana Melhem, Christophe Arnoult, Thomas Bourquard, Marta Jarlier, Muriel Busson, Adrien Laroche, Martine Cerutti, Martine Pugnières, David Ternant, Nadège Gaborit, Thierry Chardès, Anne Poupon, Valérie Gouilleux-Gruart, Andre Pèlegrin, Marie-Alix Poul
Targeting transferrin receptor 1 (TfR1) with monoclonal antibodies is a promising therapeutic strategy in cancer as tumor cells often overexpress TfR1 and show increased iron needs. We have re-engineered six anti-human TfR1 single-chain variable fragment (scFv) antibodies into fully human scFv2 -Fcγ1 and IgG1 antibodies. We selected the more promising candidate (H7), based on its ability to inhibit TfR1-mediated iron-loaded transferrin internalization in Raji cells (B-cell lymphoma). The H7 antibody displayed nanomolar affinity for its target in both formats (scFv2 -Fcγ1 and IgG1), but cross-reacted with mouse TfR1 only in the scFv2 -Fc format...
January 3, 2019: MAbs
R Ramachandran, J Bharati, I Rao, A W Kashif, R Nada, R Minz, K L Gupta, H S Kohli
AIM: A significant proportion of patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are either steroid dependent (SD) or resistant (SR), requiring long-term calcineurin inhibitors (CNIs) use. Rituximab has more favourable safety profile. The present study was undertaken to evaluate the efficacy and safety of rituximab in CNI dependent patients. METHODS: This was a prospective observational study conducted from July 2014 to February 2018...
December 26, 2018: Nephrology
Xiaowen Ge, Jianfeng Chen, Ling Li, Peipei Ding, Qi Wang, Wei Zhang, Luying Li, Xinyue Lv, Danlei Zhou, Zhengzeng Jiang, Haiying Zeng, Yifan Xu, Yingyong Hou, Weiguo Hu
An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells...
December 18, 2018: Cell Death & Disease
T Seeman, K Vondrak
Mutations in nucleoporin 93 (NUP93) gene have been shown recently to be one of the very rare causes of genetic steroid-resistant nephrotic syndrome (SRNS). Until now, none of the 7 published cases with NUP93-SRNS, experienced recurrence of nephrotic syndrome (NS) after transplantation. Here, we present the first case of recurrent NS in a patient with NUP93-SRNS ever reported. A 3-year-old boy with infantile SRNS was started on chronic peritoneal dialysis because of end-stage renal failure owing to biopsy-proven focal segmental glomerulosclerosis (FSGS)...
December 2018: Transplantation Proceedings
Koichi Kamei, Kenji Ishikura, Mayumi Sako, Shuichi Ito, Kandai Nozu, Kazumoto Iijima
Patients with steroid-resistant nephrotic syndrome (SRNS) who develop resistance to immunosuppressive agents, defined as refractory SRNS, have poor renal outcomes. Although the chimeric anti-CD20 monoclonal antibody rituximab has shown efficacy for frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome, its efficacy for refractory SRNS remains uncertain due to limited data. According to previous case reports, 50.4% of patients with refractory SRNS showed clinical improvements after rituximab treatment...
December 18, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Talia James, Sam Salman, Brittany Stevenson, Christine Bundell, Gavin Kelly, David Nolan, Mina John
Bullous pemphigoid (BP) is a blistering dermopathy and a prototypic antibody-mediated autoimmune disease. Detection of IgG autoantibodies against hemidesmosomal proteins BP180 and/or BP230 are diagnostic and levels can correlate with disease activity. Therapies include corticosteroids and oral immunosuppressants, while intravenous immunoglobulin and rituximab are reserved for treatment resistant cases. Here we describe a patient with severe BP which was refractory to standard first line therapy, intravenous immunoglobulin and rituximab induced depletion of peripheral B cells...
December 14, 2018: Clinical Immunology: the Official Journal of the Clinical Immunology Society
Jean Daniel Delbet, Gael Leclerc, Tim Ulinski
BACKGROUND: Rituximab (RTX) has been shown to be an efficient treatment for steroid-dependent nephrotic syndrome (SDNS). A long B cell depletion period seems to improve the duration of remission. This study reports the duration of B cell depletion after each RTX infusion in patients with nephrotic syndrome. METHODS: We retrospectively report the data of 22 patients with a diagnosis of a SDNS or steroid-resistant nephrotic syndrome (SRNS) and a treatment with RTX in a single center...
December 12, 2018: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Shariful Islam, Andrew L Paek, Michael Hammer, Savithri Rangarajan, Robert Ruijtenbeek, Laurence Cooke, Eric Weterings, Daruka Mahadevan
Double-hit (DH) or double-expresser (DE) lymphomas are high-grade diffuse large B-cell lymphomas (DLBCL) that are mostly incurable with standard chemo-immunotherapy due to treatment resistance. The generation of drug-induced aneuploid/polyploid (DIAP) cells is a common effect of anti-DLBCL therapies (e.g. vincristine, doxorubicin). DIAP cells are thought to be responsible for treatment resistance, as they are capable of re-entering the cell cycle during off-therapy periods. Previously we have shown that combination of alisertib plus ibrutinib plus rituximab can partially abrogate DIAP cells and induce cell death...
November 13, 2018: Oncotarget
Ilaria Marrocco, Donatella Romaniello, Yosef Yarden
Since the approval of the first monoclonal antibody (mAb), rituximab, for hematological malignancies, almost 30 additional mAbs have been approved in oncology. Despite remarkable advances, relatively weak responses and resistance to antibody monotherapy remain major open issue. Overcoming resistance might require combinations of drugs blocking both the major target and the emerging secondary target. We review clinically approved combinations of antibodies and either cytotoxic regimens (chemotherapy and irradiation) or kinase inhibitors...
2019: Methods in Molecular Biology
Di Wang, Peng Liu, Yue Zhang, Hui-Ying Liu, Di Shen, Yi-Qun Che
Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is a common subtype of non-Hodgkin's lymphoma and is very likely to infiltrate the bone marrow. Over 30% of patients are converted to relapsed/refractory DLBCL after first-line rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, with a poor prognosis. Our aim was to identify molecular markers that might be utilized to predict relapsed/refractory ABC-DLBCL patients. Hence, we collected bone marrow aspirate smears from 202 patients with ABC-DLBCL and detected expression of bone marrow molecular marker proteins by immunocytochemistry...
2018: BioMed Research International
Kyle Runckel, Matthew J Barth, Cory Mavis, Juan J Gu, Francisco J Hernandez-Ilizaliturri
Clinical observations suggest the existence of shared resistance pathways between rituximab and chemotherapy agents. To explore the mechanisms of rituximab resistance, our group created rituximab-resistant cell lines (RRCLs), which display altered expression of several inhibitor of apoptosis (IAP) family proteins. Here, we provide evidence to support pharmacologically targeting IAPs in lymphoma with LCL-161, a small molecule mimetic of the second mitochondria-derived activator of caspases (SMAC). The antitumor effect of LCL-161 was determined using luminescent adenosine triphosphate assays, flow cytometry, SCID mouse xenografts, and ex vivo patient biopsy sample studies...
December 11, 2018: Blood Advances
Shin Nagai, Junji Hiraga, Noriyuki Suzuki, Naruko Suzuki, Yusuke Takagi, Michihiko Narita, Yoshitoyo Kagami
We report a rare case of composite lymphoma comprising extranodal NK/T-cell lymphoma, nasal type, (ENKL) and diffuse large B-cell lymphoma (DLBCL) in a 70-year-old man complaining of fatigue. Computed tomography showed multiple consolidations in both lungs, and ENKL was diagnosed from transbronchial lung biopsy. Positron emission tomography also detected abnormal uptake in the stomach, and DLBCL was diagnosed from subsequent gastroscopy. Two courses of chemotherapy including rituximab achieved reduction in DLBCL, but ENKL proved resistant to this treatment and progressed...
2018: Case Reports in Hematology
Magdalena Kraft, Margitta Worm
Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies directed against desmoglein-1 located in the upper epidermal layer. Rituximab, a monoclonal anit-CD20 antibody depleting b-cells, offers an effective treatment possibility for therapy-resistant pemphigus foliaceus. Here, we present the case of 55-year-old man who did not respond sufficiently to conventional treatment with prednisolone, azathioprine, and cyclophosphamide, but underwent almost complete remission after rituximab treatment...
2018: Frontiers in Medicine
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