scholarly journals BARs (B -cell receptor a ntigens for r everse targeting): A Novel and Ultimately Specific Treatment Concept for B-Cell Neoplasms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3995-3995
Author(s):  
Michael Pfreundschuh ◽  
Lorenz Thurner ◽  
Stefan Barth ◽  
Diana Pickert ◽  
Natalie Fadle ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Specific Treatment ◽  
Primary Cns Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Antigenic Stimulation ◽  
Cns Lymphoma ◽  
Therapeutic Concept ◽  
Chronic Antigenic Stimulation

Abstract Introduction: The major task of a B-cell receptor is the binding and internalization of its antigenic target, and its processing for antigen presentation to T-cells. Chronic antigenic stimulation has been discussed to play a role in the pathogenesis of malignant B-cell lymphomas. We therefore systematically searched for the antigenic targets of BCRs from various B-cell neoplasms. Methods: Recombinant BCRs were expressed as recombinant Fabs (rFabs) based on corresponding pairs of functional variable region heavy and light chain genes, which had been amplified from isolated genomic DNA lymphoma biopsies. Whenever possible, "natural" Fabs (nFabs) were also obtained by papain digestion of fresh or cultured lymphoma cells. Both nFab and rFab were used to screen for binding to proteins expressed on macroarrays derived from human cDNA expression libraries and identical binding pattern of nFabs and rFabs was demonstrated by an antigen competition assay. Results: Two antigens (paratarg-7 and sumoylated HSP-90 which are hyperphosphorylated and sumoylated, respectively, in patients compared to healthy controls) are the targets of paraproteins from (depending on ethnicity) 30-50% of all multiple myeloma patients; the BCR from 67% of patients with primary CNS lymphoma target hyperglycosylated neurabin, 26% of the BCR from ABC-type DLBCL target hypophosphorylated ARS2 and 45% of all mantle cell BCR target LRPAP1; optineurin is the BCR target of 12% follicular lymphomas and various autoantigens have been identified as the targets of roughly 30% of all CLL cases. For all autoantigens binding to its specific BCR, rapid internalization and induction of proliferation was demonstrated, indicating partial dependence on antigenic stimulation even in cell lines that had been in culture for years. Most importantly, BCR-specific cytotoxicity of recombinant pseudomonas-exotoxin conjugated ARS2 against an ABC-DLBCL cell line with BCR specific for ARS2 (OCI-Ly3) was demonstrated in vitro and in vivo after establishment of OCI-Ly3 lymphomas in SCID beige mice. Conclusions: Assuming that only a minority of BCR targets have been identified to date, the prevalence of posttranslationally modified autoantigens strongly supports a role of chronic antigenic stimulation in many B-cell neoplasms. Due to the predominance of a single or few BCR antigens in each malignant B-cell entity studied, BARs represent an attractive and novel therapeutic concept for a broad spectrum of B-cell neoplasms and are the first therapeutic approach in oncology that targets exclusively the malignant cells. BARs can be used for conjugation with toxins, radionuclides and small molecules as well as for bispecific constructs (e. g. with CD3 or CD16) and CAR T-cells, the toxicity of which should be drastically reduced due to the ultimate specificity of BARs that spares normal B-cells. Supported by Wilhelm-Sander-Stiftung Disclosures Pfreundschuh: Roche, Janssen, Celgene: Honoraria, Research Funding.

scholarly journals Integration of the B-Cell Receptor Antigen Neurabin-I/SAMD14 Into an Antibody Format as New Therapeutic Approach for the Treatment of Primary CNS Lymphoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Moritz Bewarder ◽  
Maximilian Kiefer ◽  
Clara Moelle ◽  
Lisa Goerens ◽  
Stephan Stilgenbauer ◽  
...  
Keyword(s):  
B Cell ◽  
Therapeutic Approach ◽  
Primary Cns Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cns Lymphoma

scholarly journals Inhibition of B Cell Receptor Signaling by Ibrutinib in Primary CNS Lymphoma

Cancer Cell ◽  
2017 ◽  
Vol 31 (6) ◽  
pp. 833-843.e5 ◽  
Author(s):  
Michail S. Lionakis ◽  
Kieron Dunleavy ◽  
Mark Roschewski ◽  
Brigitte C. Widemann ◽  
John A. Butman ◽  
...  
Keyword(s):  
B Cell ◽  
Primary Cns Lymphoma ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Cns Lymphoma ◽  
Receptor Signaling ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

scholarly journals T Cells Can Induce Somatic Mutation in B Cell Receptor-Engaged BL2 Burkitt’s Lymphoma Cells Independently of CD40-CD40 Ligand Interactions

2000 ◽  
Vol 164 (3) ◽  
pp. 1306-1313 ◽  
Author(s):  
Stéphane Denépoux ◽  
Nathalie Fournier ◽  
Catherine Péronne ◽  
Jacques Banchereau ◽  
Serge Lebecque
Keyword(s):  
T Cells ◽  
B Cell ◽  
Somatic Mutation ◽  
Cell Receptor ◽  
Cd40 Ligand ◽  
Burkitt’S Lymphoma ◽  
B Cell Receptor ◽  
Lymphoma Cells ◽  
Ligand Interactions ◽  
Burkitt’S Lymphoma Cells

scholarly journals Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing

2020 ◽  
Author(s):  
Wen Wen ◽  
Wenru Su ◽  
Hao Tang ◽  
Wenqing Le ◽  
Xiaopeng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Hospital Discharge ◽  
Immune Cell ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Early Recovery ◽  
Recovery Stage

AbstractCOVID-19, caused by SARS-CoV-2, has recently affected over 300,000 people and killed more than 10,000. The manner in which the key immune cell subsets change and their states during the course of COVID-19 remain unclear. Here, we applied single-cell technology to comprehensively characterize transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19. Compared with healthy controls, in patients in the early recovery stage (ERS) of COVID-19, T cells decreased remarkably, whereas monocytes increased. A detailed analysis of the monocytes revealed that there was an increased ratio of classical CD14++ monocytes with high inflammatory gene expression as well as a greater abundance of CD14++IL1B+ monocytes in the ERS. CD4+ and CD8+ T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Our study identified several novel B cell-receptor (BCR) changes, such as IGHV3-23 and IGHV3-7, and confirmed isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2 and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting that COVID-19 patients are still vulnerable after hospital discharge. Our identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.Highlights-The immune response was sustained for more than 7 days in the early recovery stage of COVID-19, suggesting that COVID-19 patients are still vulnerable after hospital discharge.-Single-cell analysis revealed a predominant subset of CD14++ IL1β+ monocytes in patients in the ERS of COVID-19.-Newly identified virus-specific B cell-receptor changes, such as IGHV3-23, IGHV3-7, IGHV3-15, IGHV3-30, and IGKV3-11, could be helpful in the development of vaccines and antibodies against SARS-CoV-2.-IL-1β and M-CSF were discovered as novel mediators of inflammatory cytokine storm, and TNFSF13, IL-2, IL-4, and IL-18 may be beneficial for recovery.

scholarly journals Targeting B-cell malignancies through human B-cell receptor specific CD4+T cells

2016 ◽  
Vol 5 (11) ◽  
pp. e1232220 ◽  
Author(s):  
Jinsheng Weng ◽  
Flavio Egidio Baio ◽  
Kelsey E. Moriarty ◽  
Hiroki Torikai ◽  
Hua Wang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
B Cell Malignancies ◽  
Human B Cell

scholarly journals Machine Learning Analysis of Naïve B-Cell Receptor Repertoires Stratifies Celiac Disease Patients and Controls

2021 ◽  
Vol 12 ◽  
Author(s):  
Or Shemesh ◽  
Pazit Polak ◽  
Knut E. A. Lundin ◽  
Ludvig M. Sollid ◽  
Gur Yaari
Keyword(s):  
Machine Learning ◽  
T Cells ◽  
Celiac Disease ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Machine Learning Classification ◽  
Gluten Peptides

Celiac disease (CeD) is a common autoimmune disorder caused by an abnormal immune response to dietary gluten proteins. The disease has high heritability. HLA is the major susceptibility factor, and the HLA effect is mediated via presentation of deamidated gluten peptides by disease-associated HLA-DQ variants to CD4+ T cells. In addition to gluten-specific CD4+ T cells the patients have antibodies to transglutaminase 2 (autoantigen) and deamidated gluten peptides. These disease-specific antibodies recognize defined epitopes and they display common usage of specific heavy and light chains across patients. Interactions between T cells and B cells are likely central in the pathogenesis, but how the repertoires of naïve T and B cells relate to the pathogenic effector cells is unexplored. To this end, we applied machine learning classification models to naïve B cell receptor (BCR) repertoires from CeD patients and healthy controls. Strikingly, we obtained a promising classification performance with an F1 score of 85%. Clusters of heavy and light chain sequences were inferred and used as features for the model, and signatures associated with the disease were then characterized. These signatures included amino acid (AA) 3-mers with distinct bio-physiochemical characteristics and enriched V and J genes. We found that CeD-associated clusters can be identified and that common motifs can be characterized from naïve BCR repertoires. The results may indicate a genetic influence by BCR encoding genes in CeD. Analysis of naïve BCRs as presented here may become an important part of assessing the risk of individuals to develop CeD. Our model demonstrates the potential of using BCR repertoires and in particular, naïve BCR repertoires, as disease susceptibility markers.

scholarly journals CD19 directed CAR T cell therapy for treatment of primary CNS lymphoma

2021 ◽  
Author(s):  
Tanya Siddiqi ◽  
Xiuli Wang ◽  
M. Suzette Blanchard ◽  
Jamie Wagner ◽  
Leslie Popplewell ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
Study Cohort ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T

CD19-directed chimeric antigen receptor (CD19CAR) T cell therapy has been successful in treating several B cell lineage malignancies, including B cell non-Hodgkin's lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily due to concerns for potential toxicity. CD19CAR T cells administered intravenously (IV) are detectable in cerebrospinal fluid (CSF), suggesting that CAR T cells can migrate from the periphery into the CNS, where they can potentially mediate anti-lymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n=5) treated with CD19CAR T cells in our ongoing Phase 1 clinical trial (NCT02153580). All patients developed at least grade 1 cytokine release syndrome and neurotoxicity post-CAR T cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%, 90%CI [19%,92%]) appeared to achieve complete remission, as indicated by resolution of enhancing brain lesions, and the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrated that using CD19CAR T cells to treat PCNSL can be safe and feasible.

scholarly journals RasGRP1 Sensitizes an Immature B Cell Line to Antigen Receptor-induced Apoptosis

2004 ◽  
Vol 279 (19) ◽  
pp. 19523-19530 ◽  
Author(s):  
Benoit Guilbault ◽  
Robert J. Kay
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Wehi 231 ◽  
Induced Apoptosis

RasGRP1 is a guanine nucleotide exchange factor that activates Ras GTPases and is activated downstream of antigen receptors on both T and B lymphocytes. Ras-GRP1 provides signals to immature T cells that confer survival and proliferation, but RasGRP1 also promotes T cell receptor-mediated deletion of mature T cells. We used the WEHI-231 cell line as an experimental system to determine whether RasGRP1 can serve as a quantitative modifier of B cell receptor-induced deletion of immature B cells. A 2-fold elevation in RasGRP1 expression markedly increased apoptosis of WEHI-231 cells following B cell receptor ligation, whereas a dominant negative mutant of RasGRP1 suppressed B cell receptor-induced apoptosis. Activation of ERK1 or ERK2 kinases was not required for RasGRP1-mediated apoptosis. Instead, elevated RasGRP1 expression caused down-regulation of NF-κB and Bcl-xL, which provide survival signals counter-acting apoptosis induction by B cell receptor. Inhibition of NF-κB was sufficient to enhance B cell receptor-induced apoptosis of WEHI-231 cells, and ligation of co-stimulatory receptors that activate NF-κB suppressed the ability of RasGRP1 to promote B cell receptor-induced apoptosis. These experiments define a novel apoptosis-promoting pathway leading from B cell receptor to the inhibition of NF-κB and demonstrate that differential expression of RasGRP1 has the potential to modulate the sensitivities of B cells to negative selection following antigen encounter.

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