scholarly journals Radioimmunotherapy of relapsed B-cell lymphoma with yttrium 90 anti- idiotype monoclonal antibodies

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3640-3649 ◽  
Author(s):  
CA White ◽  
SE Halpern ◽  
BA Parker ◽  
RA Miller ◽  
HB Hupf ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Cell Lymphoma ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Time To Progression ◽  
Clinical Responses ◽  
Yttrium 90

Tumor-specific anti-idiotype (anti-Id) monoclonal antibodies (MoAbs) to B-cell lymphomas have been administered to patients, resulting in significant clinical responses. However, clinical responses have been limited by the emergence of Id-negative lymphoma. To overcome the problem of tumor heterogeneity, we conducted a pilot evaluation of the safety and effectiveness of yttrium 90 (90Y)-labeled anti-Id and shared Id (sId) MoAbs in non-Hodgkin's B-cell lymphoma. Nine patients with relapsed B-cell lymphoma in whom tumor was successfully targeted with 111In-labeled anti-Id MoAb were treated with 90Y-labeled anti-Id MoAb. A total of 19 courses (one to four per patient) were administered using 1,000 to 2,320 mg unlabeled clearing MoAb and 10 to 54 mCi 90Y MoAb per patient. Two of nine patients had a complete response, one a partial response, three stable disease, and three disease progression. Time to progression varied from 1 to 12 months. Toxicities were predominately hematologic, and only one patient developed infection and required transfusion. At progression, three of five assessable patients had Id- positive lymphoma and two had Id-negative lymphoma. Human antimouse antibodies (HAMA) did not develop in the patients after treatment. 90Y anti-Id MoAbs demonstrated excellent in vivo stability, produced significantly tumor regression in three of nine patients, exhibited acceptable toxicities, and elicited no HAMA formation. Further investigation of repetitive, low-dose 90Y anti-Id and MoAb therapy is warranted; however, the advantages of a pan B MoAb may prove the latter to be the agent of choice for the radio immunotherapy of B-cell lymphoma.

scholarly journals P09.01 Adoptive cell therapy of hematological malignancies using cytokine-induced killer cells retargeted with monoclonal antibodies

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A51.2-A52
Author(s):  
A Dalla Pietà ◽  
E Cappuzzello ◽  
P Palmerini ◽  
R Sommaggio ◽  
G Astori ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Cell Therapy ◽  
B Cell ◽  
Cell Lymphoma ◽  
Adoptive Cell Therapy ◽  
B Cell Lymphoma ◽  
Clinical Grade ◽  
Cik Cells

BackgroundCytokine-Induced Killer (CIK) cells are a population of effector cells that represents a promising tool for adoptive cell therapy. They are easily expandable ex-vivo, safe, and exert cytotoxicity against a broad range of tumor histotypes.1 We recently reported that they have a relevant expression of FcγRIIIa (CD16a), which can be exploited in combination with clinical-grade monoclonal antibodies (mAbs) to redirect their cytotoxicity in an antigen-specific manner, to improve their antitumor activity.2 Indeed, the engagement of CD16a on CIK cells leads to a potent antibody-dependent cell-mediated cytotoxicity (ADCC) against ovarian cancer both in vitro and in vivo. Based on this observation, we investigated whether CIK cells can be specifically retargeted against B-cell malignancies by combination with anti-CD20 mAbs, namely Rituximab® (RTX) and Obinutuzumab® (OBI).Materials and MethodsCIK cells were obtained from peripheral blood mononuclear cells of healthy donors, and stimulated in vitro with IFN-γ, CD3 mAb and IL-2 for 14 days; fresh IL-2 was provided every 3–4 days. CIK cell phenotype was analyzed by multicolor flow cytometry; cytotoxic activity was assessed by calcein AM-release assay against B-cell lines, primary samples and patient-derived xenografts (PDX) obtained from B-cell lymphoma patients after written informed consent.ResultsThe combination with both RTX and OBI significantly increased specific CIK cells lysis against several CD20-expressing lymphoma B cell lines, primary tumors from B-cell lymphoma patients and an established PDX, compared to the combination with a control mAb (cetuximab, CTX). NK-depletion demonstrated that the mAb-mediated cytotoxicity is accountable to the CIK cells fraction within the bulk population since no difference in the lytic activity was detectd in the absence of NK cells. In addition, these results are further supported by in vivo preliminary experiments where the treatment with CIK cells in combination with OBI extensively reduced the growth of PDX and increased mice survival, compared to CIK cells or OBI administered alone.ConclusionsHere we proved that CIK cells can be retargeted with clinical-grade mAbs against CD20-expressing lymphomas. These data indicate that the combination of CIK cells with mAbs can represent a novel approach for the treatment of haematological malignancies.ReferencesFranceschetti M, Pievani A, Borleri G, Vago L, Fleischhauer K, Golay J, et al. Cytokine-induced killer cells are terminally differentiated activated CD8 cytotoxic T-EMRA lymphocytes. Exp Hematol 2009;37:616–28.Cappuzzello E, Tosi A, Zanovello P, Sommaggio R, Rosato A. Retargeting cytokine-induced killer cell activity by CD16 engagement with clinical-grade antibodies. Oncoimmunology 2016 Aug;5(8):e1199311.The research leading to these results has received funding from Fondazione AIRC under IG 2018 - ID. 21354 project - P.I. Rosato AntonioDisclosure InformationA. Dalla Pietà: None. E. Cappuzzello: None. P. Palmerini: None. R. Sommaggio: None. G. Astori: None. K. Chieregato: None. O. Perbellini: None. M. Tisi: None. C. Visco: None. M. Ruggeri: None. A. Rosato: None.

scholarly journals B Cell Lymphoma, Unclassifiable, Transformed from Follicular Lymphoma: A Rare Presentation with Review of the Literature

2015 ◽  
Vol 2015 ◽  
pp. 1-9
Author(s):  
Anila Kanna ◽  
Swati Agrawal ◽  
Kumar Jayant ◽  
Varun Kumar Pala ◽  
Mohammad Altujjar ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
Excisional Biopsy ◽  
Complete Response ◽  
Rare Presentation ◽  
Mediastinal Disease ◽  
The Right

B cell lymphoma, unclassifiable, with features of diffuse large B cell lymphoma and classical Hodgkin’s lymphoma (BCLu-DLBCL/CHL) is more commonly known as gray zone lymphoma. These cases more often present with mediastinal disease. In this report, we present a very rare case of BCLu-DLBCL/CHL without mediastinal involvement, transformed from follicular lymphoma (FL) to BCLu-DLBCL/CHL. This patient initially presented with a mass in the right neck; biopsy of the lymph node showed predominantly nodular, follicular pattern. Immunohistochemical (IHC) staining of tumor cells expressed positivity for mature B cell markers CD20, CD19, CD10, CD23, CD45, and CD38 but negative for CD5,11c. Hence, diagnosed with FL, he was given rituximab, cyclophosphamide, vincristine, and prednisone (RCVP) regimen, followed by maintenance rituximab. He showed good response. After 2 years, he presented again with a mass in the right side of the neck. Although the needle core biopsy of this mass was suggestive of B cell lymphoma, excisional biopsy showed morphological features of DLBCL as well as foci of histological pattern of CHL. IHC staining expressed positivity for CD20, CD79a, PAX5, and CD15 and CD30 consistent with DLBCL and CHL. He was diagnosed with BCLu-DLBCL/CHL. The patient received “ACVBP” (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) followed by radiation. BCLu-DLBCL/CHL is clinically an aggressive tumor with poorer outcomes, but our case showed complete response to ACVBP regimen with tumor regression.

scholarly journals Epstein Barr virus-positive B-cell lymphoma is highly vulnerable to MDM2 inhibitors in vivo

2021 ◽  
Author(s):  
Xiaoshan Zhang ◽  
Ran Zhang ◽  
Chenghui Ren ◽  
Yi Xu ◽  
Shuhong Wu ◽  
...  
Keyword(s):  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Lymphoma ◽  
Tumor Regression ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
T Cell Therapy ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV)-positive B-cell lymphomas are common in immunocompromised patients and remain an unmet medical need. Here we report that MDM2 inhibitors (MDM2i) navtemadlin and idasanutlin have potent in vivo activity in EBV+ B-cell lymphoma established in immunocompromised mice. Tumor regression was observed in all 5 EBV+ xenograft-associated B-cell lymphomas treated with navtemadlin or idasanutlin. Molecular characterization showed that treatment with MDM2i resulted in activation of p53 pathways and downregulation of cell cycle effectors in human lymphoma cell lines that either were EBV+ or had undetectable expression of BCL6, a transcriptional inhibitor of the TP53 gene. Moreover, treatment with navtemadlin resulted in tumor regression and prevented systemic dissemination of EBV+ lymphoma derived from 2 juvenile patients with posttransplant lymphoproliferative diseases, including one whose tumor was resistant to virus-specific T-cell therapy. These results provide proof-of-concept for targeted therapy of EBV+ lymphoma with MDM2i and the feasibility of using EBV infection or loss of BCL6 expression to identify responders to MDM2i.

Rituximab and yttrium-90 ibritumomab tiuxetan radioimmunotherapy as treatment options in patients with indolent lymphoma of the orbit

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15532-15532
Author(s):  
B. Esmaeli ◽  
B. Pro ◽  
M. Saville ◽  
P. Mc Laughlin
Keyword(s):  
Monoclonal Antibodies ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Hyperplasia ◽  
Ibritumomab Tiuxetan ◽  
Benign Lymphoid Hyperplasia ◽  
Orbital Lymphoma ◽  
Clinical Records ◽  
Yttrium 90

15532 Objective: To report a cohort of patients with lymphoid tumors of the orbit whose disease responded to immunotherapy with rituximab alone or rituximab followed by Zevalin (yttrium-90 ibritumomab tiuxetan). Methods: Between October 2002 and June 2005, 9 patients with indolent non-Hodgkin’s lymphoma and 1 with orbital benign lymphoid hyperplasia were treated with monoclonal antibodies against CD20. 6 patients with orbital lymphoma (3 follicular B-cell, 2 MALT, and 1 mantle cell lymphoma) received rituximab followed by Zevalin. 2 patients with indolent orbital lymphoma (one with follicular B cell and the other with small lymphocytic lymphoma) and 1 patient with benign lymphoid hyperplasia received rituximab alone. 3 out of the 6 patients who received Zevalin were part of a prospective trial evaluating the efficacy of Zevalin for indolent B-cell lymphoma of the orbit; the rest were treated in other trials at M. D. Anderson. Clinical records and imaging studies were reviewed to document response. Results: 4 men and 5 women were between23 and 83 years old (median age, 63 years). Of the 8 patients with orbital lymphoma, 4 had stage IE, 4 had stage IV, and 6 had previously untreated disease. All 9 patients experienced resolution of the orbital tumor in response to monoclonal antibodies against CD20. Follow-up time ranged from 6 to 32 months (mean, 12 months) after completion of immunotherapy. There were no serious systemic or ocular side effects during the study period. The most common side effect was mild fatigue. All 6 patients treated with Zevalin had transient pancytopenia which normalized within 3 months. Conclusions: Rituximab and Zevalin may be considered as alternative treatment modalities to radiotherapy for indolent B-cell lymphoma or MALT of the orbit. Systemic targeted immunotherapy may potentially have the advantage of lower rate of distant (out-of-field) relapse and less ocular toxicity compared with radiotherapy; these potential advantages would have to be verified in long-term studies and in larger number of patients. [Table: see text]

scholarly journals B-cell–specific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice

Blood ◽  
2016 ◽  
Vol 127 (22) ◽  
pp. 2732-2741 ◽  
Author(s):  
Gero Knittel ◽  
Paul Liedgens ◽  
Darya Korovkina ◽  
Jens M. Seeger ◽  
Yussor Al-Baldawi ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Specific Expression ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Conditional Expression ◽  
Large B Cell

Key Points B-cell–specific expression of Myd88p.L252P leads to the development of DLBCL in mice. The Myd88p.L252P mutation cooperates with BCL2 amplifications in ABC-DLBCL lymphomagenesis in vivo.

scholarly journals Imaging the mechanisms of anti-CD20 therapy in vivo uncovers spatiotemporal bottlenecks in antibody-dependent phagocytosis

2021 ◽  
Vol 7 (8) ◽  
pp. eabd6167
Author(s):  
Capucine L. Grandjean ◽  
Zacarias Garcia ◽  
Fabrice Lemaître ◽  
Béatrice Bréart ◽  
Philippe Bousso
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Critical Path ◽  
B Cell Lymphoma ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Fluorescent Reporter ◽  
Cd20 Antibody ◽  
Anti Cd20 ◽  
Partial Depletion

Anti-CD20 antibody (mAb) represents an effective strategy for the treatment of B cell malignancies, possibly involving complement activity, antibody-dependent cellular cytotoxicity and phagocytosis (ADP). While ADP by Kupffer cells deplete circulating tumors, mechanisms targeting non-circulating tumors remain unclear. Using intravital imaging in a model of B cell lymphoma, we establish here the dominance and limitations of ADP in the bone marrow (BM). We found that tumor cells were stably residing in the BM with little evidence for recirculation. To elucidate the mechanism of depletion, we designed a dual fluorescent reporter to visualize phagocytosis and apoptosis. ADP by BM-associated macrophages was the primary mode of tumor elimination but was no longer active after one hour, resulting in partial depletion. Moreover, macrophages were present at low density in tumor-rich regions, targeting only neighboring tumors. Overcoming spatiotemporal bottlenecks in tumor-targeting Ab therapy thus represents a critical path towards the design of optimized therapies.

scholarly journals Validation of epigenetic mechanisms regulating gene expression in canine B-cell lymphoma: An in vitro and in vivo approach

PLoS ONE ◽  
2018 ◽  
Vol 13 (12) ◽  
pp. e0208709 ◽  
Author(s):  
Silvia Da Ros ◽  
Luca Aresu ◽  
Serena Ferraresso ◽  
Eleonora Zorzan ◽  
Eugenio Gaudio ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Epigenetic Mechanisms

scholarly journals Large B-Cell Lymphoma with T-Cell–Rich Background and Nodules Lacking Follicular Dendritic Cell Meshworks: A Case Report with Complete Response to Chemotherapy and a Review of the Literature

2020 ◽  
Vol 5 (11) ◽  
pp. 561-565
Author(s):  
Walid Shalata ◽  
Ismaell Massalha ◽  
Kayed Al-Athamen
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Follicular Dendritic Cell ◽  
Large B Cell Lymphoma ◽  
Follicular Dendritic ◽  
Large B Cell

In this report, we describe a 38-year-old male with a very rare type of lymphoma, large B cell lymphoma with T cell-rich background and nodules lacking follicular dendritic cell meshworks (THRLBCL). In 2016 the patient presented hot flashes and night sweats (B-symptoms) and peripheral edema. He was treated with R-CHOP (doxorubicin, vincristine, cyclophosphamide, rituximab and Prednisone) chemotherapy, a Positron emission tomography–computed tomography (PET-CT) scan was performed after four cycles of treatment which showed radiologic complete response and blood test (complete blood count (CBC)) results showed normal ranges. As of September, 2020 he patient remains in complete remission. We searched the literature for descriptions of cases spanning the diagnostic spectrum of THRLBCL and we identified only five cases worldwide. The last reported case was in 2014 with distinctive features that were difficult to classify according to the World Health Organization criteria or previously described variants. Our patient is the sixth case of THRLBCL to be reported. He is the youngest of the reported cases and the first from Israel and the Middle East.

scholarly journals Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis

2012 ◽  
Vol 209 (2) ◽  
pp. 291-305 ◽  
Author(s):  
Likun Du ◽  
Roujun Peng ◽  
Andrea Björkman ◽  
Noel Filipe de Miranda ◽  
Cornelia Rosner ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Class Switch Recombination ◽  
B Cell Lymphoma ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
End Joining ◽  
Class Switch

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.

scholarly journals Targeting ubiquitin-activating enzyme induces ER stress–mediated apoptosis in B-cell lymphoma cells

2019 ◽  
Vol 3 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Scott Best ◽  
Taylor Hashiguchi ◽  
Adam Kittai ◽  
Nur Bruss ◽  
Cody Paiva ◽  
...  
Keyword(s):  
Er Stress ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Proteasome Inhibitors ◽  
B Cell Lymphoma ◽  
Proteasome Inhibition ◽  
Cell Of Origin ◽  
Protein Ubiquitination

Abstract Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)–like ER kinase and phosphorylation of eukaryotic translation initiator factor 2α led to upregulation of the proapoptotic molecule C/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243–induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.

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