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Ghosh A, Meub M, Helmerich DA, Weingart J, Eiring P, Nerreter T, Kortüm KM, Doose S, Sauer M. Decoding the molecular interplay of CD20 and therapeutic antibodies with fast volumetric nanoscopy. Science 2025; 387:eadq4510. [PMID: 39787234 DOI: 10.1126/science.adq4510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 09/02/2024] [Accepted: 11/06/2024] [Indexed: 01/12/2025]
Abstract
Elucidating the interaction between membrane proteins and antibodies requires whole-cell imaging at high spatiotemporal resolution. Lattice light-sheet (LLS) microscopy offers fast volumetric imaging but suffers from limited spatial resolution. DNA-based point accumulation for imaging in nanoscale topography (DNA-PAINT) achieves molecular resolution but is restricted to two-dimensional imaging owing to long acquisition times. We have developed two-dye imager (TDI) probes that enable ~15-fold faster imaging. Combining TDI-DNA-PAINT and LLS microscopy on immunological B cells revealed the oligomeric states and interaction of endogenous CD20 with the therapeutic monoclonal antibodies (mAbs) rituximab, ofatumumab, and obinutuzumab. Our results demonstrate that CD20 is abundantly expressed on microvilli that bind mAbs, which leads to an antibody concentration-dependent B cell polarization and stabilization of microvilli protrusions. These findings could aid rational design of improved immunotherapies targeting tumor-associated antigens.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/chemistry
- Antibodies, Monoclonal, Humanized/immunology
- Antigens, CD20/chemistry
- Antigens, CD20/immunology
- B-Lymphocytes/immunology
- DNA/chemistry
- DNA/immunology
- Microscopy/methods
- Microvilli/immunology
- Rituximab/therapeutic use
- Rituximab/chemistry
- Molecular Imaging/methods
- Antigens, Neoplasm/chemistry
- Antigens, Neoplasm/immunology
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Affiliation(s)
- Arindam Ghosh
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Mara Meub
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Dominic A Helmerich
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Julia Weingart
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Patrick Eiring
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Thomas Nerreter
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - K Martin Kortüm
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Sören Doose
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Markus Sauer
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Würzburg, Germany
- Rudolf Virchow Center, Research Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany
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2
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McKeown JP, Byrne AJ, Bright SA, Charleton CE, Kandwal S, Čmelo I, Twamley B, McElligott AM, Fayne D, O’Boyle NM, Williams DC, Meegan MJ. Synthesis and Biochemical Evaluation of Ethanoanthracenes and Related Compounds: Antiproliferative and Pro-Apoptotic Effects in Chronic Lymphocytic Leukemia (CLL). Pharmaceuticals (Basel) 2024; 17:1034. [PMID: 39204139 PMCID: PMC11359702 DOI: 10.3390/ph17081034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 07/25/2024] [Accepted: 07/30/2024] [Indexed: 09/03/2024] Open
Abstract
Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells, and it is the most frequent form of leukemia diagnosed in Western countries. It is characterized by the proliferation and accumulation of neoplastic B lymphocytes in the blood, lymph nodes, bone marrow and spleen. We report the synthesis and antiproliferative effects of a series of novel ethanoanthracene compounds in CLL cell lines. Structural modifications were achieved via the Diels-Alder reaction of 9-(2-nitrovinyl)anthracene and 3-(anthracen-9-yl)-1-arylprop-2-en-1-ones (anthracene chalcones) with dienophiles, including maleic anhydride and N-substituted maleimides, to afford a series of 9-(E)-(2-nitrovinyl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones, 9-(E)-3-oxo-3-phenylprop-1-en-1-yl)-9,10-dihydro-9,10-[3,4]epipyrroloanthracene-12,14-diones and related compounds. Single-crystal X-ray analysis confirmed the structures of the novel ethanoanthracenes 23f, 23h, 24a, 24g, 25f and 27. The products were evaluated in HG-3 and PGA-1 CLL cell lines (representative of poor and good patient prognosis, respectively). The most potent compounds were identified as 20a, 20f, 23a and 25n with IC50 values in the ranges of 0.17-2.69 µM (HG-3) and 0.35-1.97 µM (PGA-1). The pro-apoptotic effects of the potent compounds 20a, 20f, 23a and 25n were demonstrated in CLL cell lines HG-3 (82-95%) and PGA-1 (87-97%) at 10 µM, with low toxicity (12-16%) observed in healthy-donor peripheral blood mononuclear cells (PBMCs) at concentrations representative of the compounds IC50 values for both the HG-3 and PGA-1 CLL cell lines. The antiproliferative effect of the selected compounds, 20a, 20f, 23a and 25n, was mediated through ROS flux with a marked increase in cell viability upon pretreatment with the antioxidant NAC. 25n also demonstrated sub-micromolar activity in the NCI 60 cancer cell line panel, with a mean GI50 value of 0.245 µM. This ethanoanthracene series of compounds offers potential for the further development of lead structures as novel chemotherapeutics to target CLL.
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Affiliation(s)
- James P. McKeown
- School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4/5, Dublin 2, D02 PN40 Dublin, Ireland (N.M.O.)
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
| | - Andrew J. Byrne
- School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4/5, Dublin 2, D02 PN40 Dublin, Ireland (N.M.O.)
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
| | - Sandra A. Bright
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland (D.C.W.)
| | - Clara E. Charleton
- School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4/5, Dublin 2, D02 PN40 Dublin, Ireland (N.M.O.)
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
| | - Shubhangi Kandwal
- Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
- Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
- DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
| | - Ivan Čmelo
- Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
- DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
| | - Brendan Twamley
- School of Chemistry, Trinity College Dublin, Dublin 2, D02 P3X2 Dublin, Ireland
| | - Anthony M. McElligott
- Discipline of Haematology, School of Medicine, Trinity Translational Medicine Institute, St. James’s Hospital and Trinity College, Dublin 8, D08 W9RT Dublin, Ireland;
| | - Darren Fayne
- Molecular Design Group, School of Chemical Sciences, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
- DCU Life Sciences Institute, Dublin City University, Glasnevin, D09 V209 Dublin, Ireland
| | - Niamh M. O’Boyle
- School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4/5, Dublin 2, D02 PN40 Dublin, Ireland (N.M.O.)
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
| | - D. Clive Williams
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland (D.C.W.)
| | - Mary J. Meegan
- School of Pharmacy and Pharmaceutical Sciences, Panoz Institute, Trinity College, The University of Dublin, East End 4/5, Dublin 2, D02 PN40 Dublin, Ireland (N.M.O.)
- School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St, Dublin 2, D02 R590 Dublin, Ireland
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Pulsoni A, Ferrero S, Tosti ME, Luminari S, Dondi A, Cavallo F, Merli F, Liberati AM, Cenfra N, Renzi D, Zanni M, Boccomini C, Ferreri AJM, Rattotti S, Zilioli VR, Bolis SA, Bernuzzi P, Musuraca G, Gaidano G, Perrone T, Stelitano C, Tucci A, Corradini P, Bigliardi S, Re F, Cencini E, Mannarella C, Mannina D, Celli M, Tani M, Annechini G, Assanto GM, Grapulin L, Guarini A, Cavalli M, De Novi LA, Bomben R, Ciabatti E, Genuardi E, Drandi D, Della Starza I, Arcaini L, Ricardi U, Gattei V, Galimberti S, Ladetto M, Foà R, Del Giudice I. Local radiotherapy and measurable residual disease-driven immunotherapy in patients with early-stage follicular lymphoma (FIL MIRO): final results of a prospective, multicentre, phase 2 trial. Lancet Haematol 2024; 11:e499-e509. [PMID: 38937025 DOI: 10.1016/s2352-3026(24)00143-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 06/29/2024]
Abstract
BACKGROUND The mainstay of treatment for early-stage follicular lymphoma is local radiotherapy, with a possible role for anti-CD20 monoclonal antibody (mAb). We aimed to evaluate the effect of these treatments using a measurable residual disease (MRD)-driven approach. METHODS This prospective, multicentre, phase 2 trial was conducted at 27 centres of the Fondazione Italiana Linfomi (FIL) in Italy. Eligible participants were adults (≥18 years) with newly diagnosed, histologically confirmed follicular lymphoma (stage I or II; grade I-IIIa). Patients were initially treated with 24 Gy involved-field radiotherapy over 12 days; those who were MRD-positive after radiotherapy or during follow-up received eight intravenous doses (1000 mg per dose; one dose per week) of the anti-CD20 mAb ofatumumab. The primary endpoint was the proportion of patients who were MRD-positive after involved-field radiotherapy and became MRD-negative after ofatumumab treatment. Patients were included in the primary endpoint analysis population if they were positive for BCL2::IGH rearrangement at enrolment in peripheral blood or bone marrow samples. MRD positivity was defined as the persistence of BCL2::IGH rearrangement in peripheral blood or bone marrow, assessed centrally by laboratories of the FIL MRD Network. The trial was registered with EudraCT, 2012-001676-11. FINDINGS Between May 2, 2015, and June 1, 2018, we enrolled 110 participants, of whom 106 (96%) were eligible and received involved-field radiotherapy. Of these, 105 (99%) were White, one (1%) was Black, 50 (47%) were male, and 56 (53%) were female. Of 105 participants in whom BCL2::IGH status was evaluable, 32 (30%) had a detectable BCL2::IGH rearrangement at baseline. After radiotherapy, 12 (40%) of 30 patients reached MRD-negative status, which was long-lasting (at least 36 or 42 months) in three (25%). In those who were MRD-positive after radiotherapy, ofatumumab induced MRD-negativity in 23 (92%; 95% CI 74-99) of 25 evaluable patients. After a median follow-up of 46·1 months (IQR 42·8-50·8), 14 (61%) of these 23 patients remain in complete response and are MRD-negative. The most common grade 3-4 adverse events were infusion-related reactions, observed in four patients. INTERPRETATION Local radiotherapy is frequently not associated with the eradication of follicular lymphoma. An MRD-driven, anti-CD20 monoclonal antibody consolidation enables molecular remission to be reached in almost all patients and is associated with a reduced incidence of relapse over time. A clinical advantage of an MRD-driven consolidation is therefore suggested. FUNDING AIRC Foundation for Cancer Research in Italy, Novartis International, and GlaxoSmithKline.
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Affiliation(s)
- Alessandro Pulsoni
- Hematology, Department of Translational and Precision Medicine, Sapienza University-Polo Pontino, S.M. Goretti Hospital, Latina, Italy.
| | - Simone Ferrero
- Hematology Division, Department of Molecular Biotechnologies and Health Sciences, University of Torino/AOU "Città della Salute e della Scienza di Torino", Turin, Italy
| | - Maria Elena Tosti
- Istituto Superiore di Sanità, National Center for Global Health, Rome, Italy
| | - Stefano Luminari
- Hematology Unit, Arcispedale S Maria Nuova, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy; Department CHIMOMO, University of Modena and Reggio Emilia, Reggio Emilia, Italy
| | | | - Federica Cavallo
- Hematology Division, Department of Molecular Biotechnologies and Health Sciences, University of Torino/AOU "Città della Salute e della Scienza di Torino", Turin, Italy
| | - Francesco Merli
- Hematology Unit, Arcispedale S Maria Nuova, Azienda Unità Sanitaria Locale-IRCCS, Reggio Emilia, Italy
| | | | - Natalia Cenfra
- Hematology Unit, S Maria Goretti Hospital, AUSL Latina, Latina, Italy
| | - Daniela Renzi
- Hematology and Stem Cells Transplantation Unit, IRCCS Istituto Nazionale dei Tumori Regina Elena, Rome, Italy
| | - Manuela Zanni
- Division of Hematology, SS Antonio e Biagio Hospital, Alessandria, Italy
| | - Carola Boccomini
- SC Hematology, AOU Città della Salute e della Scienza, Turin, Italy
| | - Andrés J M Ferreri
- Lymphoma Unit, IRCCS San Raffaele Scientific Institute, University Vita-Salute San Raffaele, Milan, Italy
| | - Sara Rattotti
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | | | - Silvia Anna Bolis
- Struttura Complessa di Ematologia, Fondazione IRCCS San Gerardo dei Tintori-Monza, Monza, Italy
| | - Patrizia Bernuzzi
- Hematology Unit, Department of Onco-Hematology, Guglielmo da Saliceto Hospital, Piacenza, Italy
| | - Gerardo Musuraca
- Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
| | - Tommasina Perrone
- Unit of Hematology with Transplantation, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
| | - Caterina Stelitano
- Department of Hematology, Azienda Ospedaliera Bianchi Melacrinò Morelli, Reggio Calabria, Italy
| | | | - Paolo Corradini
- Division of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
| | - Sara Bigliardi
- Onco-Hematology Department, Nuovo Ospedale Civile di Sassuolo, Sassuolo, Italy
| | | | - Emanuele Cencini
- Unit of Hematology, Azienda Ospedaliera Universitaria Senese and University of Siena, Siena, Italy
| | | | - Donato Mannina
- Department of Hematology, Azienda Ospedaliera Papardo, Messina, Italy
| | | | - Monica Tani
- Hematology Unit, Santa Maria delle Croci Hospital, Ravenna, Italy
| | - Giorgia Annechini
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Giovanni Manfredi Assanto
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Lavinia Grapulin
- Department of Radiotherapy, AOU Policlinico Umberto I, Rome, Italy
| | - Anna Guarini
- Hematology, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Marzia Cavalli
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Lucia Anna De Novi
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Riccardo Bomben
- Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Elena Ciabatti
- Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Elisa Genuardi
- Hematology Division, Department of Molecular Biotechnologies and Health Sciences, University of Torino/AOU "Città della Salute e della Scienza di Torino", Turin, Italy
| | - Daniela Drandi
- Hematology Division, Department of Molecular Biotechnologies and Health Sciences, University of Torino/AOU "Città della Salute e della Scienza di Torino", Turin, Italy
| | - Irene Della Starza
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy; AIL Roma, ODV, Rome, Italy
| | - Luca Arcaini
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Umberto Ricardi
- Radiation Oncology, Department of Oncology, University of Turin, Turin, Italy
| | - Valter Gattei
- Clinical and Experimental Onco-Hematology Unit, CRO Aviano National Cancer Institute, Aviano, Italy
| | - Sara Galimberti
- Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Marco Ladetto
- Department of Translational Medicine, SCDU Ematologia AO SS Antonio e Biagio E Cesare Arrigo, Università del Piemonte Orientale, Alessandria, Italy
| | - Robin Foà
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Ilaria Del Giudice
- Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.
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Tang L, Huang Z, Mei H, Hu Y. Immunotherapy in hematologic malignancies: achievements, challenges and future prospects. Signal Transduct Target Ther 2023; 8:306. [PMID: 37591844 PMCID: PMC10435569 DOI: 10.1038/s41392-023-01521-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 05/31/2023] [Accepted: 06/04/2023] [Indexed: 08/19/2023] Open
Abstract
The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.
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Affiliation(s)
- Lu Tang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, 430022, Wuhan, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, 430022, Wuhan, China
| | - Zhongpei Huang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, 430022, Wuhan, China
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, 430022, Wuhan, China
| | - Heng Mei
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, 430022, Wuhan, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, 430022, Wuhan, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
- Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease, 430022, Wuhan, China.
- Key Laboratory of Biological Targeted Therapy, the Ministry of Education, 430022, Wuhan, China.
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
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Iyer P, Wang L. Emerging Therapies in CLL in the Era of Precision Medicine. Cancers (Basel) 2023; 15:1583. [PMID: 36900373 PMCID: PMC10000606 DOI: 10.3390/cancers15051583] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 02/27/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
Over the past decade, the treatment landscape of CLL has vastly changed from the conventional FC (fludarabine and cyclophosphamide) and FCR (FC with rituximab) chemotherapies to targeted therapies, including inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) as well as inhibitors of BCL2. These treatment options dramatically improved clinical outcomes; however, not all patients respond well to these therapies, especially high-risk patients. Clinical trials of immune checkpoint inhibitors (PD-1, CTLA4) and chimeric antigen receptor T (CAR T) or NK (CAR NK) cell treatment have shown some efficacy; still, long-term outcomes and safety issues have yet to be determined. CLL remains an incurable disease. Thus, there are unmet needs to discover new molecular pathways with targeted or combination therapies to cure the disease. Large-scale genome-wide whole-exome and whole-genome sequencing studies have discovered genetic alterations associated with disease progression, refined the prognostic markers in CLL, identified mutations underlying drug resistance, and pointed out critical targets to treat the disease. More recently, transcriptome and proteome landscape characterization further stratified the disease and revealed novel therapeutic targets in CLL. In this review, we briefly summarize the past and present available single or combination therapies, focusing on potential emerging therapies to address the unmet clinical needs in CLL.
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Affiliation(s)
- Prajish Iyer
- Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, CA 91007, USA
| | - Lili Wang
- Department of Systems Biology, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Monrovia, CA 91007, USA
- Toni Stephenson Lymphoma Center, Beckman Research Institute, City of Hope National Comprehensive Cancer Center, Duarte, CA 91016, USA
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6
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Jacobsen E. Follicular lymphoma: 2023 update on diagnosis and management. Am J Hematol 2022; 97:1638-1651. [PMID: 36255040 DOI: 10.1002/ajh.26737] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 01/31/2023]
Abstract
DISEASE OVERVIEW Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. FL is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma. DIAGNOSIS The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0-1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis. RISK-ADAPTED THERAPY Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival (OS) advantage for early treatment with either chemotherapy or single-agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved overall response rates (ORR), DOR, and OS. Randomized studies have shown additional benefits for maintenance of rituximab. Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, stem cell transplantation (SCT), and chimeric antigen receptor T cells (CAR-T) are also considered for recurrent disease.
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Affiliation(s)
- Eric Jacobsen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
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7
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Alabdaljabar MS, Durani U, Thompson CA, Constine LS, Hashmi SK. The forgotten survivor: A comprehensive review on Non-Hodgkin lymphoma survivorship. Am J Hematol 2022; 97:1627-1637. [PMID: 36069675 DOI: 10.1002/ajh.26719] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 08/15/2022] [Accepted: 08/23/2022] [Indexed: 01/31/2023]
Abstract
The number of non-Hodgkin lymphoma (NHL) survivors is increasing. With the advancement of NHL therapies, it is crucial to focus on the challenges these survivors may face. Three main categories are to be considered in NHL survivorship, including quality of life and uncertainty about the future, possible physical health complications (including cardiovascular disease, infertility, and subsequent neoplasms), and the impact of novel NHL treatments and their potential complications. The latter includes CAR T-cell therapy, monoclonal antibodies, checkpoint inhibitors, and hematopoietic stem cell transplantation. In this report, we aim to shed the light on these aspects and to discuss survivorship care plan for NHL.
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Affiliation(s)
| | - Urshila Durani
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Carrie A Thompson
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Louis S Constine
- Departments of Radiation Oncology and Pediatrics, University of Rochester Medical Center, New York City, New York, USA
| | - Shahrukh K Hashmi
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Sheikh Shakhbout Medical City / Mayo Clinic, Abu Dhabi, United Arab Emirates
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8
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Lanier OL, Pérez-Herrero E, Andrea APD, Bahrami K, Lee E, Ward DM, Ayala-Suárez N, Rodríguez-Méndez SM, Peppas NA. Immunotherapy approaches for hematological cancers. iScience 2022; 25:105326. [PMID: 36325064 PMCID: PMC9619355 DOI: 10.1016/j.isci.2022.105326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hematological cancers such as leukemia, lymphoma, and multiple myeloma have traditionally been treated with chemo and radiotherapy approaches. Introduction of immunotherapies for treatment of these diseases has led to patient remissions that would not have been possible with traditional approaches. In this critical review we identify main disease characteristics, symptoms, and current treatment options. Five common immunotherapies, namely checkpoint inhibitors, vaccines, cell-based therapies, antibodies, and oncolytic viruses, are described, and their applications in hematological cancers are critically discussed.
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Affiliation(s)
- Olivia L. Lanier
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
| | - Edgar Pérez-Herrero
- Departamento de Ingeniería Química y Tecnología Farmacéutica, Universidad de La Laguna, La Laguna, 38206 Tenerife, Spain
- Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, 38206 Tenerife, Spain
- Instituto Universitario de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, 38200 Tenerife, Spain
| | - Abielle P. D.’ Andrea
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
| | - Kiana Bahrami
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
| | - Elaine Lee
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
| | - Deidra M. Ward
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
| | - Nilaya Ayala-Suárez
- Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, 38206 Tenerife, Spain
| | - Sheyla M. Rodríguez-Méndez
- Instituto Universitario de Bio-Orgánica Antonio González, Universidad de La Laguna, La Laguna, 38206 Tenerife, Spain
| | - Nicholas A. Peppas
- Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA
- Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA
- Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin, Austin, TX, USA
- Division of Molecular Pharmaceutics and Drug Delivery, College of Pharmacy, The University of Texas at Austin, Austin, TX, USA
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
- Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin, Austin, TX, USA
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9
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Hartinger JM, Kratky V, Hruskova Z, Slanar O, Tesar V. Implications of rituximab pharmacokinetic and pharmacodynamic alterations in various immune-mediated glomerulopathies and potential anti-CD20 therapy alternatives. Front Immunol 2022; 13:1024068. [PMID: 36420256 PMCID: PMC9676507 DOI: 10.3389/fimmu.2022.1024068] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/13/2022] [Indexed: 11/09/2022] Open
Abstract
The specific B-cell depleting anti-CD20 monoclonal antibody rituximab (RTX) is effective in terms of the treatment of various immune-mediated glomerulopathies. The administration of RTX has been shown to be reliable and highly effective particularly in patients with ANCA-associated vasculitis, which is manifested predominantly with non-nephrotic proteinuria. Stable long-term B-cell depletion is usually readily attained in such patients using standard dosing regimens. However, in patients with nephrotic syndrome and non-selective proteinuria, the RTX pharmacokinetics is altered profoundly and RTX does not maintain high enough levels for a sufficiently long period, which may render RTX treatment ineffective. Since complement-derived cytotoxicity is one of the important modes of action of RTX, hypocomplementemia, frequently associated with systemic lupus erythematodes, may act to hamper the efficacy of RTX in the treatment of patients with lupus nephritis. This review provides a description of RTX pharmacokinetics and pharmacodynamics in several selected glomerulopathies, as well as the impact of proteinuria, anti-drug antibodies and other clinical variables on the clearance and volume of distribution of RTX. The impact of plasmapheresis and peritoneal dialysis on the clearance of RTX is also discussed in the paper. A review is provided of the potential association between pharmacokinetic and pharmacodynamic alterations in various kidney-affecting glomerular diseases, the sustainability of B-cell depletion and the clinical efficacy of RTX, with proposals for potential dosing implications. The role of therapeutic drug monitoring in treatment tailoring is also discussed, and various previously tested RTX dosing schedules are compared in terms of their clinical and laboratory treatment responses. Since alternative anti-CD20 molecules may prove effective in RTX unresponsive patients, their pharmacokinetics, pharmacodynamics and current role in the treatment of glomerulopathies are also mentioned.
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Affiliation(s)
- Jan Miroslav Hartinger
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
- *Correspondence: Jan Miroslav Hartinger,
| | - Vojtech Kratky
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Zdenka Hruskova
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Ondrej Slanar
- Department of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
| | - Vladimir Tesar
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital Prague, Prague, Czechia
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10
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Forero-Torres A, Chandler JC, Iyer SP, Kanate AS, Quinlan M, Hoever P, Izquierdo M, Davis J, Madan S. Phase 1 Study Evaluating Pharmacokinetics and Tolerability of Ofatumumab Combined With Bendamustine in Patients With Indolent B-Cell Non-Hodgkin's Lymphoma. Clin Pharmacol Drug Dev 2022; 11:1099-1109. [PMID: 35819310 DOI: 10.1002/cpdd.1133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 05/30/2022] [Indexed: 01/26/2023]
Abstract
The pharmacokinetics (PK) and safety of ofatumumab and bendamustine alone and in combination were evaluated in patients with treatment-naive or relapsed indolent B-cell non-Hodgkin lymphoma (iNHL). Patients were randomly assigned to ofatumumab and bendamustine or ofatumumab alone. Ofatumumab PK concentration profiles and parameters were similar, alone or in combination with bendamustine. A decrease of 14% in the maximum observed plasma concentration (Cmax ) and 15% in the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable concentration sampling time (AUClast ) was observed for ofatumumab coadministered with bendamustine, which was not considered clinically relevant. Bendamustine PK concentration profiles and parameters were similar with or without ofatumumab. The most frequent treatment-related adverse event was infusion-related reaction in 53% in the combination arm and 47% in the ofatumumab arm. No relevant drug-drug interaction was observed between ofatumumab and bendamustine. Ofatumumab alone or in combination with bendamustine had a manageable safety profile.
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Affiliation(s)
| | | | | | | | | | | | | | - Jaclyn Davis
- Novartis Oncology, East Hanover, New Jersey, USA
| | - Sumit Madan
- Cancer Therapy & Research Center, San Antonio, Texas, USA
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11
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Anti-CD20 rechallenge with ofatumumab in relapsed/refractory splenic marginal zone lymphoma: the MORE trial. Blood Adv 2022; 6:5356-5359. [PMID: 35613463 PMCID: PMC9631708 DOI: 10.1182/bloodadvances.2022007138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/12/2022] [Indexed: 11/23/2022] Open
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12
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Paszkiewicz-Kozik E, Michalski W, Taszner M, Mordak-Domagała M, Romejko-Jarosińska J, Knopińska-Posłuszny W, Najda J, Borawska A, Chełstowska M, Świerkowska M, Dąbrowska-Iwanicka A, Malenda A, Druzd-Sitek A, Konecki R, Kumiega B, Osowiecki M, Ostrowska B, Szpila T, Szymański M, Targoński Ł, Domańska-Czyż K, Popławska L, Giebel S, Lange A, Pluta A, Zaucha JM, Rymkiewicz G, Walewski J. Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma. Br J Haematol 2022; 198:73-81. [PMID: 35362096 PMCID: PMC9322457 DOI: 10.1111/bjh.18166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/14/2022] [Accepted: 03/15/2022] [Indexed: 11/29/2022]
Abstract
The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.
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Affiliation(s)
| | - Wojciech Michalski
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Monika Mordak-Domagała
- Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland
| | | | - Wanda Knopińska-Posłuszny
- Maritime Hospital, Gdynia, Poland.,Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration's Hospital, Olsztyn, Poland
| | - Jacek Najda
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Anna Borawska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Monika Świerkowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Agata Malenda
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | | | - Robert Konecki
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Kumiega
- Sniadecki Memorial Specialist Hospital, Nowy Sacz, Poland
| | - Michał Osowiecki
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Beata Ostrowska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Tomasz Szpila
- Institute of Hematology and Transfusion Medicine, Warsaw, Poland
| | - Marcin Szymański
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Łukasz Targoński
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | | | - Lidia Popławska
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Sebastian Giebel
- Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland
| | - Andrzej Lange
- Lower Silesian Center for Cellular Transplantation with National Bone Marrow Donor Registry, Wroclaw, Poland
| | - Andrzej Pluta
- Department of Hematology, Brzozow Oncology Center, Brzozow, Poland
| | - Jan Maciej Zaucha
- Medical University of Gdansk, Gdansk, Poland.,Maritime Hospital, Gdynia, Poland
| | - Grzegorz Rymkiewicz
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - Jan Walewski
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
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13
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Choi AY, Manook M, Olaso D, Ezekian B, Park J, Freischlag K, Jackson A, Knechtle S, Kwun J. Emerging New Approaches in Desensitization: Targeted Therapies for HLA Sensitization. Front Immunol 2021; 12:694763. [PMID: 34177960 PMCID: PMC8226120 DOI: 10.3389/fimmu.2021.694763] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/24/2021] [Indexed: 01/11/2023] Open
Abstract
There is an urgent need for therapeutic interventions for desensitization and antibody-mediated rejection (AMR) in sensitized patients with preformed or de novo donor-specific HLA antibodies (DSA). The risk of AMR and allograft loss in sensitized patients is increased due to preformed DSA detected at time of transplant or the reactivation of HLA memory after transplantation, causing acute and chronic AMR. Alternatively, de novo DSA that develops post-transplant due to inadequate immunosuppression and again may lead to acute and chronic AMR or even allograft loss. Circulating antibody, the final product of the humoral immune response, has been the primary target of desensitization and AMR treatment. However, in many cases these protocols fail to achieve efficient removal of all DSA and long-term outcomes of patients with persistent DSA are far worse when compared to non-sensitized patients. We believe that targeting multiple components of humoral immunity will lead to improved outcomes for such patients. In this review, we will briefly discuss conventional desensitization methods targeting antibody or B cell removal and then present a mechanistically designed desensitization regimen targeting plasma cells and the humoral response.
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Affiliation(s)
| | | | | | | | | | | | | | - Stuart Knechtle
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC, United States
| | - Jean Kwun
- Duke Transplant Center, Department of Surgery, Duke University Medical Center, Durham, NC, United States
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14
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A phase 3 randomized study (HOMER) of ofatumumab vs rituximab in iNHL relapsed after rituximab-containing therapy. Blood Adv 2021; 4:3886-3893. [PMID: 32810220 DOI: 10.1182/bloodadvances.2020001942] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 06/15/2020] [Indexed: 02/03/2023] Open
Abstract
Because of high relapse rates with rituximab combinations, there is an unmet need for new therapeutic agents for treatment of indolent B-cell non-Hodgkin lymphoma (iNHL) or follicular lymphoma (FL). In previous trials, ofatumumab in combination with chemotherapy showed good results in relapsed/refractory FL pretreated with rituximab. This phase 3 trial evaluated the efficacy and safety of single-agent ofatumumab vs single-agent rituximab in rituximab-sensitive relapsed FL that relapsed at least 6 months after completing the last prior treatment with single-agent rituximab or a rituximab-containing regimen. Patients were randomized 1:1 to receive either ofatumumab (1000 mg) or rituximab (375 mg/m2) every week for 4 weeks for the induction phase, followed by once every 2 months for 4 additional doses. The primary endpoint, progression-free survival (PFS) and secondary endpoints, overall response rate (ORR) and overall survival (OS), were evaluated. Overall, 438 patients were assigned to receive ofatumumab (n = 219) and rituximab (n = 219). Baseline characteristics were similar in both arms. The independent review committee assessed whether median PFS was shorter in the ofatumumab arm than in the rituximab arm (16.33 vs 21.29 months), with no significant difference (hazard ratio, 1.15; 95% confidence interval, 0.89-1.49; P = .29) and also showed a lower ORR (50%) compared with the rituximab arm (66%). At the time of analysis, data were not matured for OS results. The number of grade >3 adverse events was higher in the ofatumumab arm (37%) than the rituximab arm (28%). Ofatumumab showed no superiority over rituximab in patients with FL who had relapsed after a rituximab-containing therapy. This study was registered at www.clinicaltrials.gov as #NCT01200589.
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15
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Rummel MJ, Janssens A, MacDonald D, Keating MM, Zaucha JM, Davis J, Lasher J, Babanrao Pisal C, Izquierdo M, Friedberg JW. A phase 3, randomized study of ofatumumab combined with bendamustine in rituximab-refractory iNHL (COMPLEMENT A + B study). Br J Haematol 2021; 193:1123-1133. [PMID: 33973233 DOI: 10.1111/bjh.17420] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/28/2021] [Indexed: 01/22/2023]
Abstract
The standard of care for indolent non-Hodgkin lymphoma (iNHL) is rituximab, an anti-CD20 antibody, with/without chemotherapy. However, multiple relapses are common in these patients. This phase 3, randomized study compared outcomes of a combination of ofatumumab (a second-generation anti-CD20 antibody) and bendamustine, with bendamustine alone in patients unresponsive to prior rituximab-based treatment. Overall, 346 patients were randomized to receive either the combination or bendamustine alone. Bendamustine was given for ≤8 cycles and ofatumumab for ≤12 cycles. The primary end-point was progression-free survival (PFS) after 215 protocol-defined events assessed by independent review committee (IRC). Median IRC-assessed PFS was 16·7 and 13·8 months in the combination and monotherapy arms respectively [hazard ratio (HR) = 0·82; P = 0·1390]. Median overall survival (OS) was 58·2 and 51·8 months in the combination and monotherapy arms respectively (HR = 0·89, P = 0·4968). The safety profile was consistent with previous reports. Overall, 73% and 80% of patients in the combination and monotherapy arms, respectively, experienced a ≥grade 3 adverse event. The study did not meet its primary end-point. No significant improvement in PFS and OS was seen with the combination of ofatumumab and bendamustine as compared with bendamustine alone in rituximab-refractory iNHL (NCT01077518).
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Affiliation(s)
- Mathias J Rummel
- Department for Haematology, Clinic for Haematology and Medical Oncology, Justus-Liebig University-Hospital, Gießen, Germany
| | - Ann Janssens
- Department of Haematology, Universitaire Ziekenhuizen Leuven, Leuven, Belgium
| | - David MacDonald
- Division of Haematology, Dalhousie University, Halifax, NS, Canada
| | | | - Jan M Zaucha
- Department of Haematology and Transplantology, Medical University of Gdańsk, Gdańsk, Poland
| | | | | | | | | | - Jonathan W Friedberg
- Wilmot Cancer Institute, University of Rochester Medical Centre, Rochester, NY, USA
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16
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Lyons RM, Shtivelband M, Kingsley E, Moezi M, Richards D, Sharman J, Feng X, Cannan M, Fellague-Chebra R, Boyd TE. Efficacy and safety of ofatumumab and bendamustine followed by ofatumumab maintenance in patients with relapsed indolent non-Hodgkin lymphoma after prior rituximab. Leuk Lymphoma 2021; 62:1353-1360. [PMID: 33448893 DOI: 10.1080/10428194.2020.1869957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
In indolent non-Hodgkin's lymphoma (iNHL), patients treated with rituximab, alone or in combination with various chemotherapeutic agents eventually relapse. This study evaluated the combination of ofatumumab and bendamustine, followed by maintenance ofatumumab in patients with relapsed iNHL with prior sensitivity to rituximab. Among the 49 patients enrolled, 24.5% achieved a complete response (CR) and 42.9% achieved a partial response (PR), with an overall response rate of 67.3% at the end of the induction therapy. Additionally, six patients with PR during induction phase achieved CR during the maintenance phase. Treatment-related adverse event was observed in 95.9% patients. The most common hematologic and biochemical abnormalities were decrease in lymphocytes (85.7%) and increase in glucose (91.8%), respectively. Overall, 42.9% progressed and 14.3% died during the study. Thus, ofatumumab in combination with bendamustine, followed by ofatumumab maintenance, was effective in the treatment of patients with iNHL with a manageable safety profile (NCT01294579).
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Affiliation(s)
- Roger M Lyons
- Texas Oncology, San Antonio, TX, USA.,US Oncology Research, The Woodlands, TX, USA
| | | | - Edwin Kingsley
- US Oncology Research, The Woodlands, TX, USA.,Ironwood Cancer and Research Center, Chandler, AZ, USA
| | - Mehdi Moezi
- Comprehensive Cancer Centers of Nevada, Las Vegas, NC, USA
| | - Donald Richards
- US Oncology Research, The Woodlands, TX, USA.,Tyler Cancer Center, Tyler, TX, USA
| | - Jeff Sharman
- US Oncology Research, The Woodlands, TX, USA.,Willamette Cancer Center, Eugene, OR, USA
| | - Xiaoshu Feng
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
| | - Megan Cannan
- Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA
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17
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Abstract
Pemphigus vulgaris (PV) is a severe chronic autoimmune blistering disease that affects the skin and mucous membranes. It is characterized by suprabasal acantholysis due to disruption of desmosomal connections between keratinocytes. Autoantibodies against desmosomal cadherins, desmoglein 3 and 1, have been shown to induce disease. Certain human leukocyte antigen (HLA) types and non-HLA foci confer genetic susceptibility. Until the discovery of corticosteroids in the 1950s, PV was 75% fatal. Since then, multiple PV treatments, such as systemic corticosteroids and adjunctive therapy with immunosuppressive medications (mycophenolate mofetil, azathioprine, cyclophosphamide, cyclosporine, methotrexate, gold, and others) have been introduced; however, none have led to long-term remissions and many have undesired adverse effects. Our growing understanding of the pathophysiologic mechanisms in PV is leading to development of new targeted therapies, such as intravenous immunoglobulin, anti-CD20 monoclonal antibodies, inhibitors of Bruton tyrosine kinase and neonatal Fc receptors, and adoptive cellular transfer, that may result in lasting control of this life-threatening disease.
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MESH Headings
- Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors
- Agammaglobulinaemia Tyrosine Kinase/metabolism
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antigens, CD20/immunology
- Antigens, CD20/metabolism
- Autoantibodies/immunology
- Autoantibodies/metabolism
- Combined Modality Therapy/methods
- Drug Therapy, Combination/methods
- Genetic Predisposition to Disease
- HLA Antigens/genetics
- HLA Antigens/immunology
- Histocompatibility Antigens Class I/metabolism
- Humans
- Immunoglobulins, Intravenous/pharmacology
- Immunoglobulins, Intravenous/therapeutic use
- Immunosuppressive Agents/pharmacology
- Immunosuppressive Agents/therapeutic use
- Immunotherapy, Adoptive/methods
- Molecular Targeted Therapy/methods
- Pemphigus/genetics
- Pemphigus/immunology
- Pemphigus/therapy
- Plasmapheresis
- Receptors, Fc/antagonists & inhibitors
- Receptors, Fc/metabolism
- Remission Induction/methods
- Signal Transduction/drug effects
- Signal Transduction/immunology
- Treatment Outcome
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Affiliation(s)
- Emily M Altman
- Department of Dermatology, University of New Mexico, 1021 Medical Arts Avenue NE, Albuquerque, NM, 87102, USA.
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18
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Vannata B, Vanazzi A, Negri M, Liptrott SJ, Bartosek AA, Miani M, Di Sanzo A, Cavalli F, Zucca E, Stathis A. A phase II trial of bendamustine in combination with ofatumumab in patients with relapsed or refractory marginal zone B-cell lymphomas. Hematol Oncol 2020; 39:60-65. [PMID: 33103778 DOI: 10.1002/hon.2822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/12/2020] [Accepted: 10/19/2020] [Indexed: 11/08/2022]
Abstract
Marginal zone lymphomas (MZLs) are indolent yet incurable lymphomas with frequent relapses following therapy. For patients with relapsed/refractory disease, no standard therapies exist. Here we report results of an exploratory phase II study aimed at assessing the efficacy and safety of the alkylator agent bendamustine in combination with the second-generation anti-CD20 monoclonal antibody, ofatumumab, in patients with relapsed or refractory MZL. Patients with MZL and previously treated with at least one line of systemic therapy were eligible. Treatment consisted in bendamustine (90 mg/m2 on days 1 and 2) and ofatumumab (1000 mg on day 1) in 28-day cycles for up to six cycles. Sixteen patients were included in the trial. In one patient, the diagnosis was revised after two cycles of treatment and was excluded from the efficacy analysis. Among 15 patients with MZL, 14 were evaluable for response: the overall and complete response rates were 92.9% and 57.1%, respectively. The median duration of response was 30.4 months (95% confidence interval [CI], 15.5 -not estimable) and 2-years progression-free survival 77% (95% CI, 43%-92%). Fifteen patients (94%) experienced grade 3-4 adverse events. Toxicity was mostly hematological. Neutropenia grade ≥3 was recorded in 27% of patients, lymphocytopenia in 93%, and infections and febrile neutropenia each in 13%. One patient discontinued treatment due to myocardial infarction; no treatment-related deaths occurred. The combination of bendamustine with ofatumumab was active with an acceptable toxicity profile in this small phase II trial and can be considered for further investigation in relapsed/refractory MZL patients.
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Affiliation(s)
- Barbara Vannata
- Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland
| | - Anna Vanazzi
- Division of Clinical Hemato-Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Mara Negri
- Division of Clinical Hemato-Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Sarah Jayne Liptrott
- Division of Clinical Hemato-Oncology, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | | | - Monica Miani
- Nerviano Medical Sciences S.r.l, Nerviano, Milan, Italy
| | | | - Franco Cavalli
- Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Institute of Oncology Research (IOR), Bellinzona, Switzerland
| | - Emanuele Zucca
- Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Institute of Oncology Research (IOR), Bellinzona, Switzerland
| | - Anastasios Stathis
- Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.,Faculty of Biomedical Sciences, Università della Svizzera italiana (USI), Lugano, Switzerland
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19
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Bordron A, Bagacean C, Tempescul A, Berthou C, Bettacchioli E, Hillion S, Renaudineau Y. Complement System: a Neglected Pathway in Immunotherapy. Clin Rev Allergy Immunol 2020; 58:155-171. [PMID: 31144209 DOI: 10.1007/s12016-019-08741-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Approved for the treatment of autoimmune diseases, hematological malignancies, and solid cancers, several monoclonal antibodies (mAb) make use of complement in their mechanism of action. Such an assessment is based on comprehensive investigations that used mouse models, in vitro studies, and analyses from patients at initiation (basal level to highlight deficiencies) and after treatment initiation (mAb impact on complement), which have further provided key insights into the importance of the complement activation and/or complement deficiencies in mAb activity. Accordingly, new approaches can now be developed with the final objective of increasing the clinical efficacy of mAb. These improvements include (i) the concurrent administration of fresh frozen plasma during mAb therapy; (ii) mAb modifications such as immunoglobulin G subclass switching, Fc mutation, or IgG hexamerization to improve the fixation and activation of C1q; (iii) optimization of the target recognition to induce a higher complement-dependent cytotoxicity (CDC) and/or complement-dependant cellular cytotoxicity (CDCC); and (iv) the control of soluble and cellular complement inhibitors.
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Affiliation(s)
- Anne Bordron
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France
| | - Cristina Bagacean
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France.,Service d'Hématologie, CHU de Brest, Brest, France
| | - Adrian Tempescul
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France.,Service d'Hématologie, CHU de Brest, Brest, France
| | - Christian Berthou
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France.,Service d'Hématologie, CHU de Brest, Brest, France
| | | | - Sophie Hillion
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France.,Laboratory of Immunology and Immunotherapy, CHU de Brest, Brest, France
| | - Yves Renaudineau
- Inserm UMR1227, B lymphocytes and autoimmunity, University of Brest, Brest, France. .,Laboratory of Immunology and Immunotherapy, CHU de Brest, Brest, France.
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20
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Shi S, Vissapragada R, Abi Jaoude J, Huang C, Mittal A, Liu E, Zhong J, Kumar V. Evolving role of biomaterials in diagnostic and therapeutic radiation oncology. Bioact Mater 2020; 5:233-240. [PMID: 32123777 PMCID: PMC7036731 DOI: 10.1016/j.bioactmat.2020.01.011] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 01/24/2020] [Accepted: 01/30/2020] [Indexed: 01/11/2023] Open
Abstract
Radiation therapy to treat cancer has evolved significantly since the discovery of x-rays. Yet, radiation therapy still has room for improvement in reducing side effects and improving control of cancer. Safer and more effective delivery of radiation has led us to novel techniques and use of biomaterials. Biomaterials in combination with radiation and chemotherapy have started to appear in pre-clinical explorations and clinical applications, with many more on the horizon. Biomaterials have revolutionized the field of diagnostic imaging, and now are being cultivated into the field of theranostics, combination therapy, and tissue protection. This review summarizes recent development of biomaterials in radiation therapy in several application areas.
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Affiliation(s)
- Siyu Shi
- Department of Medicine, Stanford School of Medicine, Stanford, CA, 94305, USA
| | - Ravi Vissapragada
- College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
| | | | - Caroline Huang
- Department of Medicine, Stanford School of Medicine, Stanford, CA, 94305, USA
| | - Anmol Mittal
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, 07102, USA
| | - Elisa Liu
- Department of Medicine, Stanford School of Medicine, Stanford, CA, 94305, USA
| | - Jim Zhong
- Department of Radiation Oncology, Emory University, Atlanta, GA, 30332, USA
| | - Vivek Kumar
- Department of Restorative Dentistry, Rutgers School of Dental Medicine, Newark, NJ, 07103, USA
- Department of Chemical and Materials Engineering, New Jersey Institute of Technology, 07102, USA
- Department of Biomedical Engineering, New Jersey Institute of Technology, 07102, USA
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21
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Freedman A, Jacobsen E. Follicular lymphoma: 2020 update on diagnosis and management. Am J Hematol 2020; 95:316-327. [PMID: 31814159 DOI: 10.1002/ajh.25696] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 12/05/2019] [Indexed: 12/13/2022]
Abstract
DISEASE OVERVIEW Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma. DIAGNOSIS The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10 and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age > 60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0-1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis. RISK-ADAPTED THERAPY Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival advantage for early treatment with either chemotherapy or single agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved response rates, duration of response and overall survival (OS). Randomized studies have shown additional benefit for maintenance rituximab. Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, other immunotherapies, and stem cell transplantation (SCT) are also considered for recurrent disease.
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Affiliation(s)
- Arnold Freedman
- Department of Medical OncologyDana‐Farber Cancer Institute Boston Massachusetts
| | - Eric Jacobsen
- Department of Medical OncologyDana‐Farber Cancer Institute Boston Massachusetts
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22
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Jin N, Lee JW, Heo W, Ryu MY, So MK, Ko BJ, Kim HY, Yoon SM, Lee J, Kim JY, Kim WT. Low binding affinity and reduced complement-dependent cell death efficacy of ofatumumab produced using a plant system (Nicotiana benthamiana L.). Protein Expr Purif 2019; 159:34-41. [PMID: 30880170 DOI: 10.1016/j.pep.2019.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/26/2019] [Accepted: 03/11/2019] [Indexed: 01/16/2023]
Abstract
The plant protein production system is a platform that can not only reduce production costs but also produce monoclonal antibodies that do not have the risk of residual proteins from the host. However, due to the difference between post-translational processes in plants and animals, there may be a modification in the Fab region of the monoclonal antibody produced in the plant; thus, it is necessary to compare the antigen affinity of this antibody with that of the prototype. In this study, ofatumumab, a fully human anti-CD20 IgG1κ monoclonal antibody used for its non-cross resistance to rituximab, was expressed in Nicotiana benthamiana, and its affinities and efficacies were compared with those of native ofatumumab produced from CHO cells. Two forms of plant ofatumumab (with or without HDEL-tag) were generated and their production yields were compared. The HDEL-tagged ofatumumab was more expressed in plants than the form without HDEL-tag. The specificity of the target recognition of plant-derived ofatumumab was confirmed by mCherry-CD20-expressing HEK cells via immuno-staining, and the capping of CD20 after ofatumumab binding was also confirmed using Ramos B cells. In the functional equivalence tests, the binding affinities and complement-dependent cell cytotoxicity efficacy of plant-ofatumumab-HDEL and plant-ofatumumab without HDEL were significantly reduced compared to those of CHO-derived ofatumumab. Therefore, we suggest that although ofatumumab is not a good candidate as a template for plant-derived monoclonal antibodies because of its decreased affinity when produced in plants, it is an interesting target to study the differences between post-translational modifications in mammals and plants.
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Affiliation(s)
- Narae Jin
- Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Jin Won Lee
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
| | - Woon Heo
- Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Moon Young Ryu
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea; Institute of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
| | - Min Kyung So
- New Drug Development Center, Osong Medical Innovation Foundation, 123, Osongsaengmyeong-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk, Republic of Korea.
| | - Byoung Joon Ko
- New Drug Development Center, Osong Medical Innovation Foundation, 123, Osongsaengmyeong-ro, Osong-eup, Heungdeok-gu, Cheongju-si, Chungbuk, Republic of Korea.
| | - Hye-Yeon Kim
- Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Sei Mee Yoon
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea; Department of Integrated OMICS for Biomedical Sciences, Yonsei University, Seoul, 03722, Republic of Korea.
| | - Jinu Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, 21983, Republic of Korea.
| | - Joo Young Kim
- Department of Pharmacology and Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
| | - Woo Taek Kim
- Department of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea; Institute of Life Science and Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
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23
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Vicioso Y, Gram H, Beck R, Asthana A, Zhang K, Wong DP, Letterio J, Parameswaran R. Combination Therapy for Treating Advanced Drug-Resistant Acute Lymphoblastic Leukemia. Cancer Immunol Res 2019; 7:1106-1119. [PMID: 31138521 DOI: 10.1158/2326-6066.cir-19-0058] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 03/05/2019] [Accepted: 05/21/2019] [Indexed: 12/23/2022]
Abstract
Drug-resistant acute lymphoblastic leukemia (ALL) patients do not respond to standard chemotherapy, and an urgent need exists to develop new treatment strategies. Our study exploited the presence of B-cell activating factor receptor (BAFF-R) on the surface of drug-resistant B-ALL cells as a therapeutic target. We used anti-BAFF-R (VAY736), optimized for natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), to kill drug-resistant ALL cells. VAY736 antibody and NK cell treatments significantly decreased ALL disease burden and provided survival benefit in vivo However, if the disease was advanced, the ADCC efficacy of NK cells was inhibited by microenvironmental transforming growth factor-beta (TGFβ). Inhibiting TGFβ signaling in NK cells using the TGFβ receptor 1 (R1) inhibitor (EW-7197) significantly enhanced VAY736-induced NK cell-mediated ALL killing. Our results highlight the potential of using a combination of VAY736 antibody with EW-7197 to treat advance-stage, drug-resistant B-ALL patients.
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Affiliation(s)
- Yorleny Vicioso
- Department of pathology, Case Western Reserve University, Cleveland, Ohio
| | - Hermann Gram
- Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Rose Beck
- Department of pathology, Case Western Reserve University, Cleveland, Ohio.,Department of Pathology, University Hospitals, Cleveland, Ohio
| | - Abhishek Asthana
- Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Keman Zhang
- Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Derek P Wong
- Department of pathology, Case Western Reserve University, Cleveland, Ohio
| | - John Letterio
- The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.,Pediatric Hematology and Oncology, The Angie Fowler Adolescent and Young Adult Cancer Institute, University Hospitals Rainbow Babies and Children's Hospital, Cleveland, Ohio
| | - Reshmi Parameswaran
- Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio. .,The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
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24
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Rosenbaum CA, Jung SH, Pitcher B, Bartlett NL, Smith SM, Hsi E, Wagner-Johnston N, Thomas SP, Leonard JP, Cheson BD. Phase 2 multicentre study of single-agent ofatumumab in previously untreated follicular lymphoma: CALGB 50901 (Alliance). Br J Haematol 2019; 185:53-64. [PMID: 30723894 DOI: 10.1111/bjh.15768] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/05/2018] [Indexed: 11/28/2022]
Abstract
Rituximab monotherapy has proven efficacy in treatment-naïve, asymptomatic advanced-stage follicular lymphoma (FL). Ofatumumab is a fully humanized anti-CD20 monoclonal antibody with increased CD20 affinity and complement-dependent cytotoxicity. This phase 2 trial (NCT01190449) evaluated ofatumumab in patients with untreated, low/intermediate-risk FL International Prognostic Index (FLIPI), advanced-stage FL to determine single-agent efficacy. Patients with measurable disease in stages III/IV or bulky stage II, regardless of Groupe d'Etude des Lymphomes Folliculaires criteria, received 4 weekly 1000 mg doses followed by four extended induction doses once every 8 weeks. Primary endpoint was overall response rate (ORR) to 1000 mg; secondary endpoints were progression-free survival (PFS) and safety. Fifty-one patients were enrolled. Fifteen patients were randomized to 500 mg prior to discontinuing that arm for slow accrual. Among 36 patients on the 1000 mg arm, ORR was 84%, median PFS was 1·9 years and median response duration was 23·7 months. All patients remain alive. No grade 4 infusion reactions or grade 3/4 infections occurred. Grade 3 infusion reactions occurred in 25% in the 1000 mg arm only (all first infusion); all but two patients continued on study. Discontinuation was 6% for the total study population. Ofatumumab monotherapy administered by extended induction in untreated, low/intermediate-risk FLIPI, advanced-stage FL is well tolerated and active. Activity appears similar to that reported with single-agent rituximab.
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Affiliation(s)
- Cara A Rosenbaum
- Meyer Cancer Center, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, NY, USA
| | | | - Brandelyn Pitcher
- MD Anderson Cancer Center, Houston, TX, USA.,Alliance Statistics and Data Center, Duke University, Durham, NC, USA
| | - Nancy L Bartlett
- Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Sonali M Smith
- University of Chicago Comprehensive Cancer Center, Chicago, IL, USA
| | - Eric Hsi
- Cleveland Clinic, Cleveland, OH, USA
| | | | | | - John P Leonard
- Meyer Cancer Center, Weill Medical College of Cornell University and New York-Presbyterian Hospital, New York, NY, USA
| | - Bruce D Cheson
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, USA
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25
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Sutamtewagul G, Link BK. Novel treatment approaches and future perspectives in follicular lymphoma. Ther Adv Hematol 2019; 10:2040620718820510. [PMID: 30719267 PMCID: PMC6348550 DOI: 10.1177/2040620718820510] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/30/2018] [Indexed: 12/14/2022] Open
Abstract
Follicular lymphoma (FL) is a common B-cell malignancy characterized by relatively indolent growth and incurability with an expected lifetime course of serial intermittent treatment courses. Many patients with FL have lives shortened by the disease and despite a relatively favorable prognosis relative to other incurable systemic malignancies, optimal management of FL has not been achieved. This review focuses on identifying both patients for whom novel therapies might be most beneficial as well as systematically reviewing novel strategies at various levels of investigation. Prognostic markers incorporating clinical measurements and tumor genetics are discussed, yet at the time of diagnosis do not yet powerfully discriminate patients for whom specific strategies are beneficial. Reassessment of prognosis after evaluating the response to initial therapy is the most powerful identifier of those in need of novel management strategies. For initial therapy of high burden systemic disease, anti-CD20 antibody along with chemotherapy or immunomodulators all offer relatively similar effects on overall survival with subtly different effects on progression-free survival and quality of life. Several new agents currently under investigation in the upfront setting are discussed. Perhaps the best testing ground for novel therapies is in patients with early relapse following initial immunochemotherapy. Ongoing research in multiple therapy classes including, novel monoclonal antibodies, antibody drug conjugates, immunomodulatory agents, intracellular pathway inhibitors, immune checkpoint inhibitors, and epigenetic regulators are discussed herein.
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Affiliation(s)
- Grerk Sutamtewagul
- Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr., C305 GH, Iowa City, IA 52242, USA
| | - Brian K. Link
- Division of Hematology, Oncology, and Blood & Marrow Transplantation, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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26
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Norman JE, Schouten HC, Dreger P, Robinson SP. The role of stem cell transplantation in the management of relapsed follicular lymphoma in the era of targeted therapies. Bone Marrow Transplant 2018; 54:787-797. [DOI: 10.1038/s41409-018-0372-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/06/2023]
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27
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Lei L, Muhammad S, Al-Obaidi M, Sebire N, Cheng IL, Eleftheriou D, Brogan P. Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C δ. Pediatr Rheumatol Online J 2018; 16:61. [PMID: 30257684 PMCID: PMC6158832 DOI: 10.1186/s12969-018-0278-1] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 09/18/2018] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND We previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE. CASE PRESENTATION All three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency. CONCLUSIONS PKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.
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Affiliation(s)
| | - Sabina Muhammad
- 0000 0004 5902 9895grid.424537.3Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - Muthana Al-Obaidi
- 0000 0004 5902 9895grid.424537.3Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - Neil Sebire
- grid.420468.cDepartment of Paediatric Histopathology, Great Ormond Street Hospital, London, UK
| | - Iek Leng Cheng
- 0000 0004 5902 9895grid.424537.3Paediatric Rheumatology Department, Great Ormond Street Hospital for Children NHS Trust, London, UK
| | - Despina Eleftheriou
- 0000000121901201grid.83440.3bInfection, Inflammation and Rheumatology Section, Infection, Immunity, Inflammation and Physiological Medicine Programme, UCL Institute of Child Health, London, UK ,ARUK centre for adolescent rheumatology, London, UK
| | - Paul Brogan
- 0000000121901201grid.83440.3bInfection, Inflammation and Rheumatology Section, Infection, Immunity, Inflammation and Physiological Medicine Programme, UCL Institute of Child Health, London, UK
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28
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Casan JML, Wong J, Northcott MJ, Opat S. Anti-CD20 monoclonal antibodies: reviewing a revolution. Hum Vaccin Immunother 2018; 14:2820-2841. [PMID: 30096012 PMCID: PMC6343614 DOI: 10.1080/21645515.2018.1508624] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/14/2018] [Accepted: 08/02/2018] [Indexed: 12/23/2022] Open
Abstract
Since the inception of rituximab in the 1990s, anti-CD20 monoclonal antibodies have revolutionised the treatment of B cell hematological malignancies and have become a cornerstone of modern gold-standard practice. Additionally, the potent efficacy of these agents in depleting the B cell compartment has been used in the management of a broad array of autoimmune diseases. Multiple iterations of these agents have been investigated and are routinely used in clinical practice. In this review, we will discuss the physiology of CD20 and its attractiveness as a therapeutic target, as well as the pharmacology, pre-clinical and clinical data for the major anti-CD20 monoclonal antibodies: rituximab, obinutuzumab and ofatumumab.
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Affiliation(s)
- J. M. L. Casan
- Haematology Department, Monash Health, Melbourne Australia
| | - J. Wong
- Haematology Department, Monash Health, Melbourne Australia
| | - M. J. Northcott
- Rheumatology Department, Monash Health, Melbourne, Australia
- School of Clinical Sciences, Monash University, Melbourne, Australia
| | - S. Opat
- Haematology Department, Monash Health, Melbourne Australia
- School of Clinical Sciences, Monash University, Melbourne, Australia
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29
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Robertson MJ, Stamatkin CW, Pelloso D, Weisenbach J, Prasad NK, Safa AR. A Dose-escalation Study of Recombinant Human Interleukin-18 in Combination With Ofatumumab After Autologous Peripheral Blood Stem Cell Transplantation for Lymphoma. J Immunother 2018; 41:151-157. [PMID: 29517616 PMCID: PMC5847481 DOI: 10.1097/cji.0000000000000220] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Interleukin-18 (IL-18) is an immunostimulatory cytokine that augments antibody-dependent cellular cytotoxicity mediated by human natural killer cells against antibody-coated lymphoma cells in vitro and that has antitumor activity in animal models. Ofatumumab is a CD20 monoclonal antibody with activity against human B-cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with ofatumumab was undertaken in patients with CD20 lymphoma who had undergone high-dose chemotherapy and autologous peripheral blood stem cell transplantation. Cohorts of 3 patients were given intravenous infusions of ofatumumab 1000 mg weekly for 4 weeks with escalating doses of rhIL-18 as a intravenous infusion weekly for 8 consecutive weeks. Nine male patients with CD20 lymphomas were given ofatumumab in combination with rhIL-18 at doses of 3, 10, and 30 μg/kg. No unexpected or dose-limiting toxicities were observed. The mean reduction from predose levels in the number of peripheral blood natural killer cells after the first rhIL-18 infusion was 91%, 96%, and 97% for the 3, 10, and 30 μg/kg cohorts, respectively. Serum concentrations of interferon-γ and chemokines transiently increased following IL-18 dosing. rhIL-18 can be given in biologically active doses by weekly infusions in combination with ofatumumab after peripheral blood stem cell transplantation to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus ofatumumab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B-cell malignancies are warranted.
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Affiliation(s)
- Michael J. Robertson
- Lymphoma Program and Bone Marrow and Stem Cell Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Christopher W. Stamatkin
- Therapeutic Validation Core, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
| | - David Pelloso
- Lymphoma Program and Bone Marrow and Stem Cell Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Jill Weisenbach
- Lymphoma Program and Bone Marrow and Stem Cell Transplantation Program, Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Nagendra K. Prasad
- Therapeutic Validation Core, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
| | - Ahmad R. Safa
- Therapeutic Validation Core, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN
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30
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Viala M, Vinches M, Alexandre M, Mollevi C, Durigova A, Hayaoui N, Homicsko K, Cuenant A, Gongora C, Gianni L, Tosi D. Strategies for clinical development of monoclonal antibodies beyond first-in-human trials: tested doses and rationale for dose selection. Br J Cancer 2018; 118:679-697. [PMID: 29438365 PMCID: PMC5846071 DOI: 10.1038/bjc.2017.473] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 11/29/2017] [Accepted: 11/30/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results. RESULTS In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD. CONCLUSIONS The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.
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Affiliation(s)
- Marie Viala
- Institut du Cancer de Montpellier, Montpellier, France
| | - Marie Vinches
- Institut du Cancer de Montpellier, Montpellier, France
| | | | | | | | - Nadia Hayaoui
- Institut du Cancer de Montpellier, Montpellier, France
| | | | - Alice Cuenant
- Institut du Cancer de Montpellier, Montpellier, France
| | - Céline Gongora
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194, Montpellier, France
| | - Luca Gianni
- San Raffaele – Scientific Institute, Milan, Italy
| | - Diego Tosi
- Institut du Cancer de Montpellier, Montpellier, France
- Institut de Recherche en Cancérologie de Montpellier, Inserm U1194, Montpellier, France
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Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. LANCET HAEMATOLOGY 2018; 4:e46-e55. [PMID: 28041583 DOI: 10.1016/s2352-3026(16)30171-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2016] [Revised: 11/02/2016] [Accepted: 11/03/2016] [Indexed: 01/05/2023]
Abstract
BACKGROUND In 2011 we reported a rituximab plus miniCHOP (reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone) combination for patients older than 80 years with diffuse large B-cell lymphoma (DLBCL). The 2-year overall survival was 59% (95% CI 49-67) with an excess of early toxicity. To improve those results we tested the same chemotherapy protocol in combination with ofatumumab and a pre-phase treatment. METHODS For this open-label, multicentre, single-group, phase 2 trial, we recruited patients older than 80 years with untreated histologically-proven CD20-positive DLBCL, Ann Arbor stage I to IV, from 41 academic and hospital centres in France and Belgium. Patients received a pre-phase with oral vincristine (1 mg total dose 1 week before cycle 1 [day -7]) and oral prednisone (60 mg total dose starting 1 week before cycle 1, for 4 days [day -7 to day -4]) before the first cycle of the ofatumumab plus miniCHOP regimen. The regimen consisted of 1000 mg total dose of intravenous ofatumumab, 25 mg/m2 of intravenous doxorubicin, 400 mg/m2 of intravenous cyclophosphamide, and 1 mg of intravenous vincristine, on day 1 of each cycle; and 40 mg/m2 of oral prednisone on days 1-5. Ofatumumab was administered with 1000 mg of paracetamol and 50 mg of diphenhydramine. The primary endpoint was overall survival in the intention-to-treat population. The statistical analysis has been done on an intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT01195714. FINDINGS Between June 2, 2010, and Nov 4, 2011, we enrolled 120 patients. Age-adjusted International Prognostic Index was 2-3 in 68 (57%) of them. The median follow-up time was 26·8 months (IQR 24·5-30·1). The 2-year overall survival was 64·7% (95% CI 55·3-72·7) and median overall survival was not reached (95% CI 30·2-not reached). 45 patients died during the treatment, of whom 28 (62%) died due to lymphoma. The most common side-effect was haematological toxicity. Among the 120 patients, grade 3-4 neutropenia was reported in 24 (21%) patients and thrombocytopenia in two (2%), during the treatment period. Grade 3-4 anaemia was reported in six (5%) patients; seven (6%) patients had one episode of febrile neutropenia. 17 (15%) of 115 patients in the modified intention-to-treat population had red blood cell transfusions and three (3%) had platelet transfusions. INTERPRETATION Our result suggest that, in patients older than 80 years with DLBCL, ofatumumab and pre-phase treatment seem to improve overall survival compared with the previously reported data. The combination of pre-phase treatment, a monoclonal antibody against CD20, and miniCHOP can be considered a new treatment platform for use in randomised clinical trial design for DLBCL treatment in patients older than 80 years. FUNDING The Lymphoma Study Association, GlaxoSmithKline.
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Freedman A. Follicular lymphoma: 2018 update on diagnosis and management. Am J Hematol 2018; 93:296-305. [PMID: 29314206 DOI: 10.1002/ajh.24937] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 10/05/2017] [Indexed: 12/22/2022]
Abstract
DISEASE OVERVIEW Follicular lymphoma is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. Follicular lymphoma (FL) is characterized by diffuse lymphadenopathy, bone marrow involvement, splenomegaly and less commonly other extranodal sites of involvement. In general, cytopenias can occur but constitutional symptoms of fever, nightsweats, and weight loss are uncommon. DIAGNOSIS Diagnosis is based on histology of preferably a biopsy of a lymph node. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION The Follicular Lymphoma International Prognostic Index prognostic model for FL uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas > 4. The presence of 0, 1, 2, and ≥ 3 adverse factors defines low, intermediate, and high-risk disease. With the use of more modern therapies, outcomes have improved. RISK-ADAPTED THERAPY Observation continues to be adequate for asymptomatic patients with low bulk disease and no cytopenias, with no survival advantage for early treatment with either chemotherapy or rituximab alone. For patients needing therapy, most patients are treated with chemotherapy plus rituximab, which has improved response rates, duration of response and overall survival. Randomized studies have shown additional benefit for maintenance rituximab both following chemotherapy-rituximab and single agent rituximab. Experimental therapies as well as stem cell transplantation (SCT) are considered for recurrent disease.
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Affiliation(s)
- Arnold Freedman
- Department of Medical Oncology; Dana-Farber Cancer Institute; Boston Massachusetts
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33
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Ferl GZ, Reyes A, Sun LL, Cheu M, Oldendorp A, Ramanujan S, Stefanich EG. A Preclinical Population Pharmacokinetic Model for Anti-CD20/CD3 T-Cell-Dependent Bispecific Antibodies. Clin Transl Sci 2018; 11:296-304. [PMID: 29351372 PMCID: PMC5944627 DOI: 10.1111/cts.12535] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 12/06/2017] [Indexed: 01/13/2023] Open
Abstract
CD20 is a cell‐surface receptor expressed by healthy and neoplastic B cells and is a well‐established target for biologics used to treat B‐cell malignancies. Pharmacokinetic (PK) and pharmacodynamic (PD) data for the anti‐CD20/CD3 T‐cell‐dependent bispecific antibody BTCT4465A were collected in transgenic mouse and nonhuman primate (NHP) studies. Pronounced nonlinearity in drug elimination was observed in the murine studies, and time‐varying, nonlinear PK was observed in NHPs, where three empirical drug elimination terms were identified using a mixed‐effects modeling approach: i) a constant nonsaturable linear clearance term (7 mL/day/kg); ii) a rapidly decaying time‐varying, linear clearance term (t½ = 1.6 h); and iii) a slowly decaying time‐varying, nonlinear clearance term (t½ = 4.8 days). The two time‐varying drug elimination terms approximately track with time scales of B‐cell depletion and T‐cell migration/expansion within the central blood compartment. The mixed‐effects NHP model was scaled to human and prospective clinical simulations were generated.
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Affiliation(s)
- Gregory Z Ferl
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Arthur Reyes
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Liping L Sun
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Melissa Cheu
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Amy Oldendorp
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Saroja Ramanujan
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
| | - Eric G Stefanich
- Genentech, Inc., Genentech Research and Early Development, South San Francisco, California, USA
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Soe ZN, Allsup D. The use of ofatumumab in the treatment of B-cell malignancies. Future Oncol 2017; 13:2611-2628. [DOI: 10.2217/fon-2017-0275] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ofatumumab has been extensively studied in the treatment of B-cell malignancies. Currently, it has been approved for the treatment of chronic lymphocytic leukemia in a number of different situations. However, there is still no compelling evidence confirming the superiority of ofatumumab over rituximab in vivo. In this article, we summarize the currently available clinical data supporting the use of ofatumumab in the treatment of B-cell malignancies. The clinical studies were searched from clinicaltrials.gov with the key words ofatumumab, HuMax-CD20. Out of 115 trials available, studies for B-cell malignancies were selected, followed by selection of completed studies with results and active ongoing studies. The results from completed studies were thoroughly analyzed and active ongoing studies were listed in tables.
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Affiliation(s)
- Zar Ni Soe
- Department of Haematology, Hull & East Yorkshire Hospitals NHS Trust, Hull, East Yorkshire, England, UK
| | - David Allsup
- Department of Haematology, Hull & East Yorkshire Hospitals NHS Trust, Hull, East Yorkshire, England, UK
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35
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Selleck MJ, Senthil M, Wall NR. Making Meaningful Clinical Use of Biomarkers. Biomark Insights 2017; 12:1177271917715236. [PMID: 28659713 PMCID: PMC5479428 DOI: 10.1177/1177271917715236] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 05/22/2017] [Indexed: 12/13/2022] Open
Abstract
This review discusses the current state of biomarker discovery for the purposes of diagnostics and therapeutic monitoring. We underscore relevant challenges that have defined the gap between biomarker discovery and meaningful clinical use. We highlight recent advancements in and propose a way to think about future biomarker development.
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Affiliation(s)
- Matthew J Selleck
- Division of Surgical Oncology, Department of Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
| | - Maheswari Senthil
- Division of Surgical Oncology, Department of Surgery, Loma Linda University Medical Center, Loma Linda, CA, USA
| | - Nathan R Wall
- Division of Biochemistry, Department of Basic Sciences and Center for Health Disparities & Molecular Medicine, Loma Linda University Medical Center, Loma Linda, CA, USA
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36
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Casulo C, Friedberg JW. Chemotherapy free treatment of indolent lymphoma. Hematol Oncol 2017; 35 Suppl 1:20-24. [PMID: 28591426 DOI: 10.1002/hon.2395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Carla Casulo
- Wilmot Cancer Institute, University of Rochester, Rochester, NY, USA
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37
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Yazdy MS, Ujjani C. Current challenges in the management of follicular lymphoma. Int J Hematol Oncol 2017; 6:13-24. [PMID: 30302218 PMCID: PMC6171972 DOI: 10.2217/ijh-2017-0003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 03/24/2017] [Indexed: 12/29/2022] Open
Abstract
Although typically indolent in nature, follicular lymphoma remains an ongoing challenge for practicing oncologists. While response rates >90% can be achieved with rituximab-based chemoimmunotherapy in advanced stage patients, the complete remission rates are substantially lower and patients inevitably relapse. The inability to achieve a complete remission and an early progression of disease have recently been determined to be indicative of poorer long-term outcomes. A greater understanding of the pathogenesis of follicular lymphoma has enabled the development of targeted therapies, which may improve standard treatment approaches. Examples include lenalidomide and obinutuzumab, which are currently in front-line Phase III investigation. Other therapies of interest include small molecule inhibitors, immune checkpoint inhibitors and chimeric antigen receptor T cells.
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Affiliation(s)
- Maryam Sarraf Yazdy
- Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC 20007, USA
| | - Chaitra Ujjani
- Lombardi Comprehensive Cancer Center, Medstar Georgetown University Hospital, Washington, DC 20007, USA
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38
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Ma B, Ujjani C. The clinical development of obinutuzumab for the treatment of follicular lymphoma. Cancer Manag Res 2017; 9:103-113. [PMID: 28435325 PMCID: PMC5391868 DOI: 10.2147/cmar.s114526] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Impressive progress has been made in recent decades for advanced-stage follicular lymphoma with the availability of anti-CD20 monoclonal antibodies, initially rituximab and more recently obinutuzumab. Obinutuzumab is a unique, third-generation, fully humanized glycoengineered IgG1 type II anti-CD20 monoclonal antibody. It has been shown to have increased antitumor activity compared to rituximab in preclinical studies, including whole-blood B-cell depletion assays, xenograft models, and primate models. This has spurred on the development of obinutuzumab through Phase I/II trials as monotherapy and in combination with chemotherapeutic agents and other targeted therapies. Its efficacy compared to rituximab and in rituximab-refractory disease has led to its continued development and eventual approval for the treatment of follicular lymphoma. Here in this review, we highlight the design and development of obinutuzumab in the treatment of advanced stage grade 1-3A follicular lymphoma and its future directions.
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Affiliation(s)
| | - Chaitra Ujjani
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington, DC, USA
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Pan L, Zhao W, Lai J, Ding D, Zhang Q, Yang X, Huang M, Jin S, Xu Y, Zeng S, Chou JJ, Chen S. Sortase A-Generated Highly Potent Anti-CD20-MMAE Conjugates for Efficient Elimination of B-Lineage Lymphomas. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2017; 13:1602267. [PMID: 27873460 DOI: 10.1002/smll.201602267] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 10/18/2016] [Indexed: 06/06/2023]
Abstract
Antibody-drug conjugate (ADC) targeting antigens expressed on the surface of tumor cells are an effective approach for delivering drugs into the cells via antigen-mediated endocytosis. One of the well-known tumor antigens, the CD20 of B-lymphocyte, has long been suggested to be noninternalizing epitope, and is thus not considered a desirable target for ADCs. Here, sortase A (srtA)-mediated transpeptidation is used to specifically conjugate triple glycine-modified monomethyl auristatin E (MMAE), a highly toxic antimitotic agent, to anti-CD20 ofatumumab (OFA) equipped with a short C-terminal LPETG (5 amino acids) tag at heavy chain (HL), which generates ADCs that show extremely strong potency in killing CD20 positive cancer cells. One of the srtA-generated ADCs with a cleavable dipeptide linker (valine-citrulline, vc), OFA-HL-vcMMAE, shows IC50 values ranging from 5 pg mL-1 to 4.1 ng mL-1 against CD20+ lymphoma cells. Confocal laser scanning microscopy confirms that OFA-HL-vcMMAE internalization by Ramos cells is significantly improved compared to OFA alone, consistent with the high antitumor activity of the new ADC. OFA-HL-vcMMAE, at 5 mg kg-1 dose, is able to eliminate tumors with mean volume ≈400 mm3 while no obvious drug-related toxicity is observed. The results show that srtA-generated OFA-MMAE conjugate system provides a viable strategy for targeting CD20+ B lineage lymphomas.
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Affiliation(s)
- Liqiang Pan
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
| | - Wenbin Zhao
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Jun Lai
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Ding Ding
- HisunPharma (Hangzhou) Co., Ltd, Xialian Village, Xukou Town, Fuyang, Hangzhou, 311404, China
| | - Qian Zhang
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Xiaoyue Yang
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Minmin Huang
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Shijie Jin
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yingchun Xu
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - Su Zeng
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
| | - James J Chou
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA
| | - Shuqing Chen
- Institute of Drug Metabolism and Drug Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China
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Abstract
Immunotherapy is an evolving modality in the treatment of non-Hodgkin lymphoma. Vaccinations with patient-specific tumor-derived antigens have been developed to strengthen immune response to tumor. The success of rituximab, a monoclonal antibody for CD20 on malignant B-cells, fueled further immunotherapy research. The power of the immune system to fight hematologic malignancies is seen in allogeneic stem cell transplant, where donor T cells attack residual malignant cells in the recipient. Now, three innovative therapeutic immunotherapy classes (I) adoptive cellular therapy; (II) immune-checkpoint inhibitors; and (III) novel antibody therapies show promising results in non-Hodgkin lymphoma. Genetically engineered T cells, CAR T cells, obtained remissions in lymphomas refractory to conventional chemotherapy. Immune-checkpoint inhibitors, such as nivolumab and pembrolizumab revolutionized the treatment of many solid tumors, and unprecedented results are now reported in relapsed/refractory lymphoma. Building on the success of rituximab, additional therapeutic monoclonal antibodies were developed for lymphoma treatment. Antibodies have recently been further engineered with multiple binding sites to directly engage both tumor and T cells. There are exciting early clinical trial results for the first bispecific T-cell engager (BiTE), blinatumomab, as well as promising ongoing studies for dual antibody molecules, Dual-Affinity Re-Targeting (DART) proteins. This review highlights these three immunotherapy classes for relapsed/refractory non-Hodgkin lymphomas and discusses the mechanism of action, clinical efficacy, and toxicities of each.
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Affiliation(s)
- Allyson Pishko
- Division of Hematology/Oncology, Department of Medicine and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sunita D Nasta
- Division of Hematology/Oncology, Department of Medicine and Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Hendriks D, Choi G, de Bruyn M, Wiersma VR, Bremer E. Antibody-Based Cancer Therapy: Successful Agents and Novel Approaches. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 331:289-383. [PMID: 28325214 DOI: 10.1016/bs.ircmb.2016.10.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Since their discovery, antibodies have been viewed as ideal candidates or "magic bullets" for use in targeted therapy in the fields of cancer, autoimmunity, and chronic inflammatory disorders. A wave of antibody-dedicated research followed, which resulted in the clinical approval of a first generation of monoclonal antibodies for cancer therapy such as rituximab (1997) and cetuximab (2004), and infliximab (2002) for the treatment of autoimmune diseases. More recently, the development of antibodies that prevent checkpoint-mediated inhibition of T cell responses invigorated the field of cancer immunotherapy. Such antibodies induced unprecedented long-term remissions in patients with advanced stage malignancies, most notably melanoma and lung cancer, that do not respond to conventional therapies. In this review, we will recapitulate the development of antibody-based therapy, and detail recent advances and new functions, particularly in the field of cancer immunotherapy. With the advent of recombinant DNA engineering, a number of rationally designed molecular formats of antibodies and antibody-derived agents have become available, and we will discuss various molecular formats including antibodies with improved effector functions, bispecific antibodies, antibody-drug conjugates, antibody-cytokine fusion proteins, and T cells genetically modified with chimeric antigen receptors. With these exciting advances, new antibody-based treatment options will likely enter clinical practice and pave the way toward more successful control of malignant diseases.
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Affiliation(s)
- D Hendriks
- Department of Surgery, Translational Surgical Oncology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
| | - G Choi
- Department of Hematology, Section Immunohematology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
| | - M de Bruyn
- Department of Obstetrics & Gynecology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands
| | - V R Wiersma
- Department of Hematology, Section Immunohematology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands.
| | - E Bremer
- Department of Hematology, Section Immunohematology, University of Groningen, University Medical Center Groningen (UMCG), Groningen, The Netherlands; University of Exeter Medical School, Exeter, UK.
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van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MDC, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol 2016; 35:544-551. [PMID: 28029326 DOI: 10.1200/jco.2016.69.0198] [Citation(s) in RCA: 164] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20+ DLBCL age ≥ 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m2 was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age ≥ 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio [HR], 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL.
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Affiliation(s)
- Gustaaf W van Imhoff
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Andrew McMillan
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Matthew J Matasar
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - John Radford
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Kirit M Ardeshna
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Kazimierz Kuliczkowski
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - WonSeog Kim
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Xiaonan Hong
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Jette Soenderskov Goerloev
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Andrew Davies
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - María Dolores Caballero Barrigón
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Michinori Ogura
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Sirpa Leppä
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Michael Fennessy
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Qiming Liao
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Bronno van der Holt
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Steen Lisby
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
| | - Anton Hagenbeek
- Gustaaf W. van Imhoff, University Medical Center, University of Groningen; Bronno van der Holt, University Medical Center, Rotterdam; Anton Hagenbeek, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Andrew McMillan, Nottingham University Hospital, Nottingham; John Radford and Kirit M. Ardeshna, Christie Hospital NHS Trust, Manchester; Andrew Davies, University of Southampton, Southampton, United Kingdom; Matthew J. Matasar, Memorial Sloan Kettering Cancer Center, New York, NY; Kazimierz Kuliczkowski, Wroclaw Medical University, Wroclaw, Poland; WonSeog Kim, Sungkyunkwan University School of Medicine, Seoul, Korea; Xiaonan Hong, Fudan University, Shanghai, China; Jette Soenderskov Goerloev, Rigshospitalet; Steen Lisby, Genmab A/S, Copenhagen, Denmark; María Dolores Caballero Barrigón, Hospital Universitario de Salamanca, Salamanca, Spain; Michinori Ogura, Nagoya Daini Red Cross Hospital, Nagoya; Michinori Ogura, Tokai Central Hospital, Kakamigahara, Japan; Sirpa Leppä, Helsinki University Central Hospital Cancer Center, Helsinki, Finland; and Michael Fennessy and Qiming Liao, Novartis AG, Basel, Switzerland
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Khademi F, Mostafaie A, Parvaneh S, Gholami Rad F, Mohammadi P, Bahrami G. Construction and characterization of monoclonal antibodies against the extracellular domain of B-lymphocyte antigen CD20 using DNA immunization method. Int Immunopharmacol 2016; 43:23-32. [PMID: 27939822 DOI: 10.1016/j.intimp.2016.11.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 10/28/2016] [Accepted: 11/29/2016] [Indexed: 12/19/2022]
Abstract
To date, several new anti-CD20 monoclonal antibodies (mAbs) have been developed for potential efficacies compared with familiar mAb rituximab. Despite the recent advances in development of anti-CD20 mAbs for the treatment of B cell malignancies, the efforts should be continued to develop novel antibodies with improved properties. However, the development of mAbs against CD20 as a multi-transmembrane protein is challenging due to the difficulty of providing a lipid environment that can maintain native epitopes. To overcome this limitation, we describe a simple and efficient DNA immunization strategy for the construction of a novel anti-CD20 mAb with improved anti-tumour properties. Using a DNA immunization strategy that includes intradermal (i.d.) immunization with naked plasmid DNA encoding the CD20 gene, we generated the hybridoma cell line D4, which secretes functional mAbs against an extracellular epitope of CD20. Immunocytochemistry analysis and a cell-based enzyme-linked immunosorbent assay using a Burkitt's lymphoma cell line showed that D4 mAbs are capable of binding to native extracellular epitopes of CD20. Moreover, the binding specificity of D4 mAbs was determined by western blot analysis. Cell proliferation was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by the annexin V/propidium iodide staining and dye exclusion assay. The results showed that D4 anti-CD20 mAbs produced by DNA immunization exhibit potent growth inhibitory activity and have superior direct B-cell cytotoxicity compared to rituximab. We propose that antibody-induced apoptosis is one of the mechanisms of cell growth inhibition. Taken together, the data reported here open the path to DNA-based immunization for generating pharmacologically active monoclonal antibodies against CD20. In addition, the data support future in vivo animal testing and subsequent procedures to produce a potential therapeutic mAb.
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Affiliation(s)
- Fatemeh Khademi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Ali Mostafaie
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Shahram Parvaneh
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Farah Gholami Rad
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Pantea Mohammadi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Gholamreza Bahrami
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Horn H, Staiger AM, Ott G. New targeted therapies for malignant lymphoma based on molecular heterogeneity. Expert Rev Hematol 2016; 10:39-51. [DOI: 10.1080/17474086.2017.1268046] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- Heike Horn
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Stuttgart, Germany
| | - Annette M. Staiger
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart and University of Tübingen, Stuttgart, Germany
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus Stuttgart, Stuttgart, Germany
| | - German Ott
- Department of Clinical Pathology, Robert-Bosch-Krankenhaus Stuttgart, Stuttgart, Germany
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Suh HY, Peck CC, Yu KS, Lee H. Determination of the starting dose in the first-in-human clinical trials with monoclonal antibodies: a systematic review of papers published between 1990 and 2013. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:4005-4016. [PMID: 27994442 PMCID: PMC5153257 DOI: 10.2147/dddt.s121520] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
A systematic review was performed to evaluate how the maximum recommended starting dose (MRSD) was determined in first-in-human (FIH) studies with monoclonal antibodies (mAbs). Factors associated with the choice of each MRSD determination method were also identified. PubMed was searched for FIH studies with mAbs published in English between January 1, 1990 and December 31, 2013, and the following information was extracted: MRSD determination method, publication year, therapeutic area, antibody type, safety factor, safety assessment results after the first dose, and number of dose escalation steps. Seventy-nine FIH studies with mAbs were identified, 49 of which clearly reported the MRSD determination method. The no observed adverse effects level (NOAEL)-based approach was the most frequently used method, whereas the model-based approach was the least commonly used method (34.7% vs 16.3%). The minimal anticipated biological effect level (MABEL)- or minimum effective dose (MED)-based approach was used more frequently in 2011–2013 than in 1990–2007 (31.6% vs 6.3%, P=0.036), reflecting a slow, but steady acceptance of the European Medicines Agency’s guidance on mitigating risks for FIH clinical trials (2007). The median safety factor was much lower for the MABEL- or MED-based approach than for the other MRSD determination methods (10 vs 32.2–53). The number of dose escalation steps was not significantly different among the different MRSD determination methods. The MABEL-based approach appears to be safer and as efficient as the other MRSD determination methods for achieving the objectives of FIH studies with mAbs faster.
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Affiliation(s)
- Hoon Young Suh
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Carl C Peck
- Department of Bioengineering and Therapeutic Sciences, School of Pharmacy, University of California, San Francisco, CA, USA
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea
| | - Howard Lee
- Department of Clinical Pharmacology and Therapeutics, College of Medicine, Seoul National University Hospital, Seoul, Korea; Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
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Sehn LH. Novel agents in follicular lymphoma: choosing the best target. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2016; 2016:284-292. [PMID: 27913493 PMCID: PMC6142508 DOI: 10.1182/asheducation-2016.1.284] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Outcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment. Given the large number of candidate drugs and potential combinations, it will be crucial to prioritize evaluation based on sound preclinical and early clinical studies. Combinations that exploit driver mechanisms within tumor cells and target parallel pathways to minimize the development of drug resistance, as well as harness the potential of the immune system would seem most logical. In order to expedite progress, future studies will need to use innovative trial designs and employ surrogate end points. The development of validated prognostic tools to identify higher risk patients and reliable predictive markers to select subgroups most likely to benefit from targeted agents will be paramount. The potential for unexpected toxicity with novel combinations must be recognized, necessitating both short- and long-term vigilance. Finally, as a greater number of treatment options become available, optimal sequencing must be determined in order to both prolong life and maintain its quality.
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Affiliation(s)
- Laurie H Sehn
- Centre for Lymphoid Cancer, British Columbia Cancer Agency, and the University of British Columbia, Vancouver, Canada
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MacDonald D, Prica A, Assouline S, Christofides A, Lawrence T, Sehn L. Emerging therapies for the treatment of relapsed or refractory follicular lymphoma. Curr Oncol 2016; 23:407-417. [PMID: 28050137 PMCID: PMC5176374 DOI: 10.3747/co.23.3405] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
With no treatment standard having been established for relapsed and refractory follicular lymphoma, a number of therapeutic approaches are used in Canada. In patients who relapse early or who eventually become resistant to subsequent treatment, prognosis is poor, and new approaches are needed. A number of novel therapies are being examined in this setting, including monoclonal antibodies, immunoconjugates, immunomodulatory agents, and signal transduction inhibitors. With the body of evidence for those emerging therapies accumulating and the standard upfront treatment changing from rituximab and chop (cyclophosphamide-doxorubicin-vincristine-prednisone) or rituximab and cvp (cyclophosphamide-vincristine-prednisone) to bendamustine and rituximab, treatment decisions in the relapsed and refractory setting have become more complex. The choice of subsequent treatment must consider type of upfront treatment; duration of remission; and patient-related factors such as age, comorbidities, and treatment preferences. This paper summarizes the evidence for novel therapies and proposes recommendations for subsequent treatment options by remission duration after induction and maintenance.
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Affiliation(s)
- D. MacDonald
- Division of Hematology, Dalhousie University, and QEII Health Sciences Centre, Halifax, NS
| | - A. Prica
- Department of Medical Oncology, University of Toronto, and Princess Margaret Hospital, Toronto, ON
| | - S. Assouline
- Department of Oncology, McGill University, and Jewish General Hospital, Montreal, QC
| | | | | | - L.H. Sehn
- Division of Medical Oncology, University of British Columbia, and BC Cancer Agency, Vancouver, BC
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Jewell RC, Kipps TJ, Dürig J, Griskevicius L, Stilgenbauer S, Smolej L, Mayer J, Hess G, Hernandez-Ilizaliturri FJ, Padmanabhan-Iyer S, Fang L, Goldstein N, Gorczyca M, Gupta I, Lisby S, Wierda WG. Associations of ofatumumab exposure and treatment outcomes in patients with untreated CLL receiving chemoimmunotherapy. Leuk Lymphoma 2016; 58:348-356. [PMID: 27389174 DOI: 10.1080/10428194.2016.1195497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Relationships between patient characteristics, ofatumumab pharmacokinetics, and treatment outcomes were investigated in this phase 2 trial of ofatumumab plus fludarabine and cyclophosphamide (FC) in untreated chronic lymphocytic leukemia. Patients were randomized 1:1 to receive 500 or 1000 mg ofatumumab (Cycle 1; 300 mg) plus FC every 4 weeks for six cycles. Median Cmax and Ctrough values were similar at Cycle 1 regardless of the ultimate clinical outcome. At later doses, these values were higher for patients with complete response (CR) than for other patients. Higher Cmax and Ctrough values at Cycles 3 and 6 were significantly associated with an increased likelihood of CR, whereas ofatumumab pharmacokinetics were not associated with an objective response (OR) on the basis of univariate analyses. Multivariate analyses indicated that baseline patient/disease factors were predominantly associated with CR (17p status) or OR (bulky lymphadenopathy, gender, and serum thymidine kinase), rather than ofatumumab pharmacokinetics. TRIAL REGISTRATION www.clinicaltrials.gov (NCT00410163).
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Affiliation(s)
| | | | - Jan Dürig
- c Klinik für Hämatologie , Universitätsklinikum Essen , Essen , Germany
| | - Laimonas Griskevicius
- d Vilnius University Hospital Santariskiu Klinikos, Vilnius University , Vilnius , Lithuania
| | - Stephan Stilgenbauer
- e Department of Internal Medicine III , Universitätsklinikum Ulm , Ulm , Germany
| | - Lukáš Smolej
- f 4th Department of Internal Medicine - Hematology , University Hospital and Faculty of Medicine , Hradec Králové , Czech Republic
| | - Jiří Mayer
- g Department of Internal Medicine/Hemato-Oncology , University Hospital Brno , Brno , Czech Republic
| | - Georg Hess
- h Johannes Gutenberg University , Mainz , Germany
| | | | | | - Lei Fang
- k Pharstat Inc. , Raleigh , NC , USA
| | | | | | - Ira Gupta
- m Novartis Pharmaceuticals , King of Prussia , PA , USA
| | | | - William G Wierda
- o MD Anderson Cancer Center, The University of Texas , Houston , TX , USA
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Costa LJ, Fanning SR, Stephenson J, Afrin LB, Kistner-Griffin E, Bentz TA, Stuart RK. Sequential ofatumumab and lenalidomide for the treatment of relapsed and refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Leuk Lymphoma 2016; 56:645-9. [PMID: 25130476 DOI: 10.3109/10428194.2014.935369] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Ofatumumab is a fully human anti-CD20 monoclonal antibody with enhanced antibody dependent and complement dependent cytotoxicity. Lenalidomide induces T cell and natural killer (NK) cell activation and in vitro enhances clearance of chronic lymphocytic leukemia (CLL) cells by monoclonal antibodies. We performed a multi-center, phase 2 trial of sequential treatment with ofatumumab and lenalidomide in patients with advanced, relapsed and refractory (R/R) CLL, consisting of ofatumumab 2000 mg intravenously on day 1 and lenalidomide 10 mg on days 8-28, for up to six cycles. Twenty-one subjects were included with median age of 63 years and two prior lines of therapy. The overall response rate was 47.6% and 23.8% had stable disease. Median overall survival was 21.5 months. Neutropenia and thrombocytopenia were the most frequent adverse events. Tumor flare reaction occurred in 43% of subjects. Intracycle sequential ofatumumab plus lenalidomide is active in high-risk R/R CLL and well tolerated except for frequent cytopenias.
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Affiliation(s)
- Luciano J Costa
- Division of Hematology and Oncology, Department of Medicine, Medical University of South Carolina , Charleston, SC , USA
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Cheah CY, Fowler NH, Wang ML. Breakthrough therapies in B-cell non-Hodgkin lymphoma. Ann Oncol 2016; 27:778-87. [PMID: 26802148 DOI: 10.1093/annonc/mdw029] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2015] [Accepted: 01/12/2016] [Indexed: 01/14/2023] Open
Abstract
The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas. This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell's signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric antigen receptor T cells.
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Affiliation(s)
- C Y Cheah
- Department of Haematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine WA, Nedlands University of Western Australia, Crawley, Australia
| | - N H Fowler
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - M L Wang
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, USA
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