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Li T, Gibiansky L, Parikh A, Putnins M, Chiu CW, Sacchi M, Feng H, Ahmadi T, Gupta M, Xu S. Optimal Dosing Regimen for Epcoritamab, a Subcutaneous Bispecific Antibody, in Relapsed or Refractory Large B-Cell Lymphoma. Clin Pharmacol Ther 2025; 117:1437-1450. [PMID: 39935086 PMCID: PMC11993285 DOI: 10.1002/cpt.3588] [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: 07/31/2024] [Accepted: 01/22/2025] [Indexed: 02/13/2025]
Abstract
Epcoritamab is a CD3xCD20 bispecific antibody that activates T cells to kill CD20-expressing B cells. Epcoritamab is approved for the treatment of adults with different types of relapsed or refractory lymphoma in various geographies, including the United States, Europe, and Japan. Epcoritamab demonstrated an overall response rate of 63%, a complete response rate of 39%, and manageable safety with the approved dosing regimen (0.16-mg and 0.8-mg step-up doses and 48-mg full dose, with dosing every week in cycles 1-3, every 2 weeks in cycles 4-9, and every 4 weeks in cycles ≥ 10) in patients with relapsed or refractory large B-cell lymphoma from the phase 1/2 EPCORE® NHL-1 trial expansion through January 31, 2022. Exposure-efficacy analyses including the EPCORE NHL-1 and EPCORE NHL-3 trials revealed that higher exposure was associated with a higher overall response rate, complete response rate, progression-free survival, and overall survival. A potential plateau of efficacy was observed at 48 mg or above. The exposure-safety analyses of these trials did not identify any safety concerns with the approved dosing regimen. No associations were detected between exposure and safety endpoints. The step-up doses were clinically active and helped mitigate cytokine release syndrome risk at the subsequent full doses. Most initial responses (94%) were observed during the weekly dosing period, and most responders with large B-cell lymphoma maintained or improved their response during every 2 weeks and every 4 weeks dosing. Overall, these analyses support the approved single-agent epcoritamab 0.16/0.8/48-mg dosing regimen in relapsed or refractory large B-cell lymphoma.
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MESH Headings
- Humans
- Antibodies, Bispecific/administration & dosage
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/pharmacokinetics
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Antineoplastic Agents, Immunological/administration & dosage
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/pharmacokinetics
- Drug Administration Schedule
- Injections, Subcutaneous
- Dose-Response Relationship, Drug
- Treatment Outcome
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Bonello F, Frascione PMM, Faraci D, Vitolo U. An evaluation of epcoritamab as a treatment for relapsed or refractory follicular lymphoma. Expert Rev Anticancer Ther 2025:1-11. [PMID: 40251963 DOI: 10.1080/14737140.2025.2492787] [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: 01/16/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/21/2025]
Abstract
INTRODUCTION The treatment landscape for relapsed refractory (RR) follicular lymphoma (FL) is rapidly evolving, and chemo-free immunotherapeutic strategies represent the major players in the field. CD20×CD3 bispecific antibodies are effective and easily manageable agents that are able to redirect the cytotoxic activity of T-cells against lymphoma cells by creating an immunological synapse. AREAS COVERED In this paper we will review the efficacy and safety profile of the bispecific antibody epcoritamab in RR FL, either as monotherapy (as it was recently approved in the United States and Europe) and in combination with other agents. We will discuss its potential role among the existing treatment options in this setting, particularly in relation with other approved bispecific antibodies and with CAR-T cell therapy. Presented data were obtained by literature search on PubMed and updated with most recent evidence presented at international hematology meetings (2022-2024). EXPERT OPINION The optimal treatment sequencing in FL is still an open issue; however, epcoritamab effectively combines key aspects such as high, rapid and durable responses, good tolerability, predictable cytokine release syndrome (CRS) kinetics, and ease of administration, representing an appealing option for patients and clinicians. Future efforts should aim at positioning epcoritamab-based treatments in earlier lines of FL.
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Affiliation(s)
- Francesca Bonello
- Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy
| | | | - Danilo Faraci
- Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy
| | - Umberto Vitolo
- Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo (Torino), Italy
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3
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Lewis CS, Barraclough A, Hawkes EA. Emerging biomarkers for CD3×CD20 bispecific antibodies in lymphoma. Blood 2025; 145:1850-1857. [PMID: 39938059 DOI: 10.1182/blood.2024025772] [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: 11/27/2024] [Revised: 01/29/2025] [Accepted: 01/29/2025] [Indexed: 02/14/2025] Open
Abstract
ABSTRACT Novel CD3×CD20 bispecific antibody (BsAb) immunotherapies have entered the armamentarium for follicular lymphoma and diffuse large B-cell lymphoma based on accelerated approvals. The primary challenge in utilizing BsAbs lies in patient selection due to variable responses, unique toxicity, and health economics. To date, no validated biomarkers of therapy response exist, however data demonstrating potential clinical, imaging, and biological markers relating to BsAbs are growing. This review examines current prognostic and potentially predictive biomarkers and explores future directions for nuanced patient selection.
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MESH Headings
- Humans
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/immunology
- Biomarkers, Tumor/immunology
- CD3 Complex/immunology
- Antigens, CD20/immunology
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/immunology
- Lymphoma, Large B-Cell, Diffuse/therapy
- Lymphoma, Follicular/immunology
- Lymphoma, Follicular/drug therapy
- Lymphoma, Follicular/therapy
- Receptors, IgG/immunology
- Prognosis
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Affiliation(s)
- Cameron S Lewis
- Department of Hematology, Austin Health, Melbourne, Australia
| | | | - Eliza A Hawkes
- Department of Hematology, Austin Health, Melbourne, Australia
- Olivia Newton-John Cancer Research Institute, La Trobe University, Melbourne, Australia
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
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4
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Brody JD, Jørgensen J, Belada D, Costello R, Trněný M, Vitolo U, Lewis DJ, Karimi YH, Sureda A, André M, Wahlin BE, Lugtenburg PJ, Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Jiang T, Karagoz K, Steele AJ, Abbas A, Wang L, Risum M, Cordoba R. Epcoritamab plus GemOx in transplant-ineligible relapsed/refractory DLBCL: results from the EPCORE NHL-2 trial. Blood 2025; 145:1621-1631. [PMID: 39792928 PMCID: PMC12000653 DOI: 10.1182/blood.2024026830] [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: 09/13/2024] [Revised: 12/13/2024] [Accepted: 12/13/2024] [Indexed: 01/12/2025] Open
Abstract
ABSTRACT Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes (complete response [CR] rates with standard salvage therapy gemcitabine plus oxaliplatin [GemOx], ∼30%; median overall survival [OS], 10 to 13 months). Patients with refractory disease fare worse (CR rate with salvage therapy, 7%; median OS, 6 months). Epcoritamab, a CD3×CD20 bispecific antibody approved for R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE NHL-2 trial evaluating epcoritamab plus GemOx in autologous stem cell transplant (ASCT)-ineligible R/R DLBCL. Patients received 48 mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given once every 2 weeks for 8 doses. The primary end point was overall response rate (ORR). As of 15 December 2023, 103 patients were enrolled (median follow-up, 13.2 months; median age, 72 years). Patients had challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior chimeric antigen receptor T-cell therapy, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR and CR rate were 85% and 61%, respectively. Median duration of CR and OS were 23.6 and 21.6 months, respectively. Common treatment-emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab plus GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT-ineligible R/R DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT04663347.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/pathology
- Female
- Male
- Middle Aged
- Aged
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Adult
- Antibodies, Bispecific/administration & dosage
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/therapeutic use
- Deoxycytidine/analogs & derivatives
- Deoxycytidine/administration & dosage
- Deoxycytidine/adverse effects
- Deoxycytidine/therapeutic use
- Aged, 80 and over
- Salvage Therapy
- Oxaliplatin/administration & dosage
- Oxaliplatin/adverse effects
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Affiliation(s)
- Joshua D. Brody
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Judit Jørgensen
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
| | - David Belada
- 4th Department of Internal Medicine, Hematology, University Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
| | - Régis Costello
- Service d'Hematologie et Thérapie Cellulaire, Assistance Publique Hôpitaux de Marseille, Marseille, France
| | - Marek Trněný
- First Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Umberto Vitolo
- Department of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
| | - David John Lewis
- Department of Haematology, Derriford Hospital, University Hospitals Plymouth National Health Service Trust, Plymouth, United Kingdom
| | - Yasmin H. Karimi
- University of Michigan Division of Hematology & Oncology, Ann Arbor, MI
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d’Oncologia, L’Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | - Marc André
- Service d'Hématologie, Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir, Belgium
| | - Björn E. Wahlin
- Division of Haematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Pieternella J. Lugtenburg
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
| | - Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
- Department of Haematology, Aarhus University Hospital, Aarhus, Denmark
- 4th Department of Internal Medicine, Hematology, University Hospital and Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
- Service d'Hematologie et Thérapie Cellulaire, Assistance Publique Hôpitaux de Marseille, Marseille, France
- First Department of Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
- Department of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy
- Department of Haematology, Derriford Hospital, University Hospitals Plymouth National Health Service Trust, Plymouth, United Kingdom
- University of Michigan Division of Hematology & Oncology, Ann Arbor, MI
- Clinical Hematology Department, Institut Català d’Oncologia, L’Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
- Service d'Hématologie, Centre Hospitalier Universitaire Université Catholique de Louvain Namur, Yvoir, Belgium
- Division of Haematology, Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands
- Oncology Clinical Development, AbbVie, North Chicago, IL
- Translational Data Science, Genmab, Plainsboro, NJ
- Translational Medicine, Genmab, Plainsboro, NJ
- Clinical Science, Genmab, Plainsboro, NJ
- Biostatistics, Genmab, Plainsboro, NJ
- Medical, Genmab, Copenhagen, Denmark
- Department of Hematology, Fundación Jiménez Diaz University Hospital, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
| | - Tony Jiang
- Oncology Clinical Development, AbbVie, North Chicago, IL
| | | | | | | | | | | | - Raul Cordoba
- Department of Hematology, Fundación Jiménez Diaz University Hospital, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain
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Li T, Gibiansky L, Parikh A, van der Linden M, Sanghavi K, Putnins M, Sacchi M, Feng H, Ahmadi T, Gupta M, Xu S. Population Pharmacokinetics of Epcoritamab Following Subcutaneous Administration in Relapsed or Refractory B Cell Non-Hodgkin Lymphoma. Clin Pharmacokinet 2025; 64:127-141. [PMID: 39708278 DOI: 10.1007/s40262-024-01464-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/20/2024] [Indexed: 12/23/2024]
Abstract
BACKGROUND AND OBJECTIVES Epcoritamab is a CD3xCD20 bispecific antibody approved for the treatment of adults with different types of relapsed or refractory (R/R) B cell non-Hodgkin lymphoma (B-NHL) after ≥ 2 lines of systemic therapy. Here we report the first results from a population pharmacokinetic model-based analysis using data from 2 phase 1/2 clinical trials (EPCORE® NHL-1, NCT03625037 and EPCORE NHL-3, NCT04542824) evaluating epcoritamab in patients with R/R B-NHL. METHODS Plasma concentration-time data included 6819 quantifiable pharmacokinetic samples from 327 patients with R/R B-NHL. A wide range of subcutaneous epcoritamab doses, 0.004-60 mg, was explored, with most patients (n = 298) following the approved dosing regimen: step-up dose (SUD) 1 of 0.16 mg on cycle 1 day 1 and SUD 2 of 0.8 mg on cycle 1 day 8, followed by a full dose of 48 mg administered weekly during cycles 1-3, biweekly in cycles 4-9, and every 4 weeks thereafter. Each cycle lasted 28 days. The data were analyzed using nonlinear mixed-effects modeling. RESULTS Quasisteady-state approximation of a two-compartment target-mediated drug disposition model with first-order absorption adequately characterized pharmacokinetics of epcoritamab following subcutaneous administration. After the first full dose and at the end of the weekly dosing regimen (end of cycle 3), the estimated median time to maximum concentration (tmax) was 4 and 2.3 days, respectively. Age and body weight were significant covariates on the pharmacokinetics of epcoritamab. The geometric mean (coefficient of variation [CV], %) of the apparent total volume of distribution was 25.6 L (82%) for patients with R/R large B cell lymphoma in EPCORE NHL-1. Epcoritamab elimination exhibited nonlinear characteristics, with exposure increasing more than proportionally over 1.5-48 mg doses. The geometric mean (CV%) values of apparent total clearance and terminal half-life were 0.53 L/day (40%) and 22 days (58%), respectively, at the end of cycle 3 for the 48 mg full dose. Clinical data analyses did not identify any association between assessed characteristics, including body weight or age, and clinical efficacy or safety. After accounting for body weight, no clinically significant differences in epcoritamab pharmacokinetics were observed for sex, race, renal or hepatic function, or other disease characteristics. Age was not found to significantly affect epcoritamab pharmacokinetic exposure. Antidrug antibodies developed in 4 (2.6%) of 156 evaluable patients treated with the approved 0.16/0.8/48 mg regimen. Antidrug antibody status did not affect epcoritamab pharmacokinetics. CONCLUSIONS Epcoritamab pharmacokinetics in R/R B-NHL were well characterized by the population pharmacokinetic model. No dosage adjustments are recommended in subpopulations based on body weight, age, sex, race, mild-to-moderate renal impairment, or mild hepatic impairment. The risk of immunogenicity was low. These are the first published results of population pharmacokinetic modeling for epcoritamab.
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MESH Headings
- Humans
- Middle Aged
- Male
- Female
- Injections, Subcutaneous
- Aged
- Adult
- Lymphoma, B-Cell/drug therapy
- Lymphoma, B-Cell/blood
- Lymphoma, B-Cell/metabolism
- Models, Biological
- Antibodies, Bispecific/pharmacokinetics
- Antibodies, Bispecific/administration & dosage
- Antibodies, Bispecific/blood
- Antibodies, Bispecific/therapeutic use
- Dose-Response Relationship, Drug
- Aged, 80 and over
- Young Adult
- Adolescent
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Affiliation(s)
- Tommy Li
- Clinical Pharmacology and Quantitative Science, Genmab, Plainsboro, NJ, USA
| | | | | | | | - Kinjal Sanghavi
- Clinical Pharmacology and Quantitative Science, Genmab, Plainsboro, NJ, USA
| | - Matthew Putnins
- Clinical Pharmacology and Quantitative Science, Genmab, Plainsboro, NJ, USA
| | | | | | | | - Manish Gupta
- Translational and Quantitative Science, Genmab, Plainsboro, NJ, USA.
| | - Steven Xu
- Clinical Pharmacology and Quantitative Science, Genmab, Plainsboro, NJ, USA.
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6
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Bisio M, Legato L, Fasano F, Benevolo Savelli C, Boccomini C, Nicolosi M, Santambrogio E, Freilone R, Novo M, Botto B. Bispecific Antibodies for Lymphoid Malignancy Treatment. Cancers (Basel) 2024; 17:94. [PMID: 39796723 PMCID: PMC11719988 DOI: 10.3390/cancers17010094] [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: 10/14/2024] [Revised: 11/30/2024] [Accepted: 12/10/2024] [Indexed: 01/13/2025] Open
Abstract
BACKGROUD The introduction of highly active immunotherapies has changed the outcome of B-cell non-Hodgkin lymphomas (B-NHLs) in the last two decades. Since then, important progress has been shown using newer and more active immunotherapies, including chimeric antigen receptor T-cell therapy (CAR-T), conjugated monoclonal antibodies, and bispecific antobodies, which currently plays a significant role in the treatment of diffuse large B-cell (DLBCL), follicular (FL), and mantle cell (MCL) lymphoma. PURPOSE In this review, we provide an updated overview of recently completed and ongoing BsAb trials in patients with relapsed/refractory(R/R) B-NHL and Hodgkin's lymphoma, including single-agent results, emerging combinations, safety data, and novel constructs. CONCLUSIONS Bispecific antibodies (BsAbs) are a novel class of "off-the-shelf" T-cell-redirecting drugs capable of targeting various cell-surface antigens. New antigen targets are currently under investigation, such as CD19 × CD3 and CD30 × CD3 or CD30 × CD16, in different settings. BsAbs are among the most promising therapeutic options for lymphoma today since they have demonstrated significant single-agent activity, along with a manageable toxicity profile, in patients with heavily pretreated B-NHL.
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Affiliation(s)
- Matteo Bisio
- Hematology Division, A.O.U. Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy (R.F.); (M.N.)
| | | | | | | | | | | | | | | | | | - Barbara Botto
- Hematology Division, A.O.U. Città della Salute e della Scienza di Torino, C.so Bramante 88, 10126 Turin, Italy (R.F.); (M.N.)
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7
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Sekiguchi Y, Tsutsumi H, Kudo M, Maseki N, Iizaki Y, Kawamura M, Kobayashi K, Nishimura Y, Kanda H, Takei D, Abe T, Hanai M, Nakayama T, Shimano Y, Kobayashi H. Treatment with epcoritamab in 10 patients in real-world clinical practice. J Clin Exp Hematop 2024; 64:332-334. [PMID: 39603633 PMCID: PMC11786157 DOI: 10.3960/jslrt.24054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 11/29/2024] Open
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8
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Russler-Germain DA, Bartlett NL. Sequencing bispecific antibodies and CAR T cells for FL. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:310-317. [PMID: 39643999 PMCID: PMC11665570 DOI: 10.1182/hematology.2024000667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Treatment for relapsed/refractory (R/R) follicular lymphoma (FL) has evolved over recent years with the introduction of multiple novel immunotherapies: anti-CD3 × CD20 bispecific antibody (BsAb) T-cell engagers and anti-CD19 chimeric antigen receptor T cells (CAR T). Both drug classes are highly active, and their adverse event profiles overlap considerably, with cytokine release syndrome, cytopenias, and infections being most common. However, key differences include accessibility and logistical considerations as well as distinct neurologic toxicities, which make recommending a BsAb or CAR T a nuanced decision for each patient with R/R FL. Notably, patients could receive both classes of therapies in sequence; however, data guiding this decision are sparse. Considering the 3 most advanced agents in each class, we generally favor BsAbs before CAR T as the standard-of-care third-line treatment for the typical patient with R/R FL without concern for aggressive histologic transformation (HT). This is based on a 3-year follow-up of the mosunetuzumab phase 2 trial in R/R FL highlighting durable complete responses after a time-limited therapy with an acceptable safety profile for patients of all ages and reasonable performance status. We generally prioritize CAR T before BsAbs for patients with proven or suspected HT given the curative-potential of this approach based on trial data from R/R diffuse large B-cell lymphoma; it is unknown whether BsAbs offer the same long-term benefit in transformed FL. Overall, with the ability to personalize the sequencing of BsAbs and CAR T, the recently expanding portfolio of highly effective immunotherapies for R/R FL is poised to offer considerable benefit to this patient population.
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Affiliation(s)
- David A Russler-Germain
- Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St Louis, MO
| | - Nancy L Bartlett
- Division of Oncology, Washington University School of Medicine, Siteman Cancer Center, St Louis, MO
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9
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Thieblemont C, Karimi YH, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, Jurczak W, Do YR, Gasiorowski R, Lewis DJ, Kim TM, van der Poel M, Poon ML, Feldman T, Linton KM, Sureda A, Hutchings M, Dinh MH, Kilavuz N, Soong D, Mark T, Sacchi M, Phillips T, Lugtenburg PJ. Epcoritamab in relapsed/refractory large B-cell lymphoma: 2-year follow-up from the pivotal EPCORE NHL-1 trial. Leukemia 2024; 38:2653-2662. [PMID: 39322711 PMCID: PMC11588654 DOI: 10.1038/s41375-024-02410-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/27/2024]
Abstract
Primary results (median follow-up, 10.7 months) from the pivotal EPCORE® NHL-1 study in relapsed or refractory (R/R) large B-cell lymphoma (LBCL) demonstrated deep, durable responses with epcoritamab, a CD3xCD20 bispecific antibody, when used as monotherapy. We report long-term efficacy and safety results in patients with LBCL (N = 157; 25.1-month median follow-up). As of April 21, 2023, overall response rate was 63.1% and complete response (CR) rate was 40.1%. Estimated 24-month progression-free survival (PFS) and overall survival (OS) rates were 27.8% and 44.6%, respectively. An estimated 64.2% of complete responders remained in CR at 24 months. Estimated 24-month PFS and OS rates among complete responders were 65.1% and 78.2%, respectively. Of 119 minimal residual disease (MRD)-evaluable patients, 45.4% had MRD negativity, which correlated with longer PFS and OS. CR rates were generally consistent across predefined subgroups: 36% prior chimeric antigen receptor (CAR) T-cell therapy, 32% primary refractory disease, and 37% International Prognostic Index ≥3. The most common treatment-emergent adverse events were cytokine release syndrome (51.0%), pyrexia (24.8%), fatigue (24.2%), and neutropenia (23.6%). These results underscore the long-term benefit of epcoritamab for treating R/R LBCL with deep responses across subgroups, including patients with hard-to-treat disease and expected poor prognosis (ClinicalTrials.gov Registration: NCT03625037).
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MESH Headings
- Humans
- Male
- Middle Aged
- Female
- Follow-Up Studies
- Aged
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/adverse effects
- Adult
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/pathology
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/therapy
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/drug therapy
- Aged, 80 and over
- Survival Rate
- Drug Resistance, Neoplasm
- Prognosis
- Young Adult
- Neoplasm, Residual
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Affiliation(s)
- Catherine Thieblemont
- Assistance Publique & Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Université de Paris, Paris, France.
| | - Yasmin H Karimi
- Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI, USA
| | - Herve Ghesquieres
- Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Chan Y Cheah
- Sir Charles Gairdner Hospital and the University of Western Australia, Nedlands, Australia
| | | | | | | | - Young Rok Do
- Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | | | - David John Lewis
- University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK
| | - Tae Min Kim
- Seoul National University Hospital, Seoul, Republic of Korea
| | - Marjolein van der Poel
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Maastricht, Department of Internal Medicine, Division of Hematology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | | | - Tatyana Feldman
- John Theurer Cancer Center at Hackensack Meridian Health, Hackensack Meridian Health School of Medicine, Hackensack, NJ, USA
| | - Kim M Linton
- The Christie NHS Foundation Trust, Manchester Cancer Research Centre, and Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d'Oncologia - L'Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | - Martin Hutchings
- Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | | | | | | | | | | | - Tycel Phillips
- University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA
- City of Hope, Duarte, CA, USA
| | - Pieternella J Lugtenburg
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Erasmus MC Cancer Institute, Department of Hematology, University Medical Center, Rotterdam, The Netherlands
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Bennett R, Dickinson M. SOHO State of the Art Updates and Next Questions | Current Evidence and Future Directions for Bispecific Antibodies in Large B-Cell Lymphoma. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:809-820. [PMID: 38871556 DOI: 10.1016/j.clml.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 05/06/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
The CD20xCD3 bispecific antibodies (bsAb) are "off-the-shelf" T-cell re-directing therapies that demonstrate remarkable single-agent clinical activity in B-cell lymphomas. Two agents, epcoritamab (epcor) and glofitamab (glofit) have recent global approvals for patients with relapsed/refractory DLBCL (RR DLBCL) following 2 prior treatment lines. Both agents demonstrate activity in patients with prior exposure to chimeric antigen receptor T-cell (CAR-T) treatment. As multiyear follow-up data become available, it is clear that the majority of patients achieving complete remissions do not relapse and that outcomes are similar between epcor and glofit. CD20xCD3 bsAb have a safety profile that reflect their mechanism of action, with cytokine release syndrome (CRS) the key management issue. Neurotoxicity is far less common than observed with CD19-directed CAR-T. BsAbs are attractive, rapidly available, treatment options for patients with RR DLBCL, without the practical and financial challenges seen with autologous CAR-T therapies. Recent data also demonstrate the feasibility and potential efficacy of bsAb in combination with chemoimmunotherapy with large randomized trials evaluating bsAb-chemotherapy combinations underway. There are open questions about the future role of bsAB for LBCL, the optimal duration of therapy, optimal CRS risk mitigation strategies, and potential resistance mechanisms. In this review we seek to describe the current evidence for bsAb in LBCL, and offer opinion regarding these open questions.
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Affiliation(s)
- Rory Bennett
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Victoria, Australia
| | - Michael Dickinson
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Victoria, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Victoria, Australia.
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Li Q, Zhang K, Yu Y, Yu Z, Xu J, Shen W, Zhang L, Qu A, Liang H. TFAB002s, novel CD20-targeting T cell-dependent bispecific Fab-FabCH3 antibodies, exhibit potent antitumor efficacy against malignant B-cell lymphoma. PLoS One 2024; 19:e0310889. [PMID: 39321199 PMCID: PMC11423992 DOI: 10.1371/journal.pone.0310889] [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: 03/16/2024] [Accepted: 09/09/2024] [Indexed: 09/27/2024] Open
Abstract
B-cell lymphoma, clinically, comprises a heterogeneous group of malignancies that encompass various subtypes. CD20 is an optimal target for therapeutic antibodies in B-cell lymphoma immunotherapy since approximately 90% of B-cell malignancies typically exhibit CD20 expression on their surface, while its presence is limited in normal tissues. In this study, we have developed a series of novel non-IgG-like T cell-dependent bispecific antibodies by constructing Fab-FabCH3, referred to as Tandem Antigen-binding Fragment 002 (TFAB002), which specifically target CD20 for the treatment of malignant B-cell lymphoma. TFAB002s display strong binding affinity with CD20 and moderate binding affinity with CD3, thereby triggering target-specific T-cell activation, cytokine release, and tumor cell lysis in vitro. Furthermore, TFAB002s exhibit potent cytotoxicity against B-cell malignancies that express varying levels of CD20. Besides, the TFAB002s show potent pharmacodynamic activity in vivo in the WIL2-S cells CDX mouse model. Collectively, these results underscore the potential of TFAB002s as a highly promising therapeutic approach for selectively depleting CD20-positive B cells, thereby warranting further clinical evaluation as a viable treatment option for CD20-expressing B-cell malignancies.
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Affiliation(s)
- Qinghong Li
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Kunming Zhang
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Yao Yu
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Zeng Yu
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Jingyi Xu
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Wenyan Shen
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Lin Zhang
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Aidong Qu
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
| | - Hongyuan Liang
- No.1 Research Laboratory, Shanghai Institute of Biological Products Co., Ltd., Shanghai, China
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Pei Q, Li Z, Zhao J, Zhang H, Qin T, Zhao J. Recombinant hirudin and PAR-1 regulate macrophage polarisation status in diffuse large B-cell lymphoma. BMC Biotechnol 2024; 24:55. [PMID: 39135175 PMCID: PMC11318299 DOI: 10.1186/s12896-024-00879-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 07/22/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Diffuse large B-cell lymphoma (DLBCL) is a malignant tumour. Although some standard therapies have been established to improve the cure rate, they remain ineffective for specific individuals. Therefore, it is meaningful to find more novel therapeutic approaches. Macrophage polarisation is extensively involved in the process of tumour development. Recombinant hirudin (rH) affects macrophages and has been researched frequently in clinical trials lately. Our article validated the regulatory role of rH in macrophage polarisation and the mechanism of PAR-1 by collecting clinical samples and subsequently establishing a cellular model to provide a scientifically supported perspective for discovering new therapeutic approaches. METHOD We assessed the expression of macrophage polarisation markers, cytokines and PAR-1 in clinical samples. We established a cell model by co-culture with THP-1 and OCI-Ly10 cell. We determined the degree of cell polarisation and expression of validation cytokines by flow cytometry, ELISA, and RT-qPCR to confirm the success of the cell model. Subsequently, different doses of rH were added to discover the function of rH on cell polarisation. We confirmed the mechanism of PAR-1 in macrophage polarisation by transfecting si-PAR-1 and pcDNA3.1-PAR-1. RESULTS We found higher expression of M2 macrophage markers (CD163 + CMAF+) and PAR-1 in 32 DLBCL samples. After inducing monocyte differentiation into M0 macrophages and co-culturing with OCI-Ly10 lymphoma cells, we found a trend of these expressions in the cell model consistent with the clinical samples. Subsequently, we discovered that rH promotes the polarisation of M1 macrophages but inhibits the polarisation of M2 macrophages. We also found that PAR-1 regulates macrophage polarisation, inhibiting cell proliferation, migration, invasion and angiogenic capacity. CONCLUSION rH inhibits macrophage polarisation towards the M2 type and PAR-1 regulates polarisation, proliferation, migration, invasion, and angiogenesis of DLBCL-associated macrophages.
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Affiliation(s)
- Qiang Pei
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China.
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China.
- Yunnan Province Clinical Center for Hematologic Disease, Yunnan, China.
| | - Zihui Li
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Medical School, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Jingjing Zhao
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Medical School, Kunming University of Science and Technology, Kunming, 650500, Yunnan, China
| | - Haixi Zhang
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Province Clinical Center for Hematologic Disease, Yunnan, China
| | - Tao Qin
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Province Clinical Center for Hematologic Disease, Yunnan, China
| | - Juan Zhao
- Department of Hematology, The First People's Hospital of Yunnan Province, No. 157 of Jinbi Street, Kunming, 650032, Yunnan, China
- Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650032, Yunnan, China
- Yunnan Province Clinical Center for Hematologic Disease, Yunnan, China
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13
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Linton KM, Vitolo U, Jurczak W, Lugtenburg PJ, Gyan E, Sureda A, Christensen JH, Hess B, Tilly H, Cordoba R, Lewis DJ, Okada C, Hutchings M, Clausen MR, Sancho JM, Cochrane T, Leppä S, Chamuleau MED, Gernhardt D, Altıntaş I, Liu Y, Ahmadi T, Dinh MH, Hoehn D, Favaro E, Elliott B, Thieblemont C, Vose JM. Epcoritamab monotherapy in patients with relapsed or refractory follicular lymphoma (EPCORE NHL-1): a phase 2 cohort of a single-arm, multicentre study. Lancet Haematol 2024; 11:e593-e605. [PMID: 38889737 DOI: 10.1016/s2352-3026(24)00166-2] [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: 04/08/2024] [Revised: 05/15/2024] [Accepted: 05/17/2024] [Indexed: 06/20/2024]
Abstract
BACKGROUND A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma. METHODS EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20+ follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing. FINDINGS Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome. INTERPRETATION Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile. FUNDING Genmab and AbbVie.
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Affiliation(s)
- Kim M Linton
- The Christie NHS Foundation Trust, Manchester Cancer Research Centre, and Division of Cancer Sciences, University of Manchester, Manchester, UK.
| | - Umberto Vitolo
- Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy
| | | | - Pieternella J Lugtenburg
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Erasmus MC Cancer Institute, University Medical Center, Department of Hematology, Rotterdam, Netherlands
| | - Emmanuel Gyan
- Service d'Hématologie et Thérapie Cellulaire, Centre Hospitalier Universitaire de Tours, CIC INSERM U1415, Tours, France
| | - Anna Sureda
- Clinical Hematology Department, Institut Català d'Oncologia-L'Hospitalet, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | | | - Brian Hess
- Medical University of South Carolina, Charleston, SC, USA
| | - Hervé Tilly
- Centre Henri Becquerel, Université de Rouen, Rouen, France
| | - Raul Cordoba
- Fundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain
| | - David John Lewis
- University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, UK
| | - Craig Okada
- Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA
| | - Martin Hutchings
- Rigshospitalet and University of Copenhagen, Copenhagen, Denmark
| | | | - Juan-Manuel Sancho
- Catalan Institute of Oncology (ICO), ICO Hospital Germans Trias i Pujol, Badalona, Spain
| | - Tara Cochrane
- Gold Coast University Hospital, Southport, QLD, Australia
| | - Sirpa Leppä
- University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
| | - Martine E D Chamuleau
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Amsterdam UMC, VU University Medical Center, Amsterdam, Netherlands
| | | | | | | | | | | | | | | | | | - Catherine Thieblemont
- Assistance Publique & Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Université de Paris, Paris, France
| | - Julie M Vose
- University of Nebraska Medical Center, Omaha, NE, USA
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Alzahrani M, Villa D. Management of relapsed/refractory mantle cell lymphoma. Leuk Lymphoma 2024; 65:1044-1054. [PMID: 38635491 DOI: 10.1080/10428194.2024.2338851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Accepted: 03/31/2024] [Indexed: 04/20/2024]
Abstract
In this review we summarize the current evidence describing the management of patients with relapsed/refractory MCL and outline the various novel therapeutics that have been developed over the past two decades. We also describe how overall response rates, complete response rates, duration of responses, and life expectancy have dramatically increased with the introduction of novel therapies, particularly covalent Bruton Tyrosine Kinase inhibitors (BTKi) and chimeric antigen receptor T-cell (CAR-T) therapy. The most recent emerging options for patients with progressive disease following BTKi or CAR-T, including non-covalent BTKi, antibody-drug conjugates, Bcl-2 inhibitors, and bispecific antibodies, may further improve response rates and outcomes. Future directions should focus on identifying the best sequencing and/or combinations of the increasingly available treatment options while prioritizing strategies with curative potential.
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Affiliation(s)
- Musa Alzahrani
- Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Diego Villa
- Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
- Division of Medical Oncology, University of British Columbia, Vancouver, BC, Canada
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15
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Ip A, Della Pia A, Goy AH. SOHO State of the Art Updates and Next Questions: Treatment Evolution of Mantle Cell Lymphoma: Navigating the Different Entities and Biological Heterogeneity of Mantle Cell Lymphoma in 2024. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2024; 24:491-505. [PMID: 38493059 DOI: 10.1016/j.clml.2024.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 02/12/2024] [Accepted: 02/18/2024] [Indexed: 03/18/2024]
Abstract
Progress in mantle cell lymphoma (MCL) has led to significant improvement in outcomes of patients even in the real world (RW) setting albeit to a lesser degree. In parallel to the demonstration of benefit using combination therapy with rituximab plus high-dose cytarabine (R-AraC) as well as dose intensive therapy-autologous stem cell transplantation (DIT-ASCT) consolidation and maintenance, it became clear over the last 2 decades that MCL is a highly heterogenous disease at the molecular level, explaining differences observed in clinical behavior and response to therapy. While clinical prognostic factors and models have helped stratify patients with distinct outcomes, they failed to help guide therapy. The identification of molecular high-risk (HR) features, in particular, but not only, p53 aberrations (including mutations and deletions [del]), as well as complex karyotype (CK), has allowed to identify subsets of patients with poorer outcomes (median overall survival [OS] <2 years) regardless of conventional therapies used. The constant pattern of relapse seen in MCL has fueled sustained and productive efforts, with 7 novel agents approved in the United States (US), showing high and durable efficacy even in HR and chemo-refractory patients and likely curing a subset of patients in the relapsed or refractory (R/R) setting. Progress in diagnostics, in particular next-generation sequencing (NGS), which is accessible in routine practice nowadays, can help recognize patients with HR features, well beyond MIPI or Ki-67 prognostication, although the impact on decision making is still unclear. The era of integrating novel agents into our prior standard of care (SOC) has begun with a confirmed benefit, for example, ibrutinib (Ib) in the TRIANGLE study, defining the first new potential SOC in younger patients in over 30 years. Expanding on novel agents, either in combination, sequentially or to replace chemotherapy altogether, using biological doublets or triplets has led to a median progression-free survival (PFS) in excess of 72 months, certainly competitive with prior SOC and will continue to reshape the management of MCL patients. Achieving minimal residual disease negative (MRD-ve) status is becoming a new endpoint in MCL, and customizing maintenance and/or de-escalation/consolidation strategies is within reach, although it will require prospective, built-in MRD-based approaches, with the goal of eliminating subclinical disease and not simply delaying time to relapse. Taking into account the biological diversity of MCL is now feasible in routine clinical practice and has already helped recognize what not to do for HR patients (i.e., avoid intensive induction chemotherapy and/or ASCT for p53 mutated patients) as well as identify promising novel options. Ongoing and future work will help expand on these dedicated approaches, to further improve the management and outcomes of all MCL patients.
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Affiliation(s)
- Andrew Ip
- Lymphoma Division, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
| | - Alexandra Della Pia
- Lymphoma Division, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
| | - Andre H Goy
- Lymphoma Division, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ.
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Goebeler ME, Stuhler G, Bargou R. Bispecific and multispecific antibodies in oncology: opportunities and challenges. Nat Rev Clin Oncol 2024; 21:539-560. [PMID: 38822215 DOI: 10.1038/s41571-024-00905-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2024] [Indexed: 06/02/2024]
Abstract
Research into bispecific antibodies, which are designed to simultaneously bind two antigens or epitopes, has advanced enormously over the past two decades. Owing to advances in protein engineering technologies and considerable preclinical research efforts, bispecific antibodies are constantly being developed and optimized to improve their efficacy and to mitigate toxicity. To date, >200 of these agents, the majority of which are bispecific immune cell engagers, are in either preclinical or clinical evaluation. In this Review, we discuss the role of bispecific antibodies in patients with cancer, including history and development, as well as innovative targeting strategies, clinical applications, and adverse events. We also discuss novel alternative bispecific antibody constructs, such as those targeting two antigens expressed by tumour cells or cells located in the tumour microenvironment. Finally, we consider future research directions in this rapidly evolving field, including innovative antibody engineering strategies, which might enable more effective delivery, overcome resistance, and thus optimize clinical outcomes.
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Affiliation(s)
- Maria-Elisabeth Goebeler
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany.
- National Center for Tumour Diseases, NCT WERA, University Hospital Würzburg, Würzburg, Germany.
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
| | - Gernot Stuhler
- National Center for Tumour Diseases, NCT WERA, University Hospital Würzburg, Würzburg, Germany
- Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
| | - Ralf Bargou
- Comprehensive Cancer Center Mainfranken, University Hospital Würzburg, Würzburg, Germany
- National Center for Tumour Diseases, NCT WERA, University Hospital Würzburg, Würzburg, Germany
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Dabkowska A, Domka K, Firczuk M. Advancements in cancer immunotherapies targeting CD20: from pioneering monoclonal antibodies to chimeric antigen receptor-modified T cells. Front Immunol 2024; 15:1363102. [PMID: 38638442 PMCID: PMC11024268 DOI: 10.3389/fimmu.2024.1363102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/25/2024] [Indexed: 04/20/2024] Open
Abstract
CD20 located predominantly on the B cells plays a crucial role in their development, differentiation, and activation, and serves as a key therapeutic target for the treatment of B-cell malignancies. The breakthrough of monoclonal antibodies directed against CD20, notably exemplified by rituximab, revolutionized the prognosis of B-cell malignancies. Rituximab, approved across various hematological malignancies, marked a paradigm shift in cancer treatment. In the current landscape, immunotherapies targeting CD20 continue to evolve rapidly. Beyond traditional mAbs, advancements include antibody-drug conjugates (ADCs), bispecific antibodies (BsAbs), and chimeric antigen receptor-modified (CAR) T cells. ADCs combine the precision of antibodies with the cytotoxic potential of drugs, presenting a promising avenue for enhanced therapeutic efficacy. BsAbs, particularly CD20xCD3 constructs, redirect cytotoxic T cells to eliminate cancer cells, thereby enhancing both precision and potency in their therapeutic action. CAR-T cells stand as a promising strategy for combatting hematological malignancies, representing one of the truly personalized therapeutic interventions. Many new therapies are currently being evaluated in clinical trials. This review serves as a comprehensive summary of CD20-targeted therapies, highlighting the progress and challenges that persist. Despite significant advancements, adverse events associated with these therapies and the development of resistance remain critical issues. Understanding and mitigating these challenges is paramount for the continued success of CD20-targeted immunotherapies.
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Affiliation(s)
- Agnieszka Dabkowska
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Krzysztof Domka
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
| | - Malgorzata Firczuk
- Laboratory of Immunology, Mossakowski Medical Research Institute Polish Academy of Sciences, Warsaw, Poland
- Department of Immunology, Medical University of Warsaw, Warsaw, Poland
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18
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McIlroy G, Lax S, Gaskell C, Jackson A, Rhodes M, Seale T, Fox S, Hopkins L, Okosun J, Barrington SF, Ringshausen I, Ramsay AG, Calaminici M, Linton K, Bishton M. Investigator choice of standard therapy versus sequential novel therapy arms in the treatment of relapsed follicular lymphoma (REFRACT): study protocol for a multi-centre, open-label, randomised, phase II platform trial. BMC Cancer 2024; 24:370. [PMID: 38528445 PMCID: PMC10962099 DOI: 10.1186/s12885-024-12112-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 03/12/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Relapsed or refractory follicular lymphoma (rrFL) is an incurable disease associated with shorter remissions and survival after each line of standard therapy. Many promising novel, chemotherapy-free therapies are in development, but few are licensed as their role in current treatment pathways is poorly defined. METHODS The REFRACT trial is an investigator-initiated, UK National Cancer Research Institute, open-label, multi-centre, randomised phase II platform trial aimed at accelerating clinical development of novel therapies by addressing evidence gaps. The first of the three sequential novel therapy arms is epcoritamab plus lenalidomide, to be compared with investigator choice standard therapy (ICT). Patients aged 18 years or older with biopsy proven relapsed or refractory CD20 positive, grade 1-3a follicular lymphoma and assessable disease by PET-CT are eligible. The primary outcome is complete metabolic response by PET-CT at 24 weeks using the Deauville 5-point scale and Lugano 2014 criteria. Secondary outcomes include overall metabolic response, progression-free survival, overall survival, duration of response, and quality of life assessed by EQ-5D-5 L and FACT-Lym. The trial employs an innovative Bayesian design with a target sample size of 284 patients: 95 in the ICT arm and 189 in the novel therapy arms. DISCUSSION Whilst there are many promising novel drugs in early clinical development for rrFL, understanding the relative efficacy and safety of these agents, and their place in modern treatment pathways, is limited by a lack of randomised trials and dearth of published outcomes for standard regimens to act as historic controls. Therefore, the aim of REFRACT is to provide an efficient platform to evaluate novel agents against standard therapies for rrFL. The adaptive Bayesian power prior methodology design will minimise patient numbers and accelerate trial delivery. TRIAL REGISTRATION ClinicalTrials.gov: NCT05848765; 08-May-2023. EUDRACT 2022-000677-75; 10-Feb-2022.
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Affiliation(s)
- Graham McIlroy
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK.
| | - Siân Lax
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Charlotte Gaskell
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Aimee Jackson
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | | | - Tania Seale
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Sonia Fox
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Lousie Hopkins
- Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham, Birmingham, UK
| | - Jessica Okosun
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Sally F Barrington
- King's College London and Guy's and St Thomas' PET Centre, School of Biomedical Engineering and Imaging Sciences, King's College London, King's Health Partners, London, UK
| | | | - Alan G Ramsay
- School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Maria Calaminici
- Department of Cellular Pathology Barts Health and Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK
| | - Kim Linton
- Division of Cancer Sciences, University of Manchester, Manchester, UK
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Mark Bishton
- Translational Medical Sciences, University of Nottingham, Nottingham, UK
- Department of Haematology, Nottingham University Hospitals NHS Trust, Nottingham, UK
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19
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Molica S, Rossi M, Allsup D. Epcoritamab in B-cell malignancies: current status and prospects. Expert Opin Biol Ther 2024; 24:1-5. [PMID: 38343083 DOI: 10.1080/14712598.2024.2310148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Accepted: 01/22/2024] [Indexed: 02/15/2024]
Affiliation(s)
- Stefano Molica
- Queens Centre for Oncology and Haematology, Castle Hill Hospital, Hull University NHS Trust, Hull, UK
| | - Marco Rossi
- Department Haematology, Azienda Ospedaliera-Universitaria "Renato Dulbecco", Catanzaro, Italy
- Università Magna Graecia, Catanzaro, Italy
| | - David Allsup
- Queens Centre for Oncology and Haematology, Castle Hill Hospital, Hull University NHS Trust, Hull, UK
- Centre of Biomedicine, Hull York Medical School, University of Hull, Hull, UK
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20
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Schipani M, Rivolta GM, Margiotta-Casaluci G, Mahmoud AM, Al Essa W, Gaidano G, Bruna R. New Frontiers in Monoclonal Antibodies for Relapsed/Refractory Diffuse Large B-Cell Lymphoma. Cancers (Basel) 2023; 16:187. [PMID: 38201614 PMCID: PMC10778309 DOI: 10.3390/cancers16010187] [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: 11/25/2023] [Revised: 12/27/2023] [Accepted: 12/28/2023] [Indexed: 01/12/2024] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Approximately 60% of patients are cured with R-CHOP as a frontline treatment, while the remaining patients experience primary refractory or relapsed disease (R/R). The prognosis for R/R DLBCL patients who are neither eligible for autologous stem-cell transplantations nor CAR-T-cell treatment is poor, representing an important unmet need. Monoclonal antibodies (mAbs) have dramatically improved therapeutic options in anti-cancer strategies, offering new opportunities to overcome chemo-refractoriness in this challenging disease, even in cases of primary non-responder DLBCL. Several novel mAbs, characterized by different mechanisms of action and targets, are now available for R/R DLBCL. Unbound mAbs induce an immune response against cancer cells, triggering different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), activation of antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) and radioimmunotherapy (RIT), respectively, deliver a cytotoxic payload or a beta-emitter radionuclide to the targeted cells and nearby bystanders. Bispecific T-cell engagers (BiTes) and immune checkpoint inhibitors (ICIs) redirect and enhance the immune response against tumor cells. Here, we review therapeutic strategies based on monoclonal antibodies for R/R DLBCL.
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Affiliation(s)
| | | | | | | | | | - Gianluca Gaidano
- Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Azienda Ospedaliero-Universitaria Maggiore della Carità, 28100 Novara, Italy; (M.S.); (G.M.R.); (G.M.-C.); (A.M.M.); (W.A.E.); (R.B.)
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21
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Kang JJ, Ohoka A, Sarkar CA. Designing Multivalent and Multispecific Biologics. Annu Rev Chem Biomol Eng 2023; 15:293-314. [PMID: 38064501 DOI: 10.1146/annurev-chembioeng-100722-112440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
In the era of precision medicine, multivalent and multispecific therapeutics present a promising approach for targeted disease intervention. These therapeutics are designed to interact with multiple targets simultaneously, promising enhanced efficacy, reduced side effects, and resilience against drug resistance. We dissect the principles guiding the design of multivalent biologics, highlighting challenges and strategies that must be considered to maximize therapeutic effect. Engineerable elements in multivalent and multispecific biologic design-domain affinities, valency, and spatial presentation-must be considered in the context of the molecular targets as well as the balance of important properties such as target avidity and specificity. We illuminate recent applications of these principles in designing protein and cell therapies and identify exciting future directions in this field, underscored by advances in biomolecular and cellular engineering and computational approaches. Expected final online publication date for the Annual Review of Chemical and Biomolecular Engineering , Volume 15 is June 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Jennifer J Kang
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA; , ,
| | - Ayako Ohoka
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA; , ,
- Present affiliation: AbbVie Inc., North Chicago, Illinois, USA
| | - Casim A Sarkar
- Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota, USA; , ,
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22
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Guo X, Wu Y, Xue Y, Xie N, Shen G. Revolutionizing cancer immunotherapy: unleashing the potential of bispecific antibodies for targeted treatment. Front Immunol 2023; 14:1291836. [PMID: 38106416 PMCID: PMC10722299 DOI: 10.3389/fimmu.2023.1291836] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 11/08/2023] [Indexed: 12/19/2023] Open
Abstract
Recent progressions in immunotherapy have transformed cancer treatment, providing a promising strategy that activates the immune system of the patient to find and eliminate cancerous cells. Bispecific antibodies, which engage two separate antigens or one antigen with two distinct epitopes, are of tremendous concern in immunotherapy. The bi-targeting idea enabled by bispecific antibodies (BsAbs) is especially attractive from a medical standpoint since most diseases are complex, involving several receptors, ligands, and signaling pathways. Several research look into the processes in which BsAbs identify different cancer targets such angiogenesis, reproduction, metastasis, and immune regulation. By rerouting cells or altering other pathways, the bispecific proteins perform effector activities in addition to those of natural antibodies. This opens up a wide range of clinical applications and helps patients with resistant tumors respond better to medication. Yet, further study is necessary to identify the best conditions where to use these medications for treating tumor, their appropriate combination partners, and methods to reduce toxicity. In this review, we provide insights into the BsAb format classification based on their composition and symmetry, as well as the delivery mode, focus on the action mechanism of the molecule, and discuss the challenges and future perspectives in BsAb development.
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Affiliation(s)
- Xiaohan Guo
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yi Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Ying Xue
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Na Xie
- West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Guobo Shen
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
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23
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Strati P, Spiotto MT. Incorporating Immunotherapy with Radiotherapy for Lymphomas. LYMPHATICS 2023; 1:273-286. [PMID: 39917366 PMCID: PMC11800356 DOI: 10.3390/lymphatics1030018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
Radiotherapy and/or chemotherapy have been used for nearly 100 years to treat lymphoma. Recently, immunotherapy has been incorporated into the treatment of lymphomas. Here, we will review both the role of immunotherapy in lymphoma as well as the feasibility of incorporating immunotherapies with conventional lymphoma treatments, especially radiotherapy. Immunotherapy agents include checkpoint inhibitors that target the PD-1/PD-L1 axis, CTLA-4, or CD47. In addition, other immunotherapy agents such as bi-specific antibodies and CD19 CAR-T cell therapy are being implemented in various non-Hodgkin's lymphomas. Extrapolating from observations in other disease sites and incorporating immunotherapy with conventional treatments of lymphoma, including radiotherapy, may have opposing effects. Radiotherapy may stimulate anti-tumor immune responses that synergize with immunotherapies. In contrast, radiotherapy, as well as chemotherapy, may also induce local and systemic immune dysfunction which reduces the efficacy of immunotherapies. With newer radiation treatment techniques and limited radiation fields, it is likely that the efficacy of immunotherapy can be maintained when included with conventional treatments. Therefore, there remains an unmet need to better understand the role of immunotherapy alone and in combination with current treatments in lymphoma patients.
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Affiliation(s)
- Paolo Strati
- Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael T. Spiotto
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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24
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Decombis S, Bellanger C, Le Bris Y, Madiot C, Jardine J, Santos JC, Boulet D, Dousset C, Menard A, Kervoelen C, Douillard E, Moreau P, Minvielle S, Moreau-Aubry A, Tessoulin B, Roue G, Bidère N, Le Gouill S, Pellat-Deceunynck C, Chiron D. CARD11 gain of function upregulates BCL2A1 expression and promotes resistance to targeted therapies combination in B-cell lymphoma. Blood 2023; 142:1543-1555. [PMID: 37562004 DOI: 10.1182/blood.2023020211] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 07/07/2023] [Accepted: 07/07/2023] [Indexed: 08/12/2023] Open
Abstract
A strategy combining targeted therapies is effective in B-cell lymphomas (BCL), such as mantle cell lymphoma (MCL), but acquired resistances remain a recurrent issue. In this study, we performed integrative longitudinal genomic and single-cell RNA-sequencing analyses of patients with MCL who were treated with targeted therapies against CD20, BCL2, and Bruton tyrosine kinase (OAsIs trial). We revealed the emergence of subclones with a selective advantage against OAsIs combination in vivo and showed that resistant cells were characterized by B-cell receptor (BCR)-independent overexpression of NF-κB1 target genes, especially owing to CARD11 mutations. Functional studies demonstrated that CARD11 gain of function not only resulted in BCR independence but also directly increased the transcription of the antiapoptotic BCL2A1, leading to resistance against venetoclax and OAsIs combination. Based on the transcriptional profile of OAsIs-resistant subclones, we designed a 16-gene resistance signature that was also predictive for patients with MCL who were treated with conventional chemotherapy, underlying a common escape mechanism. Among druggable strategies to inhibit CARD11-dependent NF-κB1 transduction, we evaluated the selective inhibition of its essential partner MALT1. We demonstrated that MALT1 protease inhibition led to a reduction in the expression of genes involved in OAsIs resistance, including BCL2A1. Consequently, MALT1 inhibition induced synergistic cell death in combination with BCL2 inhibition, irrespective of CARD11 mutational status, both in vitro and in vivo. Taken together, our study identified mechanisms of resistance to targeted therapies and provided a novel strategy to overcome resistance in aggressive BCL. The OAsIs trial was registered at www.clinicaltrials.gov #NCT02558816.
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Affiliation(s)
- Salomé Decombis
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Celine Bellanger
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Yannick Le Bris
- Hematology Department, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Candice Madiot
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Jane Jardine
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | | | - Delphine Boulet
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Christelle Dousset
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Audrey Menard
- Hematology Department, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Charlotte Kervoelen
- Therassay (Onco-Hemato) Core Facility, Nantes Université, Capacités, Nantes, France
| | - Elise Douillard
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Philippe Moreau
- Hematology Department, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Stephane Minvielle
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Agnes Moreau-Aubry
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Benoit Tessoulin
- Hematology Department, Nantes Université, Centre Hospitalier Universitaire de Nantes, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | - Gael Roue
- Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain
| | - Nicolas Bidère
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
| | | | | | - David Chiron
- Hematology Department, Nantes Université, INSERM, CNRS, Université d'Angers, CRCI2NA, Nantes, France
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25
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Raghani NR, Shah DD, Shah TS, Chorawala MR, Patel RB. Combating relapsed and refractory Mantle cell lymphoma with novel therapeutic armamentarium: Recent advances and clinical prospects. Crit Rev Oncol Hematol 2023; 190:104085. [PMID: 37536448 DOI: 10.1016/j.critrevonc.2023.104085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/27/2023] [Accepted: 07/30/2023] [Indexed: 08/05/2023] Open
Abstract
Mantle cell lymphoma (MCL) is a rare, aggressive subtype of non-Hodgkin's lymphoma (NHL), accounting for 5% of all cases. Due to its virulence factor, it is an incurable disease and keeps relapsing despite an intensive treatment regimen. Advancements in research and drug discovery have shifted the treatment strategy from conventional chemotherapy to targeted agents and immunotherapies. The establishment of the role of Bruton tyrosine kinase led to the development of ibrutinib, a first-generation BTK inhibitor, and its successors. A conditioning regimen based immunotherapeutic agent like ibritumumob, has also demonstrated a viable response with a favorable toxicity profile. Brexucabtagene Autoleucel, the only approved CAR T-cell therapy, has proven advantageous for relapsed/refractory MCL in both children and adults. This article reviews certain therapies that could help update the current approach and summarizes a few miscellaneous agents, which, seldom studied in trials, could alleviate the regression observed in traditional therapies. DATA AVAILABILITY: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Affiliation(s)
- Neha R Raghani
- Department of Pharmacology and Pharmacy practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Disha D Shah
- Department of Pharmacology and Pharmacy practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Tithi S Shah
- Department of Pharmacology and Pharmacy practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy practice, L. M. College of Pharmacy, Opp. Gujarat University, Navrangpura, Ahmedabad 380009, Gujarat, India.
| | - Rakesh B Patel
- Department of Internal Medicine, Division of Hematology and Oncology, UI Carver College of Medicine: The University of Iowa Roy J and Lucille A Carver College of Medicine, 375 Newton Rd, Iowa City, IA 52242, USA.
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26
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Chen CJJ, Choi MY, Heyman BM. Targeted Therapy in Follicular Lymphoma: Towards a Chemotherapy-Free Approach. Cancers (Basel) 2023; 15:4483. [PMID: 37760453 PMCID: PMC10526830 DOI: 10.3390/cancers15184483] [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: 06/12/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/29/2023] Open
Abstract
BACKGROUND The treatment of follicular lymphoma (FL) has previously centered on chemoimmunotherapy, which can be disadvantageous due to patient intolerance, cumulative toxicities, and disease refractoriness. Targeted therapies can produce deep responses and improve progression-free and overall survival with more tolerable adverse event profiles. METHODS We summarize the current literature and key clinical trials regarding targeted therapies in follicular lymphoma both in the front-line and in the relapsed-refractory setting. RESULTS Targeted therapies studied in FL include immune modulators, anti-CD20 antibodies, Bruton's tyrosine kinase (BTK) inhibitors, enhancers of zeste homolog 2 (EZH2) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL-2) inhibitors. Chimeric antigen receptor (CAR-T) therapy and bispecific T-cell engager (BiTE) therapies also show promise in monotherapy and in combination with targeted therapies. These therapies exhibit high overall response rates and substantial progression-free survival and overall survival, even in high-risk patients or patients previously refractory to chemotherapy or rituximab. Adverse events vary substantially but are generally manageable and compare favorably to the cumulative toxicities of chemotherapy. CONCLUSION Targeted therapies represent a paradigm shift in the treatment of FL. Further studies are needed to directly compare these targeted therapies and their combinations, as well as to investigate biomarkers predictive of response.
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Affiliation(s)
- Chung-Jiah J. Chen
- Department of Medicine, Division of Hematology-Oncology, UC San Diego Health, La Jolla, CA 92037, USA; (C.-J.J.C.); (M.Y.C.)
| | - Michael Y. Choi
- Department of Medicine, Division of Hematology-Oncology, UC San Diego Health, La Jolla, CA 92037, USA; (C.-J.J.C.); (M.Y.C.)
| | - Benjamin M. Heyman
- Department of Medicine, Division of Regenerative Medicine, UC San Diego Health, La Jolla, CA 92037, USA
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27
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Mak JWY, Law AWH, Law KWT, Ho R, Cheung CKM, Law MF. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era. World J Gastroenterol 2023; 29:4942-4961. [PMID: 37731995 PMCID: PMC10507505 DOI: 10.3748/wjg.v29.i33.4942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/22/2023] [Accepted: 08/15/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatitis due to hepatitis B virus (HBV) reactivation can be serious and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. Patients with inactive and even resolved HBV infection still have persistence of HBV genomes in the liver. The expression of these silent genomes is controlled by the immune system. Suppression or ablation of immune cells, most importantly B cells, may lead to reactivation of seemingly resolved HBV infection. Thus, all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen. Patients found to be positive for HBsAg should be given prophylactic antiviral therapy. For patients with resolved HBV infection, there are two approaches. The first is pre-emptive therapy guided by serial HBV DNA monitoring, and treatment with antiviral therapy as soon as HBV DNA becomes detectable. The second approach is prophylactic antiviral therapy, particularly for patients receiving high-risk therapy, especially anti-CD20 monoclonal antibody or hematopoietic stem cell transplantation. Entecavir and tenofovir are the preferred antiviral choices. Many new effective therapies for hematological malignancies have been introduced in the past decade, for example, chimeric antigen receptor (CAR)-T cell therapy, novel monoclonal antibodies, bispecific antibody drug conjugates, and small molecule inhibitors, which may be associated with HBV reactivation. Although there is limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, including Bruton's tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and CAR-T cell therapy. Further studies are needed to determine the risk of HBV reactivation with these agents and the best prophylactic strategy.
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Affiliation(s)
- Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | | | | | - Rita Ho
- Department of Medicine, North District Hospital, Hong Kong 852, China
| | - Carmen Ka Man Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | - Man Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
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28
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Abstract
Epcoritamab (epcoritamab-bysp; Epkinly™; Tepkinly®) is a subcutaneously administered CD3×CD20 T-cell-engaging bispecific antibody being co-developed by Genmab and AbbVie for the treatment of mature B-cell non-Hodgkin lymphoma subtypes (B-NHLs), including diffuse large B-cell lymphoma (DLBCL). Epcoritamab received its first (conditional) approval on 19 May 2023, in the USA, for the treatment of adult patients with relapsed or refractory (R/R) DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥ 2 lines of systemic therapy. Elsewhere, epcoritamab has received a positive opinion in the EU as a monotherapy for the treatment of adults with R/R DLBCL after ≥ 2 lines of systemic therapy, and is currently under regulatory review in Japan for the treatment of adults with R/R large B-cell lymphoma after ≥ 2 lines of systemic therapy. Clinical development of epcoritamab as monotherapy and in combination with standard of care agents for the treatment of mature B-NHLs is ongoing globally. This article summarizes the milestones in the development of epcoritamab leading to this first approval for R/R DLBCL.
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Affiliation(s)
- James E Frampton
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand.
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29
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Roemer MG, van de Brug T, Bosch E, Berry D, Hijmering N, Stathi P, Weijers K, Doorduijn J, Bromberg J, van de Wiel M, Ylstra B, de Jong D, Kim Y. Multi-scale spatial modeling of immune cell distributions enables survival prediction in primary central nervous system lymphoma. iScience 2023; 26:107331. [PMID: 37539043 PMCID: PMC10393746 DOI: 10.1016/j.isci.2023.107331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 05/15/2023] [Accepted: 07/05/2023] [Indexed: 08/05/2023] Open
Abstract
To understand the clinical significance of the tumor microenvironment (TME), it is essential to study the interactions between malignant and non-malignant cells in clinical specimens. Here, we established a computational framework for a multiplex imaging system to comprehensively characterize spatial contexts of the TME at multiple scales, including close and long-distance spatial interactions between cell type pairs. We applied this framework to a total of 1,393 multiplex imaging data newly generated from 88 primary central nervous system lymphomas with complete follow-up data and identified significant prognostic subgroups mainly shaped by the spatial context. A supervised analysis confirmed a significant contribution of spatial context in predicting patient survival. In particular, we found an opposite prognostic value of macrophage infiltration depending on its proximity to specific cell types. Altogether, we provide a comprehensive framework to analyze spatial cellular interaction that can be broadly applied to other technologies and tumor contexts.
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Affiliation(s)
- Margaretha G.M. Roemer
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Tim van de Brug
- Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Erik Bosch
- Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Department of Mathematics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Daniella Berry
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Nathalie Hijmering
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
- HOVON Pathology Facility and Biobank (HOP), Department of Pathology, Amsterdam University Medical Centre, Amsterdam, The Netherlands
| | - Phylicia Stathi
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Karin Weijers
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Jeannette Doorduijn
- Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jacoline Bromberg
- Department of Neuro-Oncology, Erasmus MC Cancer Institute, Brain Tumor Center, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Mark van de Wiel
- Department of Epidemiology and Data Science, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Bauke Ylstra
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Daphne de Jong
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Yongsoo Kim
- Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Pathology, Cancer Center Amsterdam, Amsterdam, The Netherlands
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30
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Gambles MT, Yang J, Kopeček J. Multi-targeted immunotherapeutics to treat B cell malignancies. J Control Release 2023; 358:232-258. [PMID: 37121515 PMCID: PMC10330463 DOI: 10.1016/j.jconrel.2023.04.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/20/2023] [Accepted: 04/27/2023] [Indexed: 05/02/2023]
Abstract
The concept of multi-targeted immunotherapeutic systems has propelled the field of cancer immunotherapy into an exciting new era. Multi-effector molecules can be designed to engage with, and alter, the patient's immune system in a plethora of ways. The outcomes can vary from effector cell recruitment and activation upon recognition of a cancer cell, to a multipronged immune checkpoint blockade strategy disallowing evasion of the cancer cells by immune cells, or to direct cancer cell death upon engaging multiple cell surface receptors simultaneously. Here, we review the field of multi-specific immunotherapeutics implemented to treat B cell malignancies. The mechanistically diverse strategies are outlined and discussed; common B cell receptor antigen targeting strategies are outlined and summarized; and the challenges of the field are presented along with optimistic insights for the future.
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Affiliation(s)
- M Tommy Gambles
- Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, USA
| | - Jiyuan Yang
- Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, USA.
| | - Jindřich Kopeček
- Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, USA; Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, UT 84112, USA; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, USA.
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Amitai I, Roos K, Rashedi I, Jiang Y, Mangoff K, Klein G, Forward N, Stewart D, Laneuville P, Bence-Bruckler I, Mangel J, Tomlinson G, Berinstein NL. PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL. Eur J Haematol 2023. [PMID: 37157906 DOI: 10.1111/ejh.13982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 04/11/2023] [Accepted: 04/12/2023] [Indexed: 05/10/2023]
Abstract
BACKGROUND Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. METHODS R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. FINDINGS We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. INTERPRETATION This immunotherapy combination was found to be active and safe in this clinically challenging patient population.
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Affiliation(s)
- Irina Amitai
- Sunnybrook Health Sciences Centre, Toronto, Canada
- Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Kim Roos
- Sunnybrook Research Institute, Toronto, Canada
| | | | - Yidi Jiang
- Sunnybrook Research Institute, Toronto, Canada
| | | | - Gail Klein
- Sunnybrook Research Institute, Toronto, Canada
| | | | | | | | | | - Joy Mangel
- London Health Sciences Centre, London, Canada
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Falchi L, Vardhana SA, Salles GA. Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities. Blood 2023; 141:467-480. [PMID: 36322929 PMCID: PMC9936308 DOI: 10.1182/blood.2021011994] [Citation(s) in RCA: 102] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/26/2022] [Accepted: 10/12/2022] [Indexed: 02/03/2023] Open
Abstract
Treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHL) have shifted dramatically in the last 2 decades following the introduction of highly active immunotherapies such as rituximab. Since then, the field has continued to witness tremendous progress with the introduction of newer, more potent immunotherapeutics, including chimeric antigen receptor T-cell therapy, which have received regulatory approval for and currently play a significant role in the treatment of these diseases. Bispecific antibodies (BsAb) are a novel class of off-the-shelf T-cell redirecting drugs and are among the most promising immunotherapeutics for lymphoma today. BsAb may target various cell-surface antigens and exist in different formats. Anti-CD20xCD3 BsAb have demonstrated remarkable single-agent activity in patients with heavily pretreated B-NHL with a manageable toxicity profile dominated by T-cell overactivation syndromes. Much work remains to be done to define the optimal setting in which to deploy these drugs for B-NHL treatment, their ideal combination partners, strategies to minimize toxicity, and, perhaps most importantly, pharmacodynamic biomarkers of response and resistance. In this review, we provide an update on BsAb development in B-NHL, from discovery to clinical applications, highlighting the achievements, limitations, and future directions of the field.
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Affiliation(s)
- Lorenzo Falchi
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Santosha A. Vardhana
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gilles A. Salles
- Lymphoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, Do YR, Feldman T, Gasiorowski R, Jurczak W, Kim TM, Lewis DJ, van der Poel M, Poon ML, Cota Stirner M, Kilavuz N, Chiu C, Chen M, Sacchi M, Elliott B, Ahmadi T, Hutchings M, Lugtenburg PJ. Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol 2022; 41:2238-2247. [PMID: 36548927 PMCID: PMC10115554 DOI: 10.1200/jco.22.01725] [Citation(s) in RCA: 281] [Impact Index Per Article: 93.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE Epcoritamab is a subcutaneously administered CD3xCD20 T-cell-engaging, bispecific antibody that activates T cells, directing them to kill malignant CD20+ B cells. Single-agent epcoritamab previously demonstrated potent antitumor activity in dose escalation across B-cell non-Hodgkin lymphoma subtypes. PATIENTS AND METHODS In the dose-expansion cohort of a phase I/II study (ClinicalTrials.gov identifier: NCT03625037), adults with relapsed or refractory CD20+ large B-cell lymphoma and at least two prior therapy lines (including anti-CD20 therapies) received subcutaneous epcoritamab in 28-day cycles (once weekly step-up doses in weeks 1-3 of cycle 1, then full doses once weekly through cycle 3, once every 2 weeks in cycles 4-9, and once every 4 weeks in cycle 10 and thereafter) until disease progression or unacceptable toxicity. The primary end point was overall response rate by the independent review committee. RESULTS As of January 31, 2022, 157 patients were treated (median age, 64 years [range, 20-83]; median of three [range, 2-11] prior therapy lines; primary refractory disease: 61.1%; prior chimeric antigen receptor (CAR) T-cell exposure: 38.9%). At a median follow-up of 10.7 months, the overall response rate was 63.1% (95% CI, 55.0 to 70.6) and the complete response rate was 38.9% (95% CI, 31.2 to 46.9). The median duration of response was 12.0 months (among complete responders: not reached). Overall and complete response rates were similar across key prespecified subgroups. The most common treatment-emergent adverse events were cytokine release syndrome (49.7%; grade 1 or 2: 47.1%; grade 3: 2.5%), pyrexia (23.6%), and fatigue (22.9%). Immune effector cell-associated neurotoxicity syndrome occurred in 6.4% of patients with one fatal event. CONCLUSION Subcutaneous epcoritamab resulted in deep and durable responses and manageable safety in highly refractory patients with large B-cell lymphoma, including those with prior CAR T-cell exposure.
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Affiliation(s)
- Catherine Thieblemont
- Assistance Publique & Hôpitaux de Paris (APHP), Hôpital Saint-Louis, Hémato-oncologie, Université de Paris, Paris, France
| | - Tycel Phillips
- University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
| | - Herve Ghesquieres
- Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Bénite, France
| | - Chan Y Cheah
- Sir Charles Gairdner Hospital, Perth, Australia.,Division of Internal Medicine, Medical School, University of Western Australia, Perth, Australia
| | | | | | - Young Rok Do
- Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Tatyana Feldman
- Hackensack Meridian Health Hackensack University Medical Center, Hackensack, NJ
| | | | | | - Tae Min Kim
- Seoul National University Hospital, Seoul, Republic of Korea
| | - David John Lewis
- University Hospitals Plymouth NHS Trust, Derriford Hospital, Plymouth, United Kingdom
| | - Marjolein van der Poel
- On behalf of the Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Maastricht, Department of Internal Medicine, Division of Hematology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | | | | | | | | | | | | | | | | | - Martin Hutchings
- Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
| | - Pieternella J Lugtenburg
- On behalf of the Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Erasmus MC Cancer Institute, University Medical Center, Department of Hematology, Rotterdam, the Netherlands
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Tannoury M, Garnier D, Susin SA, Bauvois B. Current Status of Novel Agents for the Treatment of B Cell Malignancies: What's Coming Next? Cancers (Basel) 2022; 14:6026. [PMID: 36551511 PMCID: PMC9775488 DOI: 10.3390/cancers14246026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/13/2022] Open
Abstract
Resistance to death is one of the hallmarks of human B cell malignancies and often contributes to the lack of a lasting response to today's commonly used treatments. Drug discovery approaches designed to activate the death machinery have generated a large number of inhibitors of anti-apoptotic proteins from the B-cell lymphoma/leukemia 2 family and the B-cell receptor (BCR) signaling pathway. Orally administered small-molecule inhibitors of Bcl-2 protein and BCR partners (e.g., Bruton's tyrosine kinase and phosphatidylinositol-3 kinase) have already been included (as monotherapies or combination therapies) in the standard of care for selected B cell malignancies. Agonistic monoclonal antibodies and their derivatives (antibody-drug conjugates, antibody-radioisotope conjugates, bispecific T cell engagers, and chimeric antigen receptor-modified T cells) targeting tumor-associated antigens (TAAs, such as CD19, CD20, CD22, and CD38) are indicated for treatment (as monotherapies or combination therapies) of patients with B cell tumors. However, given that some patients are either refractory to current therapies or relapse after treatment, novel therapeutic strategies are needed. Here, we review current strategies for managing B cell malignancies, with a focus on the ongoing clinical development of more effective, selective drugs targeting these molecules, as well as other TAAs and signaling proteins. The observed impact of metabolic reprogramming on B cell pathophysiology highlights the promise of targeting metabolic checkpoints in the treatment of these disorders.
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Affiliation(s)
| | | | | | - Brigitte Bauvois
- Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Cité, Inserm, Cell Death and Drug Resistance in Lymphoproliferative Disorders Team, F-75006 Paris, France
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35
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Iovino L, Wu QV, Voutsinas J, Panaite L, Mullane E, Lynch RC, Ujjani C, Smith SD, Gopal AK, Till BG, Milano F, Chow V, Gauthier J, Turtle CJ, Maloney DG, Shadman M. Predictors of response to axicabtagene-ciloleucel CAR T cells in aggressive B cell lymphomas: A real-world study. J Cell Mol Med 2022; 26:5976-5983. [PMID: 36453136 PMCID: PMC9753434 DOI: 10.1111/jcmm.17550] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 07/06/2022] [Accepted: 07/29/2022] [Indexed: 12/03/2022] Open
Abstract
Chimeric antigen receptor T-cell (CAR T) therapy has shown promising efficacy in relapsed and refractory diffuse large B cell lymphoma (DLBCL). While most patients undergo CAR T infusion with active disease, the impact of some clinical variables, such as responsiveness to the pre-CAR T chemotherapy on the response to CAR T, is unknown. In this single-institution study, we studied the impact of several pre-CAR T variables on the post-CAR outcomes. Sixty patients underwent apheresis for axicabtagene-ciloleucel (axi-cel) and 42 of them (70.0%) had primary refractory disease. Bridging therapy between apheresis and lymphodepletion was given in 34 patients (56.7%). After axi-cel, the overall response rate was 63.3%. Responsiveness to the immediate pre-CAR T therapy did not show a significant association with response to axi-cel, progression-free (PFS) or overall (OS) survival. Multivariable analysis determined that bulky disease before lymphodepletion was independently associated with inferior outcomes, and patients that presented with high-burden disease unresponsive to immediate pre-CAR T therapy had a dismal outcome. This data supports proceeding with treatment in CAR T candidates regardless of their response to immediate pre-CAR T therapy. Interim therapeutic interventions should be considered in patients who have known risk factors for poor outcomes (bulky disease, high LDH).
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Affiliation(s)
- Lorenzo Iovino
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Qian Vicky Wu
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Jenna Voutsinas
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA
| | - Lorena Panaite
- Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Erin Mullane
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Ryan C. Lynch
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Chaitra Ujjani
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Stephen D. Smith
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Ajay K. Gopal
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Brian G. Till
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Filippo Milano
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Victor Chow
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Jordan Gauthier
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Cameron J. Turtle
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - David G. Maloney
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
| | - Mazyar Shadman
- Clinical Research DivisionFred Hutchinson Cancer Research CenterSeattleWashingtonUSA,Department of MedicineUniversity of WashingtonSeattleWashingtonUSA
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Li T, Hiemstra IH, Chiu C, Oliveri RS, Elliott B, DeMarco D, Salcedo T, Egerod FL, Sasser K, Ahmadi T, Gupta M. Semimechanistic Physiologically-Based Pharmacokinetic/Pharmacodynamic Model Informing Epcoritamab Dose Selection for Patients With B-Cell Lymphomas. Clin Pharmacol Ther 2022; 112:1108-1119. [PMID: 35996883 PMCID: PMC9827893 DOI: 10.1002/cpt.2729] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/09/2022] [Indexed: 01/11/2023]
Abstract
Epcoritamab is a CD3xCD20 bispecific antibody (bsAb) that induces T-cell-mediated cytotoxicity against CD20-positive B cells. Target engagement and crosslinking of CD3 and CD20 (trimer formation) leads to activation and expansion of T cells and killing of malignant B cells. The primary objective of the dose-escalation part of the phase I/II trial of epcoritamab was to determine the maximum tolerated dose, recommended phase II dose (RP2D), or both. For bsAbs, high target saturation can negatively affect trimer formation. The unique properties and mechanisms of action of bsAbs require novel pharmacokinetic (PK) modeling methods to predict clinical activity and inform RP2D selection. Traditional PK/pharmacodynamic (PD) modeling approaches are inappropriate because they may not adequately predict exposure-response relationships. We developed a semimechanistic, physiologically-based PK/PD model to quantitatively describe biodistribution, trimer formation, and tumor response using preclinical, clinical PK, biomarker, tumor, and response data from the dose-escalation part of the phase I/II trial. Clinical trial simulations were performed to predict trimer formation and tumor response in patients with diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Model-predicted trimer formation plateaued at doses of 48 to 96 mg. Simulation results suggest that the 48-mg dose may achieve optimal response rates in DLBCL and FL. Exposure-safety analyses showed a flat relationship between epcoritamab exposure and risk of cytokine release syndrome in the dose range evaluated. This novel PK/PD modeling approach guided selection of 48 mg as the RP2D and provides a framework that may be applied to other CD3 bsAbs.
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Qualls D, Kumar A, Epstein-Peterson Z. Targeting the immune microenvironment in mantle cell lymphoma: implications for current and emerging therapies. Leuk Lymphoma 2022; 63:2515-2527. [PMID: 35704674 PMCID: PMC9741766 DOI: 10.1080/10428194.2022.2086244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 05/21/2022] [Accepted: 05/27/2022] [Indexed: 12/14/2022]
Abstract
Mantle cell lymphoma (MCL) is a morphologically and phenotypically heterogeneous subtype of non-Hodgkin lymphoma, and has historically been associated with poor outcomes. However, recent advances in our understanding of this disease have yielded new targeted and immune-based therapies with promising activity. Immune-based therapies such as monoclonal antibodies, immunomodulators, and CAR T cells have significantly improved outcomes and are now standard of care in MCL. In this review, we describe our current understanding of the immune microenvironment of MCL, discuss current immunotherapeutic approaches, and highlight promising novel immune-based therapies and combination therapies that may further improve outcomes for patients with MCL.
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Affiliation(s)
- David Qualls
- Lymphoma Service, Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center. New York, NY, USA
| | - Anita Kumar
- Lymphoma Service, Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center. New York, NY, USA
| | - Zachary Epstein-Peterson
- Lymphoma Service, Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center. New York, NY, USA
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Kusowska A, Kubacz M, Krawczyk M, Slusarczyk A, Winiarska M, Bobrowicz M. Molecular Aspects of Resistance to Immunotherapies-Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma. Int J Mol Sci 2022; 23:ijms23031501. [PMID: 35163421 PMCID: PMC8835809 DOI: 10.3390/ijms23031501] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/22/2022] [Accepted: 01/26/2022] [Indexed: 12/28/2022] Open
Abstract
Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens.
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Affiliation(s)
- Aleksandra Kusowska
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
- Doctoral School, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Matylda Kubacz
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
| | - Marta Krawczyk
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
- Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
- Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, 01-813 Warsaw, Poland
| | - Aleksander Slusarczyk
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
- Department of General, Oncological and Functional Urology, Medical University of Warsaw, 02-005 Warsaw, Poland
| | - Magdalena Winiarska
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
- Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland
| | - Malgorzata Bobrowicz
- Department of Immunology, Medical University of Warsaw, 02-097 Warsaw, Poland; (A.K.); (M.K.); (M.K.); (A.S.); (M.W.)
- Correspondence:
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Romancik JT, Cohen JB. Sequencing of Novel Therapies for Mantle Cell Lymphoma. Curr Treat Options Oncol 2021; 22:118. [PMID: 34812968 DOI: 10.1007/s11864-021-00907-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2021] [Indexed: 12/20/2022]
Abstract
OPINION STATEMENT There is no standard approach to sequencing novel therapies in mantle cell lymphoma (MCL). For initial treatment, intensive induction chemotherapy followed by autologous stem cell transplant and rituximab maintenance remains our preferred approach in young, fit patients. We consider bendamustine plus rituximab or lenalidomide plus rituximab in patients who are ineligible for intensive chemotherapy-based approaches. Bruton's tyrosine kinase inhibitors are our preferred class of agents to use in the second-line setting. When patients inevitably relapse on one of these agents, we proceed with chimeric antigen receptor T-cell (CAR T) therapy in eligible patients, often with the use of bridging therapy with corticosteroids, lenalidomide, or venetoclax. We treat patients who are ineligible for CAR T or clinic trial with venetoclax, lenalidomide, or proteosome inhibitor-based regimens, although efficacy is expected to be limited in this setting with a shortened duration of response to each subsequent line of therapy. Allogeneic stem cell transplant remains an option for carefully selected patients who progress after autologous stem cell transplant and CAR T. Clinical trials involving combinations of novel agents in early lines of therapy are ongoing, and new compounds with unique mechanisms of action are in development. The results of ongoing clinical trials with novel agents will further change the treatment landscape for patients with MCL in the coming years.
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Affiliation(s)
- Jason T Romancik
- Department of Hematology and Medical Oncology, Winship Cancer Institute At Emory University, Atlanta, GA, USA
| | - Jonathon B Cohen
- Department of Hematology and Medical Oncology, Winship Cancer Institute At Emory University, Atlanta, GA, USA.
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40
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Rampotas A, Sangha G, Collins GP. Integration of cell therapies and bispecific antibodies into the treatment pathway of relapsed diffuse large B-cell lymphoma. Ther Adv Hematol 2021; 12:20406207211053120. [PMID: 34733463 PMCID: PMC8558790 DOI: 10.1177/20406207211053120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Affiliation(s)
| | - Gina Sangha
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Graham P Collins
- Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Old Road, Headington, Oxford OX3 7LE, UK
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41
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Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, Lewis DJ, Sureda Balari A, Cunningham D, Oliveri RS, Elliott B, DeMarco D, Azaryan A, Chiu C, Li T, Chen KM, Ahmadi T, Lugtenburg PJ. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet 2021; 398:1157-1169. [PMID: 34508654 DOI: 10.1016/s0140-6736(21)00889-8] [Citation(s) in RCA: 211] [Impact Index Per Article: 52.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/19/2021] [Accepted: 04/13/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND Patients with relapsed or refractory B-cell non-Hodgkin lymphoma have few treatment options. We aimed to establish the safety and recommended phase 2 dose of epcoritamab, a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells. METHODS For the dose-escalation part of this phase 1/2 study, we enrolled adults (aged ≥18 years) with relapsed or refractory CD20+ B-cell non-Hodgkin lymphoma at ten sites across four countries (Denmark, the Netherlands, the UK, and Spain). Eligible patients received priming and intermediate doses followed by full doses of subcutaneous epcoritamab administered in 28-day cycles; each subsequent cohort involved escalation of the priming, intermediate, or full dose (0·0128-60 mg). The primary objectives were to determine the maximum tolerated dose and the recommended phase 2 dose. Safety, antitumour activity, pharmacokinetics, and immune biomarkers were also assessed. This study is registered with ClinicalTrials.gov, NCT03625037, with the dose-expansion part ongoing. FINDINGS Between June 26, 2018, and July 14, 2020, we enrolled 73 patients with relapsed, progressive, or refractory CD20+ mature B-cell non-Hodgkin lymphoma. 68 patients received escalating full doses (0·0128-60 mg) of subcutaneous epcoritamab. No dose-limiting toxic effects were observed, and the maximum tolerated dose was not reached; the full dose of 48 mg was identified as the recommended phase 2 dose. All 68 patients received at least one dose of epcoritamab and were included in safety analyses: common adverse events were pyrexia (47 patients [69%]), primarily associated with cytokine release syndrome (CRS; 40 [59%], all grade 1-2), and injection site reactions (32 [47%]; 31 grade 1). There were no grade 3 or higher CRS events. No discontinuations occurred due to treatment-related adverse events or treatment-related deaths. Overall response rate in patients with relapsed or refractory diffuse large B-cell lymphoma was 68% (95% CI 45-86), with 45% achieving a complete response at full doses of 12-60 mg. At 48 mg, the overall response rate was 88% (47-100), with 38% achieving a complete response. Patients with relapsed or refractory follicular lymphoma had an overall response rate of 90% (55-100), with 50% achieving a complete response at full doses of 0·76-48 mg. Epcoritamab induced robust and sustained B-cell depletion, and CD4+ and CD8+ T-cell activation and expansion, with modest increases in cytokine levels. INTERPRETATION Single-agent subcutaneous epcoritamab for treatment of patients with relapsed or refractory B-cell non-Hodgkin lymphoma merits investigation in ongoing phase 2 and phase 3 studies. FUNDING Genmab and AbbVie.
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Affiliation(s)
| | - Rogier Mous
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Universitair Medisch Centrum Utrecht, Utrecht, Netherlands
| | | | - Peter Johnson
- Cancer Research UK, Cancer Services, University of Southampton, Southampton, UK
| | - Kim M Linton
- Manchester Cancer Research Centre, The Christie NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Martine E D Chamuleau
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, VU University Medical Center, Amsterdam, Netherlands
| | | | - Anna Sureda Balari
- Institut Català d'Oncologia-Hospital Duran i Reynals, IDIBELL, L'Hospitalet de Llobregat, Universitat de Barcelona, Barcelona, Spain
| | | | | | | | | | | | | | | | | | | | - Pieternella J Lugtenburg
- Lunenburg Lymphoma Phase I/II Consortium-HOVON/LLPC, Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
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Wang S, Chen K, Lei Q, Ma P, Yuan AQ, Zhao Y, Jiang Y, Fang H, Xing S, Fang Y, Jiang N, Miao H, Zhang M, Sun S, Yu Z, Tao W, Zhu Q, Nie Y, Li N. The state of the art of bispecific antibodies for treating human malignancies. EMBO Mol Med 2021; 13:e14291. [PMID: 34431224 PMCID: PMC8422067 DOI: 10.15252/emmm.202114291] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/08/2021] [Accepted: 07/09/2021] [Indexed: 12/26/2022] Open
Abstract
Bispecific antibodies (bsAb) that target two independent epitopes or antigens have been extensively explored in translational and clinical studies since they were first developed in the 1960s. Many bsAbs are being tested in clinical trials for treating a variety of diseases, mostly cancer. Here, we provide an overview of various types of bsAbs in clinical studies and discuss their targets, safety profiles, and efficacy. We also highlight the current challenges, potential solutions, and future directions of bsAb development for cancer treatment.
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Affiliation(s)
- Shuhang Wang
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Kun Chen
- NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non‐profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003)Guizhou Provincial People’s HospitalGuiyangChina
| | - Qi Lei
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Peiwen Ma
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | | | - Yong Zhao
- Nanjing Umab‐biopharma Co., LtdNanjingChina
| | | | - Hong Fang
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Shujun Xing
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Yuan Fang
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Ning Jiang
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Huilei Miao
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
| | - Minghui Zhang
- Department of Medical OncologyHarbin Medical University Cancer HospitalHarbinChina
| | - Shujun Sun
- Queen Mary SchoolNanchang UniversityNanchangChina
| | | | - Wei Tao
- China Pharmaceutical UniversityNanjingChina
| | - Qi Zhu
- China Pharmaceutical UniversityNanjingChina
| | - Yingjie Nie
- NHC Key Laboratory of Pulmonary Immunological Diseases is supported by the non‐profit Central Research Institute fund of Chinese Academy of Medical Sciences (2019PT320003)Guizhou Provincial People’s HospitalGuiyangChina
| | - Ning Li
- Clinical Cancer Center/National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingChina
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43
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Immunotherapies in Non-Hodgkin's Lymphoma. Cancers (Basel) 2021; 13:cancers13143625. [PMID: 34298838 PMCID: PMC8305599 DOI: 10.3390/cancers13143625] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/08/2021] [Indexed: 11/16/2022] Open
Abstract
Immune-based therapies mobilize the immune system to promote or restore an effective antitumor immune response [...].
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44
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Ahmed Z, Afridi SS, Shahid Z, Zamani Z, Rehman S, Aiman W, Khan M, Mir MA, Awan FT, Anwer F, Iftikhar R. Primary Mediastinal B-Cell Lymphoma: A 2021 Update on Genetics, Diagnosis, and Novel Therapeutics. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:e865-e875. [PMID: 34330673 DOI: 10.1016/j.clml.2021.06.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/08/2021] [Accepted: 06/19/2021] [Indexed: 12/21/2022]
Abstract
Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive B-cell lymphoma arising from thymic B-cells having clinicopathologic features distinct from systemic diffuse large B-cell lymphoma (DLBCL). PMBCL comprises 2% to 4% of all non-Hodgkin lymphomas (NHL), 7% of DLBCL and seen predominantly in young females with a median age of 35 years at diagnosis. The annual incidence of PMBCL is 0.4 per million with a 5-year survival rate exceeding 70% with improving supportive care and genetic characterization of the disease. Pathogenesis involves dysregulation of Janus kinase-signal transducer and activator of transcription (JAK-STAT), nuclear factor-kB (NF-kB) pathways and amplification of the 9p24.1 region of chromosome 9. PMBCL patients have a prolonged life expectancy necessitating the need for treatment approaches that are based on maximizing cure with minimal long-term toxicity. Due to rarity and its recognition as a distinct entity, therapeutic decisions are guided by clinical presentation, clinician and center experience, and analysis of patients with PMBCL within DLBCL registries. Historically R-CHOP has been the usual first line treatment for PMBCL followed by involved site radiotherapy (ISRT), however clinical practice varies across centers with emerging consensus to avoid upfront RT by utilizing dose intense regimens (DA-EPOCH-R) in younger and fit patients. Prognosis of relapsed refractory PMBCL not responding to salvage chemotherapy is dismal, however there are many emerging options including Brentuximab Vedotin, immune check point inhibitors and chimeric antigen receptor T-cell therapy. In this article, we focus on the pathogenesis, current and evolving treatments, and provide recommendations for optimal management of patients with PMBCL.
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Affiliation(s)
- Zahoor Ahmed
- Department of Internal Medicine, King Edward Medical University, Lahore, Pakistan
| | - Safa Saadat Afridi
- Department of Internal Medicine, Khyber Medical College Peshawar, Peshawar, Pakistan
| | | | - Zarlakhta Zamani
- Department of Internal Medicine, King Edward Medical University, Lahore, Pakistan
| | - Sana Rehman
- Shaikh Khalifa Bin Zayyed al Nahyan Medical and Dental College, Lahore, Pakistan
| | - Wajeeha Aiman
- Department of Internal Medicine, Nishtar Medical College, Multan, Pakistan
| | - Maryam Khan
- Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan
| | | | - Farrukh T Awan
- Department of Medicine, Division of Hematology and Oncology, UT Southwestern Medical Center, Dallas, TX
| | - Faiz Anwer
- Hematology, Oncology, Stem Cell Transplantation, Multiple Myeloma Program, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH
| | - Raheel Iftikhar
- Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan.
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45
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The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential. Int J Mol Sci 2021; 22:ijms22105352. [PMID: 34069564 PMCID: PMC8160856 DOI: 10.3390/ijms22105352] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 05/04/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal stem cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.
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Molica S, Allsup D, Gianfelici V, Levato L, Aiello V, Bailey J, Polliack A. Current and emerging investigational venetoclax-based therapies in chronic lymphocytic leukemia. Expert Opin Investig Drugs 2021; 30:621-633. [PMID: 33929928 DOI: 10.1080/13543784.2021.1924669] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Introduction: Venetoclax has emerged as a breakthrough treatment which has revolutionized the therapeutic paradigm of chronic lymphocytic leukemia (CLL). This is primarily attributed to the efficacy of venetoclax as a time-limited, chemo-free, therapy in a field dominated by targeted agents given on a continuous schedule. Furthermore, compelling clinical data support the use of venetoclax in combination with other targeted agents in the hope of preventing drug resistance due to the emergence of acquired mutations.Areas covered: This paper provides an overview of clinical results of newly approved or investigational venetoclax-based therapies for CLL. In view of current and potential roles in CLL care, the strengths and disadvantages of venetoclax-combinations are discussed. The MEDLINE database, ClinicalTrials.gov and conference proceedings were all reviewed to select the relevant literature.Expert opinion: While the advent of venetoclax-based combinations has significantly expanded the therapeutic options for patients with CLL, further research with longer follow-up is required to address remaining open questions such as (I) the role of venetoclax as fixed duration therapy(II) timing and threshold of minimal residual disease (MRD) assessment for therapy discontinuation, (III) the efficacy of novel triplet combinations with venetoclax as backbone therapy, (IV) indications for the re-initiation of therapy with venetoclax.
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Affiliation(s)
- Stefano Molica
- Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro,Italy
| | - David Allsup
- Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK
| | - Valentina Gianfelici
- Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro,Italy
| | - Luciano Levato
- Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro,Italy
| | - Vincenzo Aiello
- Rheumatology, Università Degli Studi Della Campania "Luigi Vanvitelli, Napoli, Italy
| | - James Bailey
- Department of Haematology, Hull Royal Infirmary, Hull, UK
| | - Aaron Polliack
- Department Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel
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47
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Chen H, Pan T, He Y, Zeng R, Li Y, Yi L, Zang H, Chen S, Duan Q, Xiao L, Zhou H. Primary Mediastinal B-Cell Lymphoma: Novel Precision Therapies and Future Directions. Front Oncol 2021; 11:654854. [PMID: 33869061 PMCID: PMC8044947 DOI: 10.3389/fonc.2021.654854] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/01/2021] [Indexed: 11/13/2022] Open
Abstract
Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct clinicopathologic disease from other types of diffuse large B-cell lymphoma (DLBCL) with unique prognostic features and limited availability of clinical data. The current standard treatment for newly diagnosed PMBCL has long been dependent on a dose-intensive, dose-adjusted multi-agent chemotherapy regimen of rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH). Recent randomized trials have provided evidence that R-CHOP followed by consolidation radiotherapy (RT) is a valuable alternative option to first-line treatment. For recurrent/refractory PMBCL (rrPMBCL), new drugs such as pembrolizumab and CAR-T cell therapy have proven to be effective in a few studies. Positron emission tomography-computed tomography (PET-CT) is the preferred imaging modality of choice for the initial phase of lymphoma treatment and to assess response to treatment. In the future, baseline quantitative PET-CT can be used to predict prognosis in PMBCL. This review focuses on the pathology of PMBCL, underlying molecular basis, treatment options, radiotherapy, targeted therapies, and the potential role of PET-CT to guide treatment choices in this disease.
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Affiliation(s)
- Huan Chen
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Tao Pan
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.,The Third Xiangya Hospital, Central South University, Changsha, China
| | - Yizi He
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Ruolan Zeng
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Yajun Li
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Liming Yi
- Department of Human Anatomy, Hunan University of Medicine, Huaihua, China
| | - Hui Zang
- Department of Basic Medicine, Yiyang Medical College, Yiyang, China
| | - Siwei Chen
- Department of Histology and Embryology of School of Basic Medical Science, Central South University, Changsha, China
| | - Qintong Duan
- Department of Histology and Embryology of School of Basic Medical Science, Central South University, Changsha, China
| | - Ling Xiao
- Department of Histology and Embryology of School of Basic Medical Science, Central South University, Changsha, China
| | - Hui Zhou
- Department of Lymphoma and Hematology, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China
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