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Cancer Biology & Medicine Feb 2021Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmic CD3, CD56, cytotoxic markers, including... (Review)
Review
Natural killer/T-cell lymphoma (NKTCL) is a highly invasive subtype of non-Hodgkin lymphoma, typically positive for cytoplasmic CD3, CD56, cytotoxic markers, including granzyme B and TIA1, and Epstein-Barr virus (EBV). The current treatment methods for NKTCL are associated with several drawbacks. For example, chemotherapy can lead to drug resistance, while treatment with radiotherapy alone is inadequate and results in frequent relapses. Moreover, hematopoietic stem cell transplantation exhibits limited efficacy and is not well recognized by domestic and foreign experts. In recent years, immunotherapy has shown good clinical results and has become a hot spot in cancer research. Clinical activity of targeted antibodies, such as daratumumab (anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody), have been reported in NKTCL. Additionally, dacetuzumab and Campath-1H have demonstrated promising results. Further encouraging data have been obtained using checkpoint inhibitors. The success of these immunotherapy agents is attributed to high expression levels of programmed death-ligand 1 in NKTCL. Furthermore, anti-CCR4 monoclonal antibodies (mAbs) exert cytotoxic actions on both CCR4+ tumor cells and regulatory T cells. Depletion of these cells and the long half-life of anti-CCR4 mAbs result in enhanced induction of antitumor effector T cells. The role of IL10 in NKTCL has also been investigated. It has been proposed that exploitation of this cytokine might provide potential novel therapeutic strategies. Cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 has shown promising results and sustained remission. Cellular immunotherapy may be used either as maintenance therapy following initial induction chemotherapy or in cases of relapsed/refractory disease. The present review outlines the known immunotherapy targets for the treatment of NKTCL.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B7-H1 Antigen; Brentuximab Vedotin; Herpesvirus 4, Human; Humans; Immunotherapy; Lymphoma, Extranodal NK-T-Cell; Natural Killer T-Cells; T-Lymphocytes, Cytotoxic
PubMed: 33628584
DOI: 10.20892/j.issn.2095-3941.2020.0400 -
Expert Opinion on Emerging Drugs Jun 2016Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in... (Review)
Review
INTRODUCTION
Monoclonal antibodies mark the beginning of a new era in the context of multiple myeloma (MM) treatment. Numerous antibodies have been tested or are currently in development for patients with MM, in order to improve tolerability and quality of life.
AREAS COVERED
This manuscript reviews emerging antibodies for the treatment of MM i.e. elotuzumab, daratumumab, MOR03087, isatuximab, bevacizumab, cetuximab, siltuximab, tocilizumab, elsilimomab, azintrel, rituximab, tositumomab, milatuzumab, lucatumumab, dacetuzumab, figitumumab, dalotuzumab, AVE1642, tabalumab, pembrolizumab, pidilizumab, nivolumab.
EXPERT OPINION
Amongst these antibodies, elotuzumab which targets SLAMF-7 and daratumumab which targets CD38, have been recently approved by FDA for patients with relapsed/refractory MM. Both agents are well tolerated. Multiple clinical trials incorporating these monoclonal antibodies in MM treatment are currently ongoing. Of special interest are the anticipated results of phase III clinical trials with elotuzumab [NCT0189164; NCT01335399; NCT02495922] and daratumumab [NCT02252172; NCT02195479] in newly diagnosed MM patients. Moreover, of great interest are the awaited data on pembrolizumabin combination with pomalidomide and dexamethasone in refractory/relapsed MM patients [NCT02576977] and in combination with lenalidomide and dexamethasone in newly diagnosed MM patients. It seems that the incorporation of monoclonal antibodies will change the landscape of myeloma therapy in the near future.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Design; Humans; Multiple Myeloma; Quality of Life
PubMed: 27195659
DOI: 10.1080/14728214.2016.1186644 -
Leukemia & Lymphoma 2015Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved... (Randomized Controlled Trial)
Randomized Controlled Trial
Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial.
Single-agent dacetuzumab has demonstrated antitumor activity in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Preclinical data demonstrated improved dacetuzumab antitumor activity in combination with rituximab, ± chemotherapy. We designed a phase 2b, double-blind, placebo-controlled trial to compare rituximab, ifosfamide, carboplatin and etoposide (R-ICE) + dacetuzumab with R-ICE + placebo in patients with DLBCL who relapsed after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) (ClinicalTrials.gov #NCT00529503). The primary endpoint was complete response (CR); additional endpoints included failure-free survival and overall survival (OS). Overall, 151 patients were randomized (75 dacetuzumab, 76 placebo). No notable differences between arms in demographics or subsequent treatment parameters were observed. Cytopenias, cough and infection were more frequent with dacetuzumab. Futility analysis failed to demonstrate higher CR rates with dacetuzumab (36% dacetuzumab, 42% placebo); consequently, enrollment was stopped. Unplanned post hoc analysis showed that patients who underwent subsequent autologous stem cell transplant experienced improvement in OS (hazard ratio = 0.195, p = 0.004), which may be explained by potential immunomodulatory effects of dacetuzumab on antigen-presenting cells.
Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cough; Cyclophosphamide; Double-Blind Method; Doxorubicin; Etoposide; Female; Humans; Ifosfamide; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Neoplasm Recurrence, Local; Prednisolone; Remission Induction; Rituximab; Salvage Therapy; Thrombocytopenia; Treatment Outcome; Vincristine
PubMed: 25651427
DOI: 10.3109/10428194.2015.1007504 -
BMC Cancer Dec 2020The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The purpose of this network meta-analysis of randomized controlled trials (RCTs) was to compare rank targeted therapies for patients with diffuse large B-cell lymphoma (DLBCL).
METHODS
The PubMed, EmBase, and Cochrane library electronic databases were systematically searched throughout December 2019. Direct and indirect evidence from relevant RCTs was identified for network meta-analysis. The pooled results for grade 3 or greater adverse events between targeted therapies and chemotherapy were calculated using a random-effects model.
RESULTS
A total of 18 RCTs enrolling 8207 DLBCL patients were selected for the final meta-analysis. The results of the network analysis indicated that the addition of dacetuzumab (74.8%) to rituximab-based regimens or lenalidomide (77.1%) was associated with better therapeutic effects on overall survival, whereas dacetuzumab (80.4%) or bortezomib (70.8%) added to rituximab was most likely to improve events-free survival. Moreover, lenalidomide (93.8%) and I-tositumomab (77.2%) were associated with higher overall response rates. Finally, patients receiving targeted therapies were associated with an increased risk of diarrhea (RR: 2.63; 95%CI: 1.18-5.86; P = 0.019), and thrombocytopenia (RR: 1.41; 95%CI: 1.05-1.90; P = 0.023).
CONCLUSIONS
This study provides the best treatment strategy for DLBCL patients in terms of overall survival, events-free survival, and overall response rate. The findings of this study require validation with further large-scale RCTs.
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Humans; Lymphoma, Large B-Cell, Diffuse; Molecular Targeted Therapy; Prognosis; Survival Rate
PubMed: 33308179
DOI: 10.1186/s12885-020-07715-2 -
Biochemical and Biophysical Research... Jun 2024CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the...
CD40 is a member of the tumor necrosis factor receptor superfamily, and it is widely expressed on immune and non-immune cell types. The interaction between CD40 and the CD40 ligand (CD40L) plays an essential function in signaling, and the CD40/CD40L complex works as an immune checkpoint molecule. CD40 has become a therapeutic target, and a variety of agonistic/antagonistic anti-CD40 monoclonal antibodies (mAbs) have been developed. To better understand the mode of action of anti-CD40 mAbs, we determined the X-ray crystal structures of dacetuzumab (agonist) and bleselumab (antagonist) in complex with the extracellular domain of human CD40, respectively. The structure reveals that dacetuzumab binds to CD40 on the top of cysteine-rich domain 1 (CRD1), which is the domain most distant from the cell surface, and it does not compete with CD40L binding. The binding interface of bleselumab spread between CRD2 and CRD1, overlapping with the binding surface of the ligand. Our results offer important insights for future structural and functional studies of CD40 and provide clues to understanding the mechanism of biological response. These data can be applied to developing new strategies for designing antibodies with more therapeutic efficacy.
Topics: Humans; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Binding Sites; CD40 Antigens; CD40 Ligand; Crystallography, X-Ray; Models, Molecular; Protein Binding; Protein Conformation
PubMed: 38657446
DOI: 10.1016/j.bbrc.2024.149969 -
Frontiers in Oncology 2020Primary cutaneous B-cell lymphomas (pCBCL) include an infrequent group of non-Hodgkin lymphomas that are limited to skin sites at the time of diagnosis. They comprise... (Review)
Review
Primary cutaneous B-cell lymphomas (pCBCL) include an infrequent group of non-Hodgkin lymphomas that are limited to skin sites at the time of diagnosis. They comprise roughly 20-25% of all cutaneous lymphomas and are subdivided into primary cutaneous marginal zone lymphoma (PCMZL), primary cutaneous follicle center lymphoma (PCFCL), and primary cutaneous diffuse large cell B cell lymphoma, leg type (PCDLCBCL, LT). The first two show a rather indolent course while PCDLCBCL, LT carries a worse prognosis. Intravascular large cell B-cell lymphoma is the most infrequent subtype, and its therapy is not covered in this review. For solitary, single-site PCMZL and PCFCL, several topical treatment options exist. They include, but are not limited to, excision, radiotherapy, and intralesional therapies, discussed in this review. However, in selected cases, even "watchful waiting" is reasonable. Indolent types of pCBCL rarely require systemic treatment. However, in extended cases and more importantly DLCBCL, LT, systemic treatment is the first choice. Monoclonal anti-CD20-antibody rituximab is often used as monotherapy in PCMZL and PCFCL or combined with chemotherapy in PCDLBCL, LT. Newer options are monoclonal anti-CD40 antibody dacetuzumab, anti-PD-1 and anti-PD-L1 checkpoint inhibitors, and Bruton tyrosine kinase inhibitors. Indolent pCBCL are treated with a risk-adapted strategy using intralesional steroids, RT, and interferon-α as first-line treatments. Relapsing cases may profit from rituximab. In aggressive PCDLCBCL, LT, rituximab with polychemotherapy is recommended. Innovative therapies include intralesional oncolytic virotherapy, systemic monoclonal antibodies, and small molecules.
PubMed: 32850331
DOI: 10.3389/fonc.2020.01163 -
Antibodies (Basel, Switzerland) May 2019Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug... (Review)
Review
BACKGROUND
Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively.
CONCLUSIONS
Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.
PubMed: 31544840
DOI: 10.3390/antib8020034 -
Immunotherapy Feb 2018We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy...
We reviewed emerging immune strategies for multiple myeloma (MM) therapy excluding US FDA approved drugs. In relapsed refractory MM, isatuximab (anti-CD38) monotherapy achieved overall response (OR) of 24%. Other monoclonal antibodies that have shown efficacy in combination therapy include siltuximab (OR: 66%), indatuximab (OR: 78%), isatuximab (OR: 64.5%), pembrolizumab (OR: 60%), bevacizumab (OR: 70%), dacetuzumab (OR: 39%) and lorvotuzumab (OR: 56.4%). No OR was observed with monotherapy using BI-505, siltuximab, bevacizumab, AVE-1642, figitumumab, atacicept, milatuzumab, dacetuzumab, lucatumumab, IPH2101, lorvotuzumab, BT062 and nivolumab. We included seven clinical trials on chimeric antigen receptor (CAR) T cells. CAR T-cell targets include BCMA, CD19, KLC and CD138. A recent experience of CAR T-cell (B-cell maturation antigen) therapy in advanced MM has shown global response of 100%. The future of monoclonal antibodies and adoptive T cells for MM treatment seems promising.
Topics: Humans; Immunotherapy; Multiple Myeloma
PubMed: 29421983
DOI: 10.2217/imt-2017-0136 -
Expert Review of Hematology Dec 2014Anti-CD20 monoclonal antibodies (mAbs), rituximab, ofatumumab and obinutuzumab, have a significant impact in the treatment of chronic lymphocytic leukemia (CLL),... (Review)
Review
Anti-CD20 monoclonal antibodies (mAbs), rituximab, ofatumumab and obinutuzumab, have a significant impact in the treatment of chronic lymphocytic leukemia (CLL), particularly in combination with chemotherapy. Over the last few years, several new mAbs have been developed and investigated in CLL. The most promising newer mAbs are directed against CD20, CD19, CD37 and CD40. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib or lenalidomide will probably replace chemotherapy-based combinations in the near future. This review gives a critical overview of established mAbs as well as new antibodies potentially useful in CLL.
Topics: Animals; Antibodies, Monoclonal; Antigens, CD19; Antigens, CD20; Antigens, Neoplasm; CD40 Antigens; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Tetraspanins
PubMed: 25249370
DOI: 10.1586/17474086.2014.963048 -
Clinical Microbiology and Infection :... Jun 2018The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. (Review)
Review
ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).
BACKGROUND
The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies.
AIMS
To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations.
SOURCES
Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family.
CONTENT
The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended.
IMPLICATIONS
Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents.
Topics: ADP-ribosyl Cyclase 1; Antigens, Surface; Biological Therapy; CD40 Antigens; Clinical Trials as Topic; Communicable Diseases; Consensus; Humans; Immunocompromised Host; Ki-1 Antigen; Lymphocytes; Membrane Glycoproteins; Molecular Targeted Therapy; Myeloid Cells; Receptors, CCR4; Sialic Acid Binding Ig-like Lectin 2; Sialic Acid Binding Ig-like Lectin 3; Signaling Lymphocytic Activation Molecule Family
PubMed: 29572070
DOI: 10.1016/j.cmi.2018.03.022