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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 -
Journal of Hematology & Oncology Jun 2014Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms...
BACKGROUND
Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study.
METHODS
A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies.
RESULTS
Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity.
CONCLUSIONS
Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT00435916.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; CD40 Antigens; Chills; Dose-Response Relationship, Drug; Drug Administration Schedule; Fatigue; Female; Headache; Humans; Kaplan-Meier Estimate; Lymphoma, Large B-Cell, Diffuse; Lymphopenia; Male; Middle Aged; Neoplasm Recurrence, Local; Polymorphism, Single Nucleotide; Receptors, IgG; Remission Induction; Treatment Outcome; Young Adult
PubMed: 24919462
DOI: 10.1186/1756-8722-7-44 -
Immunopharmacology and Immunotoxicology Apr 2014The costimulatory molecule CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on various antigen presenting cells (APCs) as well... (Review)
Review
The costimulatory molecule CD40 is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed on various antigen presenting cells (APCs) as well as some tumor cells. The binding to the natural ligand CD40L, which is expressed on T helper cells, leads to APC activation and thus enhancement of immune responses. Treatment with anti-CD40 monoclonal antibodies has been exploited in several cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use. Here, Dacetuzumab and Lucatumumab are in the most advanced stage and are being tested as treatment for malignancies such as chronic lymphatic leukemia (CLL), Multiple Myeloma (MM), and non-Hodgkin's lymphoma (NHL). The promising results from these early clinical trials have encouraged clinical drug development in order to investigate the effect of CD40 mAbs in combination with other cancer immunotherapies, in particular interleukin (IL)-2. An in-depth analysis of this immunotherapy is provided elsewhere. In the present review, we provide an update of the most recent clinical trials with anti-CD40 antibodies. We present and discuss recent and ongoing clinical trials in this field, including clinical studies which combine anti-CD40 treatment with other cancer-treatments, such as Rituximab and Tremelimumab.
Topics: Animals; Antibodies, Monoclonal; CD40 Antigens; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Humans; Immunotherapy; Neoplasms
PubMed: 24555495
DOI: 10.3109/08923973.2014.890626 -
British Medical Bulletin 2013Antibody is a major cause of allograft injury. However, it has not been routinely tested post-transplant. (Review)
Review
INTRODUCTION
Antibody is a major cause of allograft injury. However, it has not been routinely tested post-transplant.
SOURCES OF DATA
A literature search was performed using PubMed on the topics of 'antibody monitoring', 'autoantibody and allograft dysfunction' and 'prevention and treatment of antibody-mediated rejection (AMR)'.
AREAS OF AGREEMENT
Donor-specific antibody (DSA) monitoring not only helps to identify patients at risk of AMR, but also serves as a biomarker to personalize patient's maintenance immunosuppression. Development of autoantibody is a secondary response following primary tissue injury. Some autoantibodies are directly involved in allograft injury, while others only serve as biomarkers of tissue injury.
AREAS OF CONTROVERSY
It remains controversial whether DSA-positive patients without symptoms need to be treated. In addition, given the variation in study designs and patient's characteristics, there is discrepancy regarding which treatment regimens provide optimal clinical outcome in preventing/treating AMR.
GROWING POINTS
Efficacy of B-cell and/or antibody-targeted therapies in treating or preventing AMR would be better measured by the incorporation of antibody monitoring into current functional and pathological assays.
AREAS TIMELY FOR DEVELOPING RESEARCH
Research in B-cell targeted therapies to prevent and treat AMR is rapidly growing, which includes monoclonal antibodies against B-cell markers CD20, CD40, CD19, BlyS, etc. It requires extensive clinical research to determine the best approach to inhibit or delete antibody and how to balance the drug efficacy with safety.
Topics: Antibodies; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; Boronic Acids; Bortezomib; Complement C4b; Graft Rejection; Humans; Isoantibodies; Peptide Fragments; Pyrazines; Rituximab; Transplantation
PubMed: 23396319
DOI: 10.1093/bmb/lds037 -
Leukemia & Lymphoma Feb 2013Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical...
Dacetuzumab, a CD40-targeted, humanized antibody, mediates antitumor activity through effector cell functions and direct apoptotic signal transduction. Preclinical studies demonstrated synergistic activity between dacetuzumab, gemcitabine and rituximab against non-Hodgkin lymphoma in vivo. A phase 1b safety/efficacy study of dacetuzumab in combination with rituximab and gemcitabine was conducted in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received dacetuzumab at doses of 8 or 12 mg/kg IV weekly with rituximab (375 mg/m(2) IV weekly in cycle 1, then every 28 days) and gemcitabine (1000 mg/m(2) IV, days 1, 8 and 15, or days 1 and 15). Thirty-three patients with a median age of 67 years were enrolled. Common adverse events (≥ 15%) were grade 1/2 cytokine release syndrome, nausea, fatigue, thrombocytopenia, headache, decreased appetite, dyspnea, neutropenia, pyrexia, anemia, diarrhea, edema, constipation and cough. Dacetuzumab-related grade 3/4 adverse events occurred infrequently. Six of 30 evaluable patients achieved a complete response (CR) and eight a partial response (PR) per investigator assessment for an overall response rate (ORR) of 47%.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Female; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Pilot Projects; Recurrence; Rituximab; Treatment Outcome; Gemcitabine
PubMed: 22775314
DOI: 10.3109/10428194.2012.710328 -
CA: a Cancer Journal For Clinicians 2012The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and... (Review)
Review
The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.
Topics: Alemtuzumab; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Cancer Vaccines; Cetuximab; Dendritic Cells; ErbB Receptors; Gene Transfer Techniques; Genetic Vectors; Histocompatibility Antigens; Humans; Immunotherapy; Neoplasms; Nivolumab; Programmed Cell Death 1 Receptor; Receptor, ErbB-2; T-Lymphocytes; Trastuzumab; Tumor Necrosis Factor Receptor Superfamily, Member 9; Vaccines, DNA; Vascular Endothelial Growth Factor A; Yttrium Radioisotopes; alpha-Fetoproteins
PubMed: 22576456
DOI: 10.3322/caac.20132 -
Clinical Cancer Research : An Official... Jul 2011Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor...
PURPOSE
Individually targeting B-cell antigens with monoclonal antibody therapeutics has improved the treatment of non-Hodgkin lymphoma (NHL). We examined if the antitumor activity of rituximab, CD20-specific antibody, could be improved by simultaneously targeting CD40 with the humanized monoclonal antibody dacetuzumab (SGN-40).
EXPERIMENTAL DESIGN
Dacetuzumab was dosed with rituximab to determine the in vivo activity of this combination in a subcutaneous Ramos xenograft model of non-Hodgkin lymphoma (NHL). The effect of dacetuzumab on rituximab antibody-dependent cell mediated-cytotoxicity (ADCC), antiproliferative, and apoptotic activities were evaluated in vitro using NHL cell lines. Western blotting and flow cytometry were used to contrast the signaling pathways activated by dacetuzumab and rituximab in NHL cells.
RESULTS
The dacetuzumab-rituximab combination had significantly improved antitumor activity over the equivalent dose of rituximab in the Ramos xenograft model (P = 0.0021). Dacetuzumab did not augment rituximab-mediated ADCC activity; however, these antibodies were additive to synergistic in cell-proliferation assays and produced increased apoptosis in combination. Rituximab signaling downregulated BCL-6 oncoprotein in a cell line-specific manner, whereas dacetuzumab strongly downregulated BCL-6 in each cell line. Dacetuzumab induced expression of the proapoptotic proteins TAp63 and Fas, whereas rituximab did not affect basal expression of either protein. Finally, rituximab partially blocked dacetuzumab-mediated upregulation of the prosurvival protein BCL-x(L).
CONCLUSIONS
Targeting CD40 with dacetuzumab enhanced the antitumor activity of rituximab in cell line and xenograft NHL models. The distinct but complementary apoptotic signal transduction profiles of dacetuzumab and rituximab are an important mechanism behind the improved activity of this combination.
Topics: Animals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Apoptosis; CD40 Antigens; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Kaplan-Meier Estimate; Lymphoma, Non-Hodgkin; Mice; Mice, SCID; Rituximab; Signal Transduction; Xenograft Model Antitumor Assays
PubMed: 21610152
DOI: 10.1158/1078-0432.CCR-11-0479 -
Science Translational Medicine Mar 2011The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype...
The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; B-Lymphocytes; CD40 Antigens; CD40 Ligand; Cell Line, Tumor; Gene Expression Profiling; Humans; Immunotherapy; In Situ Hybridization, Fluorescence; Lymphoma, Large B-Cell, Diffuse; Mice; Microarray Analysis; Proto-Oncogene Mas; Transplantation, Heterologous; Tumor Suppressor Protein p53
PubMed: 21411738
DOI: 10.1126/scitranslmed.3001620 -
Leukemia Jun 2011Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The...
Non-Hodgkin lymphoma (NHL) is a genetically heterogeneous disease with several oncogenic events implicated in the transformation of normal developing B lymphocytes. The objective of this study was to elucidate the signal transduction-based antitumor mechanism(s) of action for the anti-CD40 monoclonal antibody dacetuzumab (SGN-40) in NHL. We report that dacetuzumab activates two distinct proapoptotic signaling pathways, overcoming transformation events key to the pathogenesis of NHL. Dacetuzumab-mediated CD40 signaling constitutively activated the nuclear factor-κB and mitogen-activated protein kinase signaling pathways producing the sustained downregulation of B-cell lymphoma 6 (BCL-6), an oncoprotein implicated in lymphomagenesis. Loss of BCL-6 resulted in c-Myc downregulation and activation of a transcriptional program characteristic of early B-cell maturation, concomitant with reduced proliferation and cell death. In a second mechanism, dacetuzumab signaling induced the expression of the proapoptotic p53 family member TAp63α and downstream proteins associated with the intrinsic and extrinsic apoptotic machinery. Dacetuzumab was synergistic in combination with DNA-damaging chemotherapeutic drugs, correlating with TAp63α upregulation. Furthermore, dacetuzumab augmented the activity of rituximab in combination with multiple chemotherapies in the xenograft models of NHL. The ability of dacetuzumab signaling to circumvent oncogenic events and potentiate the activity of chemotherapy regimens provides a unique therapeutic approach to NHL.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; Gene Expression Regulation; Humans; Lymphoma, Non-Hodgkin; Signal Transduction; Transcription, Genetic; Tumor Cells, Cultured
PubMed: 21394099
DOI: 10.1038/leu.2011.21 -
BMC Cancer Oct 2010Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will...
BACKGROUND
Developing the right drugs for the right patients has become a mantra of drug development. In practice, it is very difficult to identify subsets of patients who will respond to a drug under evaluation. Most of the time, no single diagnostic will be available, and more complex decision rules will be required to define a sensitive population, using, for instance, mRNA expression, protein expression or DNA copy number. Moreover, diagnostic development will often begin with in-vitro cell-line data and a high-dimensional exploratory platform, only later to be transferred to a diagnostic assay for use with patient samples. In this manuscript, we present a novel approach to developing robust genomic predictors that are not only capable of generalizing from in-vitro to patient, but are also amenable to clinically validated assays such as qRT-PCR.
METHODS
Using our approach, we constructed a predictor of sensitivity to dacetuzumab, an investigational drug for CD40-expressing malignancies such as lymphoma using genomic measurements of cell lines treated with dacetuzumab. Additionally, we evaluated several state-of-the-art prediction methods by independently pairing the feature selection and classification components of the predictor. In this way, we constructed several predictors that we validated on an independent DLBCL patient dataset. Similar analyses were performed on genomic measurements of breast cancer cell lines and patients to construct a predictor of estrogen receptor (ER) status.
RESULTS
The best dacetuzumab sensitivity predictors involved ten or fewer genes and accurately classified lymphoma patients by their survival and known prognostic subtypes. The best ER status classifiers involved one or two genes and led to accurate ER status predictions more than 85% of the time. The novel method we proposed performed as well or better than other methods evaluated.
CONCLUSIONS
We demonstrated the feasibility of combining feature selection techniques with classification methods to develop assays using cell line genomic measurements that performed well in patient data. In both case studies, we constructed parsimonious models that generalized well from cell lines to patients.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Cell Line; Cell Line, Tumor; Data Interpretation, Statistical; Drug Screening Assays, Antitumor; Genomics; Humans; Lymphoma; Models, Statistical; Oligonucleotide Array Sequence Analysis; Prognosis; RNA, Messenger; Regression Analysis; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome
PubMed: 20979617
DOI: 10.1186/1471-2407-10-586