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  1. Article ; Online: Targeting the DLL/Notch Signaling Pathway in Cancer: Challenges and Advances in Clinical Development.

    You, Weon-Kyoo / Schuetz, Thomas J / Lee, Sang Hoon

    Molecular cancer therapeutics

    2022  Volume 22, Issue 1, Page(s) 3–11

    Abstract: The DLL/Notch signaling pathway plays an important role in cancer as a key driver in maintaining cancer stemness and inducing tumor angiogenesis. Many different types of DLL/Notch inhibitors have been developed and explored in clinical trials for cancer ... ...

    Abstract The DLL/Notch signaling pathway plays an important role in cancer as a key driver in maintaining cancer stemness and inducing tumor angiogenesis. Many different types of DLL/Notch inhibitors have been developed and explored in clinical trials for cancer treatment, including small-molecule compounds to inhibit gamma-secretase and antibodies targeting Notch ligands or receptors. Despite promising efficacy of these inhibitors in preclinical studies, the overall clinical outcomes have been insufficient to advance to the next stage of clinical development primarily due to safety concerns or modest efficacy. To overcome the narrow therapeutic window of DLL/Notch inhibitors, diverse strategies for improving the balance between the safety and efficacy are currently being explored. Here, we review the clinical perspective and potential of DLL/Notch inhibitors as anticancer agents based on recent results from multiple clinical studies. An antibody specifically targeting Notch ligands or receptors may offer a better approach to reduce concerns about toxicity derived from broad-spectrum DLL/Notch blockers. In addition, combination therapy with an angiogenesis inhibitor targeting VEGF could be a better option for increasing anticancer efficacy. Taken together, the results of clinical trials suggest a bispecific antibody blocking the DLL/Notch and VEGF/VEGFR signaling pathways as a promising approach for effective anticancer treatment.
    MeSH term(s) Humans ; Vascular Endothelial Growth Factor A ; Ligands ; Receptors, Notch/metabolism ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Signal Transduction
    Chemical Substances Vascular Endothelial Growth Factor A ; Ligands ; Receptors, Notch
    Language English
    Publishing date 2022-10-12
    Publishing country United States
    Document type Review ; Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-22-0243
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5750: Show issues Location:
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    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: A bispecific anti-PD-1 and PD-L1 antibody induces PD-1 cleavage and provides enhanced anti-tumor activity.

    Albu, Diana I / Wolf, Benjamin J / Qin, Yan / Wang, Xianzhe / Daniel Ulumben, Amy / Su, Mei / Li, Vivian / Ding, Eirene / Angel Gonzalo, Jose / Kong, Jason / Jadhav, Ruturaj / Kuklin, Nelly / Visintin, Alberto / Gong, Bing / Schuetz, Thomas J

    Oncoimmunology

    2024  Volume 13, Issue 1, Page(s) 2316945

    Abstract: Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which ... ...

    Abstract Combinatorial strategies, such as targeting different immune checkpoint receptors, hold promise to increase the breadth and duration of the response to cancer therapy. Here we describe the preclinical evaluation of CTX-8371, a protein construct which combines PD-1 and PD-L1 targeting in one bispecific, tetravalent antibody. CTX-8371 matched or surpassed the activity of anti-PD-1 and PD-L1 benchmark antibodies in several
    MeSH term(s) Mice ; Animals ; B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Lymphocyte Activation ; Lung Neoplasms
    Chemical Substances B7-H1 Antigen ; Programmed Cell Death 1 Receptor ; Antibodies, Bispecific
    Language English
    Publishing date 2024-02-16
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2645309-5
    ISSN 2162-402X ; 2162-402X
    ISSN (online) 2162-402X
    ISSN 2162-402X
    DOI 10.1080/2162402X.2024.2316945
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity.

    Eskiocak, Ugur / Guzman, Wilson / Wolf, Benjamin / Cummings, Christine / Milling, Lauren / Wu, Hsin-Jung / Ophir, Michael / Lambden, Conner / Bakhru, Pearl / Gilmore, Dana C / Ottinger, Samantha / Liu, Lucy / McConaughy, William K / He, Sunny Q / Wang, Chao / Leung, Cheuk Lun / Lajoie, Jason / Carson, William F / Zizlsperger, Nora /
    Schmidt, Michael M / Anderson, Ana C / Bobrowicz, Piotr / Schuetz, Thomas J / Tighe, Robert

    JCI insight

    2020  Volume 5, Issue 5

    Abstract: CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these ... ...

    Abstract CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor-dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
    MeSH term(s) Animals ; Antibodies, Monoclonal/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Chemical and Drug Induced Liver Injury/prevention & control ; Epitope Mapping ; Gene Expression Profiling ; HEK293 Cells ; Humans ; Immunotherapy/adverse effects ; Immunotherapy/methods ; Lymphocyte Activation ; Lymphocytes, Tumor-Infiltrating/metabolism ; Macaca fascicularis ; Mice ; Mice, Nude ; Neoplasms/immunology ; Neoplasms/therapy ; T-Lymphocytes/immunology ; Tumor Necrosis Factor Receptor Superfamily, Member 9/chemistry ; Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology ; Xenograft Model Antitumor Assays
    Chemical Substances Antibodies, Monoclonal ; Tumor Necrosis Factor Receptor Superfamily, Member 9
    Language English
    Publishing date 2020-03-12
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2379-3708
    ISSN (online) 2379-3708
    DOI 10.1172/jci.insight.133647
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the CGRP Binding Monoclonal Antibody LY2951742 (Galcanezumab) in Healthy Volunteers.

    Monteith, David / Collins, Emily C / Vandermeulen, Corinne / Van Hecken, Anne / Raddad, Eyas / Scherer, Joel C / Grayzel, David / Schuetz, Thomas J / de Hoon, Jan

    Frontiers in pharmacology

    2017  Volume 8, Page(s) 740

    Abstract: Background: ...

    Abstract Background:
    Language English
    Publishing date 2017-10-17
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2587355-6
    ISSN 1663-9812
    ISSN 1663-9812
    DOI 10.3389/fphar.2017.00740
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: A phase I/II clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter syndrome).

    Muenzer, Joseph / Gucsavas-Calikoglu, Muge / McCandless, Shawn E / Schuetz, Thomas J / Kimura, Alan

    Molecular genetics and metabolism

    2007  Volume 90, Issue 3, Page(s) 329–337

    Abstract: Objective: To evaluate the safety and explore the efficacy of idursulfase (recombinant human iduronate-2-sulfatase) treatment for mucopolysaccharidosis II (MPS II).: Study design: Twelve patients were enrolled into a randomized, double-blind, placebo- ...

    Abstract Objective: To evaluate the safety and explore the efficacy of idursulfase (recombinant human iduronate-2-sulfatase) treatment for mucopolysaccharidosis II (MPS II).
    Study design: Twelve patients were enrolled into a randomized, double-blind, placebo-controlled trial for 24 weeks followed by an open-label extension study. Three groups of 4 patients were enrolled sequentially, with 3 patients in each group receiving idursulfase and 1 patient receiving placebo. The first group received idursulfase at 0.15 mg/kg infused every other week with the 2nd and 3rd groups receiving 0.5 and 1.5 mg/kg, respectively. After 24 weeks the placebo-treated patients were changed to idursulfase at the dose of their group. The primary endpoint was a change from baseline in urinary excretion of glycosaminoglycans. Results were pooled for analysis by ANOVA and compared to baseline.
    Results: Urinary glycosaminoglycans were reduced within 2 weeks of initiating idursulfase and were decreased 49% after 48 weeks of treatment (P<0.0001). Both liver and spleen volume were decreased at 24 weeks (P<0.01) and 48 weeks (P<0.001). The 6-minute walk test distance increased an average of 48 meters after 48 weeks (P=0.013). Six patients in the higher dose groups developed IgG antibodies that did not influence the clinical effects of idursulfase.
    Conclusions: This study describes the first experience with enzyme replacement therapy for the treatment of patients with MPS II. Idursulfase was generally well tolerated and was associated with reductions in urine glycosaminoglycans levels and organ size, as well as an increased 6-minute walk test distance.
    MeSH term(s) Adolescent ; Adult ; Child ; Double-Blind Method ; Glycosaminoglycans/urine ; Humans ; Iduronate Sulfatase/administration & dosage ; Iduronate Sulfatase/adverse effects ; Iduronate Sulfatase/immunology ; Iduronate Sulfatase/therapeutic use ; Immunoglobulin G/biosynthesis ; Infusions, Intravenous ; Joints/drug effects ; Joints/physiopathology ; Liver/drug effects ; Liver/pathology ; Male ; Mucopolysaccharidosis II/drug therapy ; Mucopolysaccharidosis II/pathology ; Mucopolysaccharidosis II/physiopathology ; Recombinant Proteins/administration & dosage ; Recombinant Proteins/adverse effects ; Recombinant Proteins/immunology ; Recombinant Proteins/therapeutic use ; Respiratory Function Tests ; Safety ; Spleen/drug effects ; Spleen/pathology
    Chemical Substances Glycosaminoglycans ; Immunoglobulin G ; Recombinant Proteins ; Iduronate Sulfatase (EC 3.1.6.13)
    Language English
    Publishing date 2007-03
    Publishing country United States
    Document type Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1418518-0
    ISSN 1096-7206 ; 1096-7192
    ISSN (online) 1096-7206
    ISSN 1096-7192
    DOI 10.1016/j.ymgme.2006.09.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 617: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)

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  6. Article ; Online: Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer.

    Kantoff, Philip W / Schuetz, Thomas J / Blumenstein, Brent A / Glode, L Michael / Bilhartz, David L / Wyand, Michael / Manson, Kelledy / Panicali, Dennis L / Laus, Reiner / Schlom, Jeffrey / Dahut, William L / Arlen, Philip M / Gulley, James L / Godfrey, Wayne R

    Journal of clinical oncology : official journal of the American Society of Clinical Oncology

    2010  Volume 28, Issue 7, Page(s) 1099–1105

    Abstract: Purpose: Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival ( ... ...

    Abstract Purpose: Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study.
    Patients and methods: In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections.
    Results: Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061.
    Conclusion: PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.
    MeSH term(s) Aged ; Aged, 80 and over ; Cancer Vaccines/immunology ; Double-Blind Method ; Genetic Vectors/immunology ; Humans ; Immunization ; Male ; Middle Aged ; Neoplasm Metastasis ; Orchiectomy ; Poxviridae/immunology ; Prostate-Specific Antigen/antagonists & inhibitors ; Prostate-Specific Antigen/immunology ; Prostatic Neoplasms/mortality ; Prostatic Neoplasms/pathology ; Prostatic Neoplasms/therapy ; Vaccines, Synthetic/immunology
    Chemical Substances Cancer Vaccines ; Vaccines, Synthetic ; Prostate-Specific Antigen (EC 3.4.21.77)
    Language English
    Publishing date 2010-01-25
    Publishing country United States
    Document type Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, N.I.H., Extramural
    ZDB-ID 604914-x
    ISSN 1527-7755 ; 0732-183X
    ISSN (online) 1527-7755
    ISSN 0732-183X
    DOI 10.1200/JCO.2009.25.0597
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 650: Show issues

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