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  1. Article ; Online: Correction: Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy.

    Zhang, Songfa / Yan, Chuan / Millar, David G / Yang, Qiqi / Heather, James M / Langenbucher, Adam / Morton, Laura T / Sepulveda, Sean / Alpert, Eric / Whelton, Lauren R / Zarrella, Dominique T / Guo, Mei / Minogue, Eleanor / Lawrence, Michael S / Rueda, Bo R / Spriggs, David R / Lu, Weiguo / Langenau, David M / Cobbold, Mark

    Cancer research

    2024  Volume 84, Issue 9, Page(s) 1534

    Language English
    Publishing date 2024-05-02
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-24-0718
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Antibody-Peptide Epitope Conjugates for Personalized Cancer Therapy.

    Zhang, Songfa / Yan, Chuan / Millar, David G / Yang, Qiqi / Heather, James M / Langenbucher, Adam / Morton, Laura T / Sepulveda, Sean / Alpert, Eric / Whelton, Lauren R / Zarrella, Dominique T / Guo, Mei / Minogue, Eleanor / Lawrence, Michael S / Rueda, Bo R / Spriggs, David R / Lu, Weiguo / Langenau, David M / Cobbold, Mark

    Cancer research

    2021  Volume 82, Issue 5, Page(s) 773–784

    Abstract: Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T-cell viral immunity against tumor cells. APECs contain a tumor-specific protease cleavage site linked to a patient-specific viral epitope, ... ...

    Abstract Antibody-peptide epitope conjugates (APEC) are a new class of modified antibody-drug conjugates that redirect T-cell viral immunity against tumor cells. APECs contain a tumor-specific protease cleavage site linked to a patient-specific viral epitope, resulting in presentation of viral epitopes on cancer cells and subsequent recruitment and killing by CD8+ T cells. Here we developed an experimental pipeline to create patient-specific APECs and identified new preclinical therapies for ovarian carcinoma. Using functional assessment of viral peptide antigen responses to common viruses like cytomegalovirus (CMV) in patients with ovarian cancer, a library of 192 APECs with distinct protease cleavage sequences was created using the anti-epithelial cell adhesion molecule (EpCAM) antibody. Each APEC was tested for in vitro cancer cell killing, and top candidates were screened for killing xenograft tumors grown in zebrafish and mice. These preclinical modeling studies identified EpCAM-MMP7-CMV APEC (EpCAM-MC) as a potential new immunotherapy for ovarian carcinoma. Importantly, EpCAM-MC also demonstrated robust T-cell responses in primary ovarian carcinoma patient ascites samples. This work highlights a robust, customizable platform to rapidly develop patient-specific APECs.
    Significance: This study develops a high-throughput preclinical platform to identify patient-specific antibody-peptide epitope conjugates that target cancer cells and demonstrates the potential of this immunotherapy approach for treating ovarian carcinoma.
    MeSH term(s) Animals ; Antibodies ; CD8-Positive T-Lymphocytes ; Carcinoma, Ovarian Epithelial/drug therapy ; Cytomegalovirus ; Cytomegalovirus Infections ; Epithelial Cell Adhesion Molecule ; Epitopes ; Female ; Humans ; Immunoconjugates/therapeutic use ; Mice ; Ovarian Neoplasms/drug therapy ; Peptide Hydrolases ; Peptides ; Zebrafish
    Chemical Substances Antibodies ; Epithelial Cell Adhesion Molecule ; Epitopes ; Immunoconjugates ; Peptides ; Peptide Hydrolases (EC 3.4.-)
    Language English
    Publishing date 2021-12-26
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-21-2200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
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  3. Article ; Online: Single-cell imaging of T cell immunotherapy responses in vivo.

    Yan, Chuan / Yang, Qiqi / Zhang, Songfa / Millar, David G / Alpert, Eric J / Do, Daniel / Veloso, Alexandra / Brunson, Dalton C / Drapkin, Benjamin J / Stanzione, Marcello / Scarfò, Irene / Moore, John C / Iyer, Sowmya / Qin, Qian / Wei, Yun / McCarthy, Karin M / Rawls, John F / Dyson, Nick J / Cobbold, Mark /
    Maus, Marcela V / Langenau, David M

    The Journal of experimental medicine

    2021  Volume 218, Issue 10

    Abstract: T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution ...

    Abstract T cell immunotherapies have revolutionized treatment for a subset of cancers. Yet, a major hurdle has been the lack of facile and predicative preclinical animal models that permit dynamic visualization of T cell immune responses at single-cell resolution in vivo. Here, optically clear immunocompromised zebrafish were engrafted with fluorescent-labeled human cancers along with chimeric antigen receptor T (CAR T) cells, bispecific T cell engagers (BiTEs), and antibody peptide epitope conjugates (APECs), allowing real-time single-cell visualization of T cell-based immunotherapies in vivo. This work uncovered important differences in the kinetics of T cell infiltration, tumor cell engagement, and killing between these immunotherapies and established early endpoint analysis to predict therapy responses. We also established EGFR-targeted immunotherapies as a powerful approach to kill rhabdomyosarcoma muscle cancers, providing strong preclinical rationale for assessing a wider array of T cell immunotherapies in this disease.
    MeSH term(s) Adolescent ; Adult ; Animals ; Animals, Genetically Modified ; Child ; Child, Preschool ; DNA-Binding Proteins/genetics ; ErbB Receptors/immunology ; Female ; Humans ; Immunotherapy/methods ; Immunotherapy, Adoptive ; Interleukin Receptor Common gamma Subunit/genetics ; Male ; Mice, Inbred Strains ; Phthalazines/pharmacology ; Piperazines/pharmacology ; Rhabdomyosarcoma/pathology ; Rhabdomyosarcoma/therapy ; Single-Cell Analysis/methods ; T-Lymphocytes/immunology ; Temozolomide/pharmacology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays/methods ; Zebrafish/genetics ; Zebrafish Proteins/genetics ; Mice
    Chemical Substances DNA-Binding Proteins ; Interleukin Receptor Common gamma Subunit ; Phthalazines ; Piperazines ; RAG2 protein, zebrafish ; Zebrafish Proteins ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; olaparib (WOH1JD9AR8) ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2021-08-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20210314
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ua VI Zs.107: Show issues Location:
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    Zs.MG 45: Show issues

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  4. Article ; Online: Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia.

    Laukkanen, Saara / Veloso, Alexandra / Yan, Chuan / Oksa, Laura / Alpert, Eric J / Do, Daniel / Hyvärinen, Noora / McCarthy, Karin / Adhikari, Abhinav / Yang, Qiqi / Iyer, Sowmya / Garcia, Sara P / Pello, Annukka / Ruokoranta, Tanja / Moisio, Sanni / Adhikari, Sadiksha / Yoder, Jeffrey A / Gallagher, Kayleigh / Whelton, Lauren /
    Allen, James R / Jin, Alex H / Loontiens, Siebe / Heinäniemi, Merja / Kelliher, Michelle / Heckman, Caroline A / Lohi, Olli / Langenau, David M

    Blood

    2022  Volume 140, Issue 17, Page(s) 1891–1906

    Abstract: Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL ... ...

    Abstract Relapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
    MeSH term(s) Child ; Humans ; Mice ; Animals ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Dasatinib/pharmacology ; Dasatinib/therapeutic use ; Zebrafish/metabolism ; Tyrosine ; Cell Line, Tumor ; Signal Transduction ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Receptors, Antigen, T-Cell/therapeutic use ; T-Lymphocytes/metabolism ; Recurrence ; Mammals/metabolism
    Chemical Substances Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (EC 2.7.10.2) ; Dasatinib (RBZ1571X5H) ; temsirolimus (624KN6GM2T) ; Tyrosine (42HK56048U) ; Protein Kinase Inhibitors ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Receptors, Antigen, T-Cell ; MTOR protein, human (EC 2.7.1.1)
    Language English
    Publishing date 2022-05-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2021015106
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.140: Show issues Location:
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    Zs.MO 364: Show issues

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