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  1. Article ; Online: T-cell Receptor Gene Therapy Clinically Targeting a TP53 Public Neoantigen.

    Klebanoff, Christopher A

    Cancer immunology research

    2022  Volume 10, Issue 8, Page(s) 919

    Abstract: T-cell receptors (TCR) are an antigen receptor class that can uniquely respond to epitopes resulting from cytosolic and intranuclear proteins. In this issue, Kim and colleagues report the first successful application of TCR gene therapy targeting a ... ...

    Abstract T-cell receptors (TCR) are an antigen receptor class that can uniquely respond to epitopes resulting from cytosolic and intranuclear proteins. In this issue, Kim and colleagues report the first successful application of TCR gene therapy targeting a shared, or public, neoantigen resulting from a TP53 hotspot mutation. These results establish clinical proof of concept that an off-the-shelf TCR targeting a recurrent mutation in a molecular driver of oncogenesis can benefit patients with metastatic cancer. See related article by Kim et al., p. 932 (4) .
    MeSH term(s) Antigens, Neoplasm/immunology ; Genes, T-Cell Receptor ; Humans ; Lymphocytes, Tumor-Infiltrating/immunology ; Mutation ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/immunology ; T-Lymphocytes/immunology ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Antigens, Neoplasm ; Receptors, Antigen, T-Cell ; TP53 protein, human ; Tumor Suppressor Protein p53
    Language English
    Publishing date 2022-06-30
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-22-0386
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: Less, but better: A simplified design for T cell redirection and conditional payload delivery.

    Kropp, Korbinian N / Klebanoff, Christopher A

    Cancer cell

    2022  Volume 40, Issue 12, Page(s) 1454–1456

    Abstract: Combining immune receptor engineering with conditional expression of accessory molecules holds great promise for advancing the field of cell-based immunotherapies. In this issue of Cancer Cell, Smole et al. introduce a modular single vector system to ... ...

    Abstract Combining immune receptor engineering with conditional expression of accessory molecules holds great promise for advancing the field of cell-based immunotherapies. In this issue of Cancer Cell, Smole et al. introduce a modular single vector system to simultaneously redirect T cell specificity toward cancer antigens while achieving activation-gated delivery of customizable payloads.
    MeSH term(s) Humans ; T-Lymphocytes ; Immunotherapy ; Neoplasms/therapy
    Language English
    Publishing date 2022-12-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2022.11.012
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Erasing iatrogenic neoantigens from in vivo CRISPR screens.

    Yi, Fei / Klebanoff, Christopher A

    Immunity

    2021  Volume 54, Issue 3, Page(s) 406–408

    Abstract: In vivo genetic screens using CRISPR-Cas9 are a powerful tool to resolve the molecular determinants of response and resistance to cancer immunotherapies; however, vector immunogenicity can introduce artifact. In this issue of Immunity, Dubrot et al. ... ...

    Abstract In vivo genetic screens using CRISPR-Cas9 are a powerful tool to resolve the molecular determinants of response and resistance to cancer immunotherapies; however, vector immunogenicity can introduce artifact. In this issue of Immunity, Dubrot et al. report a strategy to "erase" vector-associated neoantigens, enabling a more physiologic assessment of tumor-immune cell interactions in immunocompetent hosts.
    MeSH term(s) Antigens ; CRISPR-Cas Systems/genetics ; Genetic Therapy ; Humans ; Iatrogenic Disease ; Immunotherapy
    Chemical Substances Antigens
    Language English
    Publishing date 2021-03-10
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2021.02.017
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  4. Article: The resting state of the human T-cell receptor-CD3 complex.

    Notti, Ryan Q / Yi, Fei / Heissel, Søren / Bush, Martin W / Molina, Henrik / Molvi, Zaki / Klebanoff, Christopher A / Walz, Thomas

    bioRxiv : the preprint server for biology

    2024  

    Abstract: The T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune ... ...

    Abstract The T-cell receptor (TCR) is central to the ligand-dependent activation of T lymphocytes and as such orchestrates both adaptive and pathologic immune processes
    Language English
    Publishing date 2024-04-08
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.08.22.554360
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: T cell receptor therapeutics: immunological targeting of the intracellular cancer proteome.

    Klebanoff, Christopher A / Chandran, Smita S / Baker, Brian M / Quezada, Sergio A / Ribas, Antoni

    Nature reviews. Drug discovery

    2023  Volume 22, Issue 12, Page(s) 996–1017

    Abstract: The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins ... ...

    Abstract The T cell receptor (TCR) complex is a naturally occurring antigen sensor that detects, amplifies and coordinates cellular immune responses to epitopes derived from cell surface and intracellular proteins. Thus, TCRs enable the targeting of proteins selectively expressed by cancer cells, including neoantigens, cancer germline antigens and viral oncoproteins. As such, TCRs have provided the basis for an emerging class of oncology therapeutics. Herein, we review the current cancer treatment landscape using TCRs and TCR-like molecules. This includes adoptive cell transfer of T cells expressing endogenous or engineered TCRs, TCR bispecific engagers and antibodies specific for human leukocyte antigen (HLA)-bound peptides (TCR mimics). We discuss the unique complexities associated with the clinical development of these therapeutics, such as HLA restriction, TCR retrieval, potency assessment and the potential for cross-reactivity. In addition, we highlight emerging clinical data that establish the antitumour potential of TCR-based therapies, including tumour-infiltrating lymphocytes, for the treatment of diverse human malignancies. Finally, we explore the future of TCR therapeutics, including emerging genome editing methods to safely enhance potency and strategies to streamline patient identification.
    MeSH term(s) Humans ; Proteome/metabolism ; CD8-Positive T-Lymphocytes/metabolism ; Antigens, Neoplasm ; Receptors, Antigen, T-Cell ; Neoplasms/drug therapy
    Chemical Substances Proteome ; Antigens, Neoplasm ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-10-27
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-023-00809-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 334: Show issues
    Zs.MG 63: Show issues

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  6. Article ; Online: Clinical implications of T cell exhaustion for cancer immunotherapy.

    Chow, Andrew / Perica, Karlo / Klebanoff, Christopher A / Wolchok, Jedd D

    Nature reviews. Clinical oncology

    2022  Volume 19, Issue 12, Page(s) 775–790

    Abstract: Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated ... ...

    Abstract Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.
    MeSH term(s) Humans ; T-Lymphocytes ; Immune Checkpoint Inhibitors ; Immunotherapy ; Immunotherapy, Adoptive ; Tumor Microenvironment ; Neoplasms
    Chemical Substances Immune Checkpoint Inhibitors
    Language English
    Publishing date 2022-10-10
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2491410-1
    ISSN 1759-4782 ; 1759-4774
    ISSN (online) 1759-4782
    ISSN 1759-4774
    DOI 10.1038/s41571-022-00689-z
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    Zs.A 6029: Show issues Location:
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    Zs.MG 103: Show issues

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  7. Article ; Online: T cell receptor-based cancer immunotherapy: Emerging efficacy and pathways of resistance.

    Chandran, Smita S / Klebanoff, Christopher A

    Immunological reviews

    2019  Volume 290, Issue 1, Page(s) 127–147

    Abstract: Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)-modified T cells can induce durable remissions in patients with refractory B-lymphoid cancers. By contrast, results applying CAR-modified T cells to solid malignancies have been ... ...

    Abstract Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)-modified T cells can induce durable remissions in patients with refractory B-lymphoid cancers. By contrast, results applying CAR-modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR-signaling. Herein, we summarize recent clinical data demonstrating that TCR-based immunotherapies can mediate regression of solid malignancies, including immune-checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR-based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non-viral genome integration techniques.
    MeSH term(s) Animals ; Antigens, Neoplasm/immunology ; Clinical Studies as Topic ; Genetic Engineering ; Humans ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/metabolism ; T-Cell Antigen Receptor Specificity ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Treatment Outcome
    Chemical Substances Antigens, Neoplasm ; Receptors, Antigen, T-Cell ; Receptors, Chimeric Antigen
    Language English
    Publishing date 2019-09-13
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.12772
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Shared cancer neoantigens: Making private matters public.

    Klebanoff, Christopher A / Wolchok, Jedd D

    The Journal of experimental medicine

    2017  Volume 215, Issue 1, Page(s) 5–7

    Abstract: In this issue of JEM, Chheda et al. (https://doi.org/10.1084/jem.20171046) report that a conserved hotspot mutation associated with an aggressive form of brain cancer generates an immunogenic T cell epitope restricted by a common HLA subtype, thereby ... ...

    Abstract In this issue of JEM, Chheda et al. (https://doi.org/10.1084/jem.20171046) report that a conserved hotspot mutation associated with an aggressive form of brain cancer generates an immunogenic T cell epitope restricted by a common HLA subtype, thereby creating a "public" neoantigen.
    MeSH term(s) Cell- and Tissue-Based Therapy ; Epitopes, T-Lymphocyte ; Glioma ; Histones ; Humans ; Mutation
    Chemical Substances Epitopes, T-Lymphocyte ; Histones
    Language English
    Publishing date 2017-12-21
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20172188
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  9. Article ; Online: Silencing stemness in T cell differentiation.

    Henning, Amanda N / Klebanoff, Christopher A / Restifo, Nicholas P

    Science (New York, N.Y.)

    2018  Volume 359, Issue 6372, Page(s) 163–164

    MeSH term(s) Cell Differentiation ; Humans ; Neoplastic Stem Cells
    Language English
    Publishing date 2018-01-08
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 128410-1
    ISSN 1095-9203 ; 0036-8075
    ISSN (online) 1095-9203
    ISSN 0036-8075
    DOI 10.1126/science.aar5541
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  10. Article ; Online: Customizing Functionality and Payload Delivery for Receptor-Engineered T Cells.

    Klebanoff, Christopher A / Restifo, Nicholas P

    Cell

    2016  Volume 167, Issue 2, Page(s) 304–306

    Abstract: Adoptive immunotherapy using receptor engineering to achieve specific tumor targeting by T cells holds much promise for advancing cancer therapy. Here, two studies by Boice et al. and Roybal et al. provide distinct and potentially complimentary ... ...

    Abstract Adoptive immunotherapy using receptor engineering to achieve specific tumor targeting by T cells holds much promise for advancing cancer therapy. Here, two studies by Boice et al. and Roybal et al. provide distinct and potentially complimentary approaches to improve the efficacy and curb potential toxicities of this approach.
    MeSH term(s) Humans ; Immunotherapy, Adoptive ; Neoplasms/therapy ; Receptors, Antigen, T-Cell ; T-Lymphocytes
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2016-10-14
    Publishing country United States
    Document type Journal Article ; Comment
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2016.09.033
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