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  1. Article ; Online: Challenges and solutions for therapeutic TCR-based agents.

    Malviya, Manish / Aretz, Zita E H / Molvi, Zaki / Lee, Jayop / Pierre, Stephanie / Wallisch, Patrick / Dao, Tao / Scheinberg, David A

    Immunological reviews

    2023  Volume 320, Issue 1, Page(s) 58–82

    Abstract: Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that ... ...

    Abstract Recent development of methods to discover and engineer therapeutic T-cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR-based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR-mimic antibodies, and TCR-based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR-based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off-target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.
    MeSH term(s) Humans ; Receptors, Antigen, T-Cell/metabolism ; Neoplasms/therapy ; Antibodies
    Chemical Substances Receptors, Antigen, T-Cell ; Antibodies
    Language English
    Publishing date 2023-07-16
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.13233
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Challenges and solutions for therapeutic TCR‐based agents

    Malviya, Manish / Aretz, Zita E. H. / Molvi, Zaki / Lee, Jayop / Pierre, Stephanie / Wallisch, Patrick / Dao, Tao / Scheinberg, David A.

    Immunological Reviews. 2023 Nov., v. 320, no. 1 p.58-82

    2023  

    Abstract: Recent development of methods to discover and engineer therapeutic T‐cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that ... ...

    Abstract Recent development of methods to discover and engineer therapeutic T‐cell receptors (TCRs) or antibody mimics of TCRs, and to understand their immunology and pharmacology, lag two decades behind therapeutic antibodies. Yet we have every expectation that TCR‐based agents will be similarly important contributors to the treatment of a variety of medical conditions, especially cancers. TCR engineered cells, soluble TCRs and their derivatives, TCR‐mimic antibodies, and TCR‐based CAR T cells promise the possibility of highly specific drugs that can expand the scope of immunologic agents to recognize intracellular targets, including mutated proteins and undruggable transcription factors, not accessible by traditional antibodies. Hurdles exist regarding discovery, specificity, pharmacokinetics, and best modality of use that will need to be overcome before the full potential of TCR‐based agents is achieved. HLA restriction may limit each agent to patient subpopulations and off‐target reactivities remain important barriers to widespread development and use of these new agents. In this review we discuss the unique opportunities for these new classes of drugs, describe their unique antigenic targets, compare them to traditional antibody therapeutics and CAR T cells, and review the various obstacles that must be overcome before full application of these drugs can be realized.
    Keywords T-lymphocytes ; antibodies ; patients ; pharmacokinetics ; therapeutics
    Language English
    Dates of publication 2023-11
    Size p. 58-82.
    Publishing place John Wiley & Sons, Ltd
    Document type Article ; Online
    Note REVIEW
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.13233
    Database NAL-Catalogue (AGRICOLA)

    Full text online

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    In stock of ZB MED Cologne/Königswinter

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  3. Article: Host-cell Interactions of Engineered T cell Micropharmacies.

    Bourne, Christopher M / Wallisch, Patrick / Dacek, Megan / Gardner, Thomas / Pierre, Stephanie / Vogt, Kristen / Corless, Broderick C / Bah, Mamadou A / Romero Pichardo, Jesus / Charles, Angel / Kurtz, Keifer G / Tan, Derek S / Scheinberg, David A

    bioRxiv : the preprint server for biology

    2023  

    Abstract: Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, ... ...

    Abstract Genetically engineered, cytotoxic, adoptive T cells localize to antigen positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with an orthogonal killing mechanism to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Here, we also expand the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with TCR-engineered T cells. We demonstrate that SEAKER cells localize specifically to tumors, and activate bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells are efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
    Language English
    Publishing date 2023-05-01
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2023.04.05.535717
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Host Interactions with Engineered T-cell Micropharmacies.

    Bourne, Christopher M / Wallisch, Patrick / Dacek, Megan M / Gardner, Thomas J / Pierre, Stephanie / Vogt, Kristen / Corless, Broderick C / Bah, Mamadou A / Romero-Pichardo, Jesus E / Charles, Angel / Kurtz, Keifer G / Tan, Derek S / Scheinberg, David A

    Cancer immunology research

    2023  Volume 11, Issue 9, Page(s) 1253–1265

    Abstract: Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More ... ...

    Abstract Genetically engineered, cytotoxic, adoptively transferred T cells localize to antigen-positive cancer cells inside patients, but tumor heterogeneity and multiple immune escape mechanisms have prevented the eradication of most solid tumor types. More effective, multifunctional engineered T cells are in development to overcome the barriers to the treatment of solid tumors, but the interactions of these highly modified cells with the host are poorly understood. We previously engineered prodrug-activating enzymatic functions into chimeric antigen receptor (CAR) T cells, endowing them with a killing mechanism orthogonal to conventional T-cell cytotoxicity. These drug-delivering cells, termed Synthetic Enzyme-Armed KillER (SEAKER) cells, demonstrated efficacy in mouse lymphoma xenograft models. However, the interactions of an immunocompromised xenograft with such complex engineered T cells are distinct from those in an immunocompetent host, precluding an understanding of how these physiologic processes may affect the therapy. Herein, we expanded the repertoire of SEAKER cells to target solid-tumor melanomas in syngeneic mouse models using specific targeting with T-cell receptor (TCR)-engineered T cells. We demonstrate that SEAKER cells localized specifically to tumors, and activated bioactive prodrugs, despite host immune responses. We additionally show that TCR-engineered SEAKER cells were efficacious in immunocompetent hosts, demonstrating that the SEAKER platform is applicable to many adoptive cell therapies.
    MeSH term(s) Mice ; Animals ; Humans ; Immunotherapy, Adoptive ; T-Lymphocytes, Cytotoxic ; Genetic Engineering ; Melanoma ; Receptors, Antigen, T-Cell/genetics
    Chemical Substances Receptors, Antigen, T-Cell
    Language English
    Publishing date 2023-07-17
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2732489-8
    ISSN 2326-6074 ; 2326-6066
    ISSN (online) 2326-6074
    ISSN 2326-6066
    DOI 10.1158/2326-6066.CIR-22-0879
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7022: Show issues Location:
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  5. Article ; Online: Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.

    Dacek, Megan M / Kurtz, Keifer G / Wallisch, Patrick / Pierre, Stephanie A / Khayat, Shireen / Bourne, Christopher M / Gardner, Thomas J / Vogt, Kristen C / Aquino, Nica / Younes, Anas / Scheinberg, David A

    Blood

    2023  Volume 141, Issue 16, Page(s) 2003–2015

    Abstract: Chimeric antigen receptor (CAR) T-cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high-affinity CD47 ... ...

    Abstract Chimeric antigen receptor (CAR) T-cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high-affinity CD47 blocker, CV1, at the tumor and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus the antibody had an additive effect in xenograft models, and this effect was potentiated by CAR T-cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed the immunosuppression of myelomonocytoid cells both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T-cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each monotherapy.
    MeSH term(s) Humans ; CD47 Antigen ; Neoplasm Recurrence, Local ; Neoplasms/pathology ; T-Lymphocytes ; Immunotherapy, Adoptive ; Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal/pharmacology ; Tumor Microenvironment
    Chemical Substances CD47 Antigen ; Antibodies, Monoclonal ; CD47 protein, human
    Language English
    Publishing date 2023-01-10
    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.2022016101
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MO 364: Show issues

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  6. Article ; Online: Liver-Kidney-on-Chip To Study Toxicity of Drug Metabolites.

    Theobald, Jannick / Ghanem, Ali / Wallisch, Patrick / Banaeiyan, Amin A / Andrade-Navarro, Miguel A / Taškova, Katerina / Haltmeier, Manuela / Kurtz, Andreas / Becker, Holger / Reuter, Stefanie / Mrowka, Ralf / Cheng, Xinlai / Wölfl, Stefan

    ACS biomaterials science & engineering

    2017  Volume 4, Issue 1, Page(s) 78–89

    Abstract: Advances in organ-on-chip technologies for the application in in vitro drug development provide an attractive alternative approach to replace ethically controversial animal testing and to establish a basis for accelerated drug development. In recent ... ...

    Abstract Advances in organ-on-chip technologies for the application in in vitro drug development provide an attractive alternative approach to replace ethically controversial animal testing and to establish a basis for accelerated drug development. In recent years, various chip-based tissue culture systems have been developed, which are mostly optimized for cultivation of one single cell type or organoid structure and lack the representation of multi organ interactions. Here we present an optimized microfluidic chip design consisting of interconnected compartments, which provides the possibility to mimic the exchange between different organ specific cell types and enables to study interdependent cellular responses between organs and demonstrate that such tandem system can greatly improve the reproducibility and efficiency of toxicity studies. In a simplified liver-kidney-on-chip model, we showed that hepatic cells that grow in microfluidic conditions abundantly and stably expressed metabolism-related biomarkers. Moreover, we applied this system for investigating the biotransformation and toxicity of Aflatoxin B1 (AFB1) and Benzoalphapyrene (BαP), as well as the interaction with other chemicals. The results clearly demonstrate that the toxicity and metabolic response to drugs can be evaluated in a flow-dependent manner within our system, supporting the importance of advanced interconnected multiorgans in microfluidic devices for application in in vitro toxicity testing and as optimized tissue culture systems for in vitro drug screening.
    Language English
    Publishing date 2017-12-04
    Publishing country United States
    Document type Journal Article
    ISSN 2373-9878
    ISSN (online) 2373-9878
    DOI 10.1021/acsbiomaterials.7b00417
    Database MEDical Literature Analysis and Retrieval System OnLINE

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