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  1. Thesis ; Online: A cellular platform for high-throughput functional engineering of cytokine receptors

    Kucharczyk, Jakub

    2023  

    Abstract: Adoptive cell transfer of engineered T cell therapies, such as chimeric antigen receptor (CAR-T) and T cell receptor (TCR-T) cell therapies, are a highly promising modality for the treatment of advanced cancers (Britten et al., 2021). However, major ... ...

    Abstract Adoptive cell transfer of engineered T cell therapies, such as chimeric antigen receptor (CAR-T) and T cell receptor (TCR-T) cell therapies, are a highly promising modality for the treatment of advanced cancers (Britten et al., 2021). However, major challenges related to the safety and efficacy of engineered T cell products currently limit their full therapeutic potential. In terms of safety, T cell therapies can elicit deleterious systemic side effects such as cytokine release syndrome (CRS). CRS is a systemic inflammatory response condition resulting from the excessive production of cytokines and overactivation of the patient’s own immune system that can lead to symptoms ranging from fever to organ failure. In terms of efficacy, engineered T cell therapies can be hindered by terminal differentiation and exhaustion during manufacturing leading to a reduced overall efficacy of the T cell product. Furthermore, inhibitory mechanisms in the tumor microenvironment are a major challenge limiting the efficacy of engineered T cell products against solid tumors. Cytokines are soluble proteins that act as key regulators of T cell biology and have been used as immunotherapeutic agents over the past three decades. Despite their crucial biological function, unmodified cytokines display suboptimal therapeutic activity due to a short serum half-life, toxicity and simultaneous activation of multiple T cell subsets (i.e., pleiotropy). To address these limitations, molecular engineering of therapeutic cytokines has been applied to enhance their pharmacokinetic and pharmacodynamic parameters, with several engineered cytokines (most notably interleukin-2, IL-2) rapidly making their way into the clinic. Thus, much like with soluble cytokines, engineering of cytokine receptors that display increased sensitivity, are fine-tuned for enhanced T cell activity or that respond only to specific ligands are all attractive strategies for the development of T cell products with enhanced, function, potency and safety. Here, we describe a ...
    Keywords info:eu-repo/classification/ddc/570 ; Life sciences
    Subject code 616
    Language English
    Publisher ETH Zurich
    Publishing country ch
    Document type Thesis ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity.

    Vazquez-Lombardi, Rodrigo / Jung, Johanna S / Schlatter, Fabrice S / Mei, Anna / Mantuano, Natalia Rodrigues / Bieberich, Florian / Hong, Kai-Lin / Kucharczyk, Jakub / Kapetanovic, Edo / Aznauryan, Erik / Weber, Cédric R / Zippelius, Alfred / Läubli, Heinz / Reddy, Sai T

    Immunity

    2022  Volume 55, Issue 10, Page(s) 1953–1966.e10

    Abstract: A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of ... ...

    Abstract A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications.
    MeSH term(s) Antigens, Neoplasm ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Peptides ; Receptors, Antigen, T-Cell
    Chemical Substances Antigens, Neoplasm ; Peptides ; Receptors, Antigen, T-Cell
    Language English
    Publishing date 2022-09-28
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1217235-2
    ISSN 1097-4180 ; 1074-7613
    ISSN (online) 1097-4180
    ISSN 1074-7613
    DOI 10.1016/j.immuni.2022.09.004
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  3. Article ; Online: A Functional Screening Strategy for Engineering Chimeric Antigen Receptors with Reduced On-Target, Off-Tumor Activation.

    Di Roberto, Raphaël B / Castellanos-Rueda, Rocío / Frey, Samara / Egli, David / Vazquez-Lombardi, Rodrigo / Kapetanovic, Edo / Kucharczyk, Jakub / Reddy, Sai T

    Molecular therapy : the journal of the American Society of Gene Therapy

    2020  Volume 28, Issue 12, Page(s) 2564–2576

    Abstract: In recent years, chimeric antigen receptor (CAR) T cell cancer immunotherapies have advanced substantially in the clinic. However, challenges related to safety persist; one major concern occurs when CARs trigger a response to antigen present on healthy ... ...

    Abstract In recent years, chimeric antigen receptor (CAR) T cell cancer immunotherapies have advanced substantially in the clinic. However, challenges related to safety persist; one major concern occurs when CARs trigger a response to antigen present on healthy cells (on-target, off-tumor response). A strategy to ameliorate this relies on the complex relationship between receptor affinity and signaling, such that one can engineer a CAR that is only activated by tumor cells expressing high antigen levels. Here, we developed a CAR T cell display platform with stable genomic expression and rapid functional screening based on interleukin-2 signaling. Starting with a CAR with high affinity toward its target antigen, we combined CRISPR-Cas9 genome editing and deep mutational scanning to generate a library of antigen-binding domain variants. This library was subjected to multiple rounds of selection based on either antigen binding or cell signaling. Deep sequencing of the resulting libraries and a comparative analysis revealed the enrichment and depletion of specific variants from which we selected CARs that were selectively activated by tumor cells based on antigen expression levels. Our platform demonstrates how directed evolution based on functional screening and deep sequencing-guided selection can be combined to enhance the selectivity and safety of CARs.
    MeSH term(s) Animals ; Antibody Affinity ; Antigens, Neoplasm/immunology ; Antigens, Neoplasm/metabolism ; Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; CRISPR-Cas Systems ; Cell Engineering/methods ; Coculture Techniques ; Female ; Gene Editing/methods ; HEK293 Cells ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Immunotherapy, Adoptive/methods ; Interleukin-2/genetics ; Interleukin-2/metabolism ; MCF-7 Cells ; Mice ; Receptor, ErbB-2/immunology ; Receptor, ErbB-2/metabolism ; Receptors, Antigen, T-Cell, alpha-beta/genetics ; Receptors, Antigen, T-Cell, alpha-beta/immunology ; Receptors, Antigen, T-Cell, alpha-beta/metabolism ; Receptors, Chimeric Antigen/genetics ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/metabolism ; Single-Chain Antibodies/immunology
    Chemical Substances Antigens, Neoplasm ; IL2 protein, human ; Interleukin-2 ; Receptors, Antigen, T-Cell, alpha-beta ; Receptors, Chimeric Antigen ; Single-Chain Antibodies ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2020-08-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2010592-7
    ISSN 1525-0024 ; 1525-0016
    ISSN (online) 1525-0024
    ISSN 1525-0016
    DOI 10.1016/j.ymthe.2020.08.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5640: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    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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