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Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma

Authors

  • Markus Chmielewski,

    1. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    2. Clinic I for Internal Medicine, University Hospital Cologne, Cologne, Germany
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  • Andreas A. Hombach,

    1. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    2. Clinic I for Internal Medicine, University Hospital Cologne, Cologne, Germany
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  • Hinrich Abken

    Corresponding author
    1. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
    2. Clinic I for Internal Medicine, University Hospital Cologne, Cologne, Germany
    • Correspondence to:

      Hinrich Abken

      Center for Molecular Medicine Cologne (CMMC)

      University of Cologne

      Robert-Koch-Str. 21

      Cologne D-50931, Germany

      e-mail: hinrich.abken@uk-koeln.de

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Summary

Adoptive T-cell therapy recently achieved impressive efficacy in early phase trials, in particular in hematologic malignancies, strongly supporting the notion that the immune system can control cancer. A current strategy of favor is based on ex vivo-engineered patient T cells, which are redirected by a chimeric antigen receptor (CAR) and recognize a predefined target by an antibody-derived binding domain. Such CAR T cells can substantially reduce the tumor burden as long as the targeted antigen is present on the cancer cells. However, given the tremendous phenotypic diversity in solid tumor lesions, a reasonable number of cancer cells are not recognized by a given CAR, considerably reducing the therapeutic success. This article reviews a recently described strategy for overcoming this shortcoming of the CAR T-cell therapy by modulating the tumor stroma by a CAR T-cell-secreted transgenic cytokine like interleukin-12 (IL-12). The basic process is that CAR T cells, when activated by their CAR, deposit IL-12 in the targeted tumor lesion, which in turn attracts an innate immune cell response toward those cancer cells that are invisible to CAR T cells. Such TRUCKs, T cells redirected for universal cytokine-mediated killing, exhibited remarkable efficacy against solid tumors with diverse cancer cell phenotypes, suggesting their evaluation in clinical trials.

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