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A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control

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Abstract

Adoptive transfer of genetically modified T cells to treat cancer has shown promise in several clinical trials. Two main strategies have been applied to redirect T cells against cancer: (1) introduction of a full-length T cell receptor (TCR) specific for a tumor-associated peptide—MHC, or (2) introduction of a chimeric antigen receptor, including an antibody fragment specific for a tumor cell surface antigen, linked intracellularly to T cell signaling domains. Each strategy has advantages and disadvantages for clinical applications. Here, we present data on the in vitro and in vivo effectiveness of a single-chain signaling receptor incorporating a TCR variable fragment as the targeting element (referred to as TCR-SCS). This receptor contained a single-chain TCR (Vα-linker-Vβ) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3ζ. This format avoided mispairing with endogenous TCR chains and mediated specific T cell activity when expressed in either CD4 or CD8 T cells. TCR-SCS-transduced CD8-negative cells showed an intriguing sensitivity, compared to full-length TCRs, to higher densities of less stable pepMHC targets. T cells that expressed this peptide-specific receptor persisted in vivo, and exhibited polyfunctional responses. Growth of metastatic antigen-positive tumors was significantly inhibited by T cells that expressed this receptor, and tumor cells that escaped were antigen-loss variants. TCR-SCS receptors represent an alternative targeting receptor strategy that combines the advantages of single-chain expression, avoidance of TCR chain mispairing, and targeting of intracellular antigens presented in complex with MHC proteins.

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Abbreviations

CAR:

Chimeric antigen receptor

MHC:

Major histocompatability complex

scFv:

Single-chain variable fragment of an antibody

TCR:

T cell receptor

TCR-SCS:

TCR single-chain signaling receptor

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Acknowledgments

We thank Hans Schreiber and his colleagues from the University of Chicago for helpful discussions, Barbara Pilas from the University of Illinois Flow Cytometry Facility for flow cytometry support, and Wendy Woods for experimental assistance. This work was supported by a grant from the Melanoma Research Alliance (to David M. Kranz) and by National Institutes of Health grant R01 CA178844 (to David M. Kranz). Jennifer D. Stone was supported by the Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute. Daniel T. Harris was supported by a Ruth L. Kirschstein National Research Service Award Predoctoral Fellowship from the National Institutes of Health FCA180723A.

Conflict of interest

David M. Kranz co-founded a company called ImmuVen that has acquired rights from the University of Illinois for some T cell receptor-based technologies. Jennifer D. Stone, Daniel T. Harris, Carolina M. Soto, Adam S. Chervin, David H. Aggen, and Edward J. Roy declare they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry, University of Illinois, 600 S. Mathews Ave., Urbana, IL, 61801, USA

    Jennifer D. Stone, Daniel T. Harris, Adam S. Chervin, David H. Aggen & David M. Kranz

  2. Neuroscience Program, University of Illinois, Urbana, IL, 61801, USA

    Carolina M. Soto & Edward J. Roy

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  1. Jennifer D. Stone
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  2. Daniel T. Harris
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  7. David M. Kranz
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Correspondence to David M. Kranz.

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Stone, J.D., Harris, D.T., Soto, C.M. et al. A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. Cancer Immunol Immunother 63, 1163–1176 (2014). https://doi.org/10.1007/s00262-014-1586-z

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