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01.11.2014 | Original Article | Ausgabe 11/2014

Cancer Immunology, Immunotherapy 11/2014

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

Zeitschrift:
Cancer Immunology, Immunotherapy > Ausgabe 11/2014
Autoren:
Jennifer D. Stone, Daniel T. Harris, Carolina M. Soto, Adam S. Chervin, David H. Aggen, Edward J. Roy, David M. Kranz
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s00262-014-1586-z) contains supplementary material, which is available to authorized users.
A portion of the work presented here was presented previously by Jennifer D. Stone in the conference abstract/poster book for Keystone Symposium 2013—Cancer Immunology and Immunotherapy (J4), January 27–February 1, 2013, Vancouver, British Columbia, Canada.

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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