Journal
BLOOD
Volume 115, Issue 25, Pages 5154-5163Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-11-254078
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Funding
- Erasmus University of Rotterdam
- University Medical Center, Leiden
- University Hospital of Erlangen
- Deutsche Forschungsgemeinschaft (DFG) [SFB-432-A3]
- Faculty of Medicine, Mainz [KFO 183-TP1]
- European Commission
- Wilhelm-Laupitz foundation
- Helmholtz Association on Immunotherapy of Cancer
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Transfer of tumor antigen-specific T-cell receptors (TCRs) into human T cells aims at redirecting their cytotoxicity toward tumors. Efficacy and safety may be affected by pairing of natural and introduced TCR alpha/beta chains potentially leading to autoimmunity. We hypothesized that a novel single-chain (sc) TCR framework relying on the coexpression of the TCR alpha constant alpha (C alpha) domain would prevent undesired pairing while preserving structural and functional similarity to a fully assembled double-chain (dc) TCR/CD3 complex. We confirmed this hypothesis for a murine p53-specific scTCR. Substantial effector function was observed only in the presence of a murine C alpha domain preceded by a TCR alpha signal peptide for shuttling to the cell membrane. The generalization to a human gp100-specific TCR required the murinization of both C domains. Structural and functional T-cell avidities of an accessory disulfide-linked scTCR gp100/C alpha were higher than those of a dcTCR. Antigen-dependent phosphorylation of the proximal effector zeta-chain-associated protein kinase 70 at tyrosine 319 was not impaired, reflecting its molecular integrity in signaling. In melanoma-engrafted nonobese diabetic/severe combined immunodeficient mice, adoptive transfer of scTCR gp100/C alpha transduced T cells conferred superior delay in tumor growth among primary and long-term secondary tumor challenges. We conclude that the novel scTCR constitutes a reliable means to immunotherapeutically target hematologic malignancies. (Blood. 2010; 115(25):5154-5163)
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