期刊
CANCER IMMUNOLOGY IMMUNOTHERAPY
卷 63, 期 11, 页码 1163-1176出版社
SPRINGER
DOI: 10.1007/s00262-014-1586-z
关键词
Adoptive T cell transfer; T cell receptors; Chimeric antigen receptors; Tumor targeting; Melanoma
资金
- Melanoma Research Alliance
- National Institutes of Health [R01 CA178844]
- Samuel and Ruth Engelberg/Irvington Institute Fellowship of the Cancer Research Institute
- Ruth L. Kirschstein National Research Service Award Predoctoral Fellowship from the National Institutes of Health [FCA180723A]
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 (V alpha-linker-V beta) from a high-affinity TCR called m33, linked to the intracellular signaling domains of CD28 and CD3 zeta. 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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