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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1163-1176 |
| Number of pages | 14 |
| Journal | Cancer Immunology, Immunotherapy |
| Volume | 63 |
| Issue number | 11 |
| DOIs | |
| State | Published - Jan 1 2014 |
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Keywords
- Adoptive T cell transfer
- Chimeric antigen receptors
- Melanoma
- T cell receptors
- Tumor targeting
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
- Oncology
- Cancer Research
Cite this
A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control. / Stone, Jennifer D.; Harris, Daniel T.; Soto, Carolina M.; Chervin, Adam S.; Aggen, David H.; Roy, Edward J; Kranz, David M.
In: Cancer Immunology, Immunotherapy, Vol. 63, No. 11, 01.01.2014, p. 1163-1176.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A novel T cell receptor single-chain signaling complex mediates antigen-specific T cell activity and tumor control
AU - Stone, Jennifer D.
AU - Harris, Daniel T.
AU - Soto, Carolina M.
AU - Chervin, Adam S.
AU - Aggen, David H.
AU - Roy, Edward J
AU - Kranz, David M
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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.
AB - 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.
KW - Adoptive T cell transfer
KW - Chimeric antigen receptors
KW - Melanoma
KW - T cell receptors
KW - Tumor targeting
UR - http://www.scopus.com/inward/record.url?scp=84939886228&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84939886228&partnerID=8YFLogxK
U2 - 10.1007/s00262-014-1586-z
DO - 10.1007/s00262-014-1586-z
M3 - Article
VL - 63
SP - 1163
EP - 1176
JO - Cancer Immunology and Immunotherapy
JF - Cancer Immunology and Immunotherapy
SN - 0340-7004
IS - 11
ER -