Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection

Thomas M. Schmitt, David H. Aggen, Ingunn M. Stromnes, Michelle L. Dossett, Sarah A. Richman, David M Kranz, Philip D. Greenberg

Research output: Contribution to journalArticle

Abstract

Many of the most promising tumor antigens for T-cell-based cancer immunotherapies are unmodified self-antigens. Unfortunately, the avidity of T cells specific for these antigens is limited by central tolerance during T-cell development in the thymus, resulting in decreased anti-tumor efficacy of these T cells. One approach to overcoming this obstacle is to mutate T-cell receptor (TCR) genes from naturally occurring T cells to enhance the affinity for the target antigen. These enhanced-affinity TCRs can then be developed for use in TCR gene therapy. Although TCRs with significantly enhanced affinity have been generated using this approach, it is not clear whether these TCRs, which bypass the affinity limits imposed by negative selection, remain unresponsive to the low levels of self-antigen generally expressed by some normal tissues. Here we show that 2 variants of a high-affinity WT1-specific TCR with enhanced affinity for WT1 are safe and do not mediate autoimmune tissue infiltration or damage when transduced into peripheral CD8 T cells and transferred in vivo. However, if expressed in developing T cells and subjected to thymic selection, the same enhanced-affinity TCRs signal tolerance mechanisms in the thymus, resulting in T cells with attenuated antigen sensitivity in the periphery.

Original languageEnglish (US)
Pages (from-to)348-356
Number of pages9
JournalBlood
Volume122
Issue number3
DOIs
StatePublished - Jul 18 2013

Fingerprint

Gene therapy
T-cells
Autoantigens
Neoplasm Antigens
T-Cell Antigen Receptor
Genetic Therapy
Tumors
T-Lymphocytes
T-Cell Receptor Genes
Thymus
Antigens
Thymus Gland
Central Tolerance
Tissue
Infiltration
Immunotherapy
Neoplasms
Genes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. / Schmitt, Thomas M.; Aggen, David H.; Stromnes, Ingunn M.; Dossett, Michelle L.; Richman, Sarah A.; Kranz, David M; Greenberg, Philip D.

In: Blood, Vol. 122, No. 3, 18.07.2013, p. 348-356.

Research output: Contribution to journalArticle

Schmitt, Thomas M. ; Aggen, David H. ; Stromnes, Ingunn M. ; Dossett, Michelle L. ; Richman, Sarah A. ; Kranz, David M ; Greenberg, Philip D. / Enhanced-affinity murine T-cell receptors for tumor/self-antigens can be safe in gene therapy despite surpassing the threshold for thymic selection. In: Blood. 2013 ; Vol. 122, No. 3. pp. 348-356.
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