CD3 limits the efficacy of TCR gene therapy in vivo

Blood. 2011 Sep 29;118(13):3528-37. doi: 10.1182/blood-2011-04-346338. Epub 2011 Jul 12.

Abstract

The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.

Publication types

  • Evaluation Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD3 Complex / genetics
  • CD3 Complex / metabolism
  • CD3 Complex / physiology*
  • Cells, Cultured
  • Down-Regulation
  • Female
  • Genes, T-Cell Receptor / genetics*
  • Genetic Therapy* / methods
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / pathology
  • Lymphoma, T-Cell / therapy
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Treatment Outcome

Substances

  • CD3 Complex
  • Recombinant Fusion Proteins
  • Green Fluorescent Proteins