Antitumor activity of chimeric immunoreceptor gene-modified Tc1 and Th1 cells against autologous carcinoembryonic antigen-expressing colon cancer cells

Cancer Sci. 2006 Sep;97(9):920-7. doi: 10.1111/j.1349-7006.2006.00271.x. Epub 2006 Jul 13.

Abstract

To generate tumor-specific and interferon (IFN)-gamma-producing Tc1 and Th1 cells applicable for many cancer patients, we previously developed a protocol for generating carcinoembryonic antigen (CEA)-specific Tc1 and Th1 cells from healthy human T cells by transduction with a lentivirus containing a chimeric immunoglobulin T-cell receptor (cIgTCR) gene composed of single-chain variable fragments from an anti-CEA-specific monoclonal antibody fused to an intracellular signaling domain of CD28 and CD3zeta. These cells, designated Tc1-T and Th1-T bodies, respectively, showed strong antitumor activity against CEA-expressing tumor cells in RAG2-/- mice when both of them were transferred. However, it remains unclear whether it is possible to generate Tc1-T and Th1-T bodies from cancer patients with defective T-cell function because of significant immunosuppression. Here, we prepared Tc1-T and Th1-T bodies from T cells of a colon cancer patient, and asked whether these T bodies can exert effective T-cell function against autologous tumor cells. These T bodies showed high cytotoxicity and produced IFN-gamma in response to CEA-expressing autologous tumor cells, even in the presence of soluble CEA. It was also demonstrated that Th1-T bodies supported the survival of Tc1-T bodies through cell-to-cell interactions. Furthermore, our protocol utilized retrovirus for cIgTCR transduction to achieve better induction efficiency compared to lentivirus-mediated transduction. Taken together, our findings here indicate that retrovirally transduced Tc1-T and Th1-T bodies will become a promising strategy for adoptive immunotherapy of human cancer.

MeSH terms

  • Carcinoembryonic Antigen / immunology
  • Carcinoembryonic Antigen / metabolism*
  • Cell Communication / immunology
  • Cell Line, Tumor
  • Chimera
  • Coculture Techniques
  • Colorectal Neoplasms / immunology*
  • Female
  • Genetic Vectors
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Interferon-gamma / biosynthesis
  • Lentivirus / genetics
  • Middle Aged
  • Receptors, Antigen, T-Cell / genetics*
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Transduction, Genetic

Substances

  • Carcinoembryonic Antigen
  • Receptors, Antigen, T-Cell
  • Interferon-gamma