Dynamics of tumor cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor.
Chimeric immunoglobulin T-cell receptors (IgTCR) join the antigen-binding portion of an antibody to one of the signaling chains of the TCR. A previous report described the construction and functional testing of an IgTCR gene directed against the carcinoembryonic tumor antigen ( CEA). These preclinical studies showed the proper assembly and cell surface expression of anti- CEA IgTCR molecules, specific target antigen binding, and activation of T-cell effector functions. Although IgTCR-modified T cells function well in vitro, therapeutic applications in humans may be complicated by various factors, such as the availability of appropriate T-cell cytokines, high systemic levels of antagonistic soluble CEA, and antigenic diversity in tumor cell populations. The current study analyzes tumor cell killing by IgTCR-modified human T cells under conditions that more closely model those that may be encountered in persons with cancer. This analysis shows that 1) depriving IgTCR-modified T cells of interleukin-2 does not diminish anti- CEA cytotoxic T lymphocyte activity, but does eliminate killing by lymphokine-activated killer cells; 2) high levels of soluble CEA do not significantly inhibit tumor cell killing even when approximately 80% of the chimeric receptors are blocked; and 3) CEA+ tumor cells that can down-regulate cell surface CEA evade immune destruction by IgTCR-modified T cells. These results have important implications for application strategies and protocol design considerations for early clinical testing of IgTCR anti-tumor therapies.[1]References
- Dynamics of tumor cell killing by human T lymphocytes armed with an anti-carcinoembryonic antigen chimeric immunoglobulin T-cell receptor. Beecham, E.J., Ortiz-Pujols, S., Junghans, R.P. J. Immunother. (2000) [Pubmed]
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