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 p ortion 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 preclinica l studies showed the proper assembly and cell surface expression of anti-CE A IgTCR molecules, specific target antigen binding, and activation of T-cel l effector functions, Although IgTCR-modified T cells Function well in vitr o, therapeutic applications in humans may be complicated by various factors , such as the availability of appropriate T-cell cytokines, high systemic l evels of antagonistic soluble CEA. and antigenic diversity in tumor cell po pulations. The current study analyzes tumor cell killing by IgTCR-modified human T cells under renditions that more closely model those that may be en countered in persons with cancer. This analysis shows that 1) depriving IgT CR modified T cells of interleukin-2 does not diminish anti-CEA cytotoxic T lymphocyte activity, but does eliminate killing by lymphokine-activated ki ller cells: 2) high levels of soluble CEA do not significantly inhibit tumo r cell killing even when approximately 80% of the chimeric receptors are bl ocked; and 3') CEA(+) tumor cells that can downregulate cell surface CEA ev ade immune destruction by IgTCR-modified T cells. These results have import ant implications for application strategies and protocol design considerati ons for early clinical testing of IgTCR anti-tumor therapies.