Carcinoembryonic antigen (CEA) is expressed as a tumor-associated antigen in a large number of human malignancies. CEA is expressed on 60-90 percent of metastatic colorectal carcinomas, the number two cancer killer in United States, 60 percent of metastatic breast cancer (No. 2 killer in women), and more than 30 percent malignancies of the lung (No. 1 killer in men and women), liver, pancreas, head and neck, bladder, cervix, and prostate, with approximately 150,000 deaths in CEA+ malignancies each year. Therefore, an effective therapy which can specifically direct anti-tumor immunity against the CEA antigen would have a major impact on oncologic diseases in this country. T lymphocytes transduced with immunoglobulin-T cell receptor (IgTCR) chimeric genes provide for the creation of new designer lineages of immune effector cells. In the present study, a humanized single chain anti-CEA antibody fragment (sFv) was fused to the zeta chain of the TCR. T cell transduced with this vector specifically bind CEA and undergo activation in an MHC-independent manner against CEA+ target cells. The overall objectives of this application are to evaluate the safety and efficacy of antiCEA-chimeric TCR transduced T cells in phase I and Phase II cancer clinical trials, to assess the pharmacokinetics of antiCEA-IgTCR transduced T cells by their persistence in blood and tissues, and to follow other immunologic and oncologic parameters that may indicate anti-tumor efficacy in patients with CEA+ tumors. The principal hypothesis is that expression of a single chain IgTCR-zeta construct by peripheral blood T cells will redirect those T cells to lyse CEA+ tumor cells in vitro and in vivo, and will mediate regression of established CEA+ tumors in vivo. Therapy will consist of collecting patient lymphocytes by leukapheresis, modifying the T cells by retroviral- mediated insertion of the chimeric IgTCR genes, and expanding the transduced T cells which are now specific for the CEA tumor antigen. These cells are then reinfused back into the patients, and toxicity and response are monitored. Parallel laboratory efforts will be directed at creating second-generation reagents to improve current technologies for T cell transduction and selective expansion of IgTCR-modified T cells to facilitate the implementation and expansion of this modality.
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