Recognition of human colon cancer by T cells transduced with a chimeric receptor gene

Transduction with chimeric T-cell receptor genes can be used to redirect pr imary T lymphocytes to recognize specific antigens (Ags), including, ovaria n and breast cancer Ags. To extend this approach to colon cancer we report here redirection of T cells using a chimeric receptor recognizing the colon cancer-associated Ag EGP40. Chimeric T cell receptors were constructed by ligating single-chain genes of either of two EGP40-specific monoclonal anti bodies (CO17.1A, GA733) to the Fe receptor gamma-signaling chain. Retrovira l vectors incorporating these constructs were used to transduce a murine T- cell line and human peripheral blood lymphocytes. These modified T cells we re analyzed for specific recognition of colon cancer lines by measuring cyt okine release and lyric activity against tumor targets. Murine lymphocytes transduced with the chimeric receptor based on GA733, but not CO17.1A, rele ased cytokine specifically in response to EGP40-expressing colon cancer cel l lines. Recognition of colon cancer targets by murine lymphocytes was bloc ked by the addition of GA733 antibody or soluble EGP40 Ag, confirming that colon cancer recognition is based on specific chimeric receptor-Ag interact ion. Human lymphocytes transduced with chimeric GA733 specifically recogniz ed colon carcinoma cells in cytokine release assays and lysed EGP40-express ing tumor cells. Genetic modification of T cells can be used to redirect T cells against EGP40-expressing tumor cells. The expression of chimeric GA73 3 in the autologous lymphocytes of patients may provide a source of tumor-r eactive cells with therapeutic application against colon cancer.