Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR

Primary human activated T lymphocytes were genetically grafted with chimeri c T cell receptors (TCR). Three domain single chain (sc-) TCR as well as tw o chain (tc-) TCR gene constructs were derived from the melanoma-specific c ytotoxic human T cell (CTL) clone 82/30, and linked to the CD3-zeta signali ng element. Chimeric TCR alpha and beta receptor genes were structurally de signed to prevent pairing with endogenous TCR alpha and beta chains in orde r to prevent the generation of unpredictable immune specificities. After tr ansduction of polyclonally activated human peripheral blood lymphocytes wit h retroviral vectors harboring the chimeric receptor genes, genetically eng ineered cells specifically recognized and responded to MAGE-A1(POS)/HLA-A1( POS) cells. Importantly, each type of transduced T lymphocytes that bound s pecifically to peptide/MHC complexes also showed specific antitumor reactiv ity as well as lymphokine production. Genetically engineered primary human T lymphocytes expressing chimeric sc- or tc-TCR therefore hold promise for disease-specific therapies.