T-cell killing of heterogenous tumor or viral targets with bispecific chimeric immune receptors

We have previously described several novel chimeric immune receptors (CIRs) that redirect human T cells to kill malignant or HIV-infected cells. These CIRs comprise a cancer- or virus-specific ligand or single-chain antibody fused to the signaling domain of the T-ccll receptor CD3-zeta subunit. Bind ing of the ligand- or antibody-based CIR to the target antigen (Ag) trigger s T-cell-mediated cytolysis of the tumor- or virus-infected cell independen t of target cell major histocompatibility complex class I expression. A new type of CIR was developed to mediate the lysis of cells that expressed one or more distinct viral or tumor Ags; three bispecific CIRs (BCIRs) were ge nerated that recognized the carcinoembryonic Ag (CEA) and TAG-72 tumor Ags or, alternatively, distinct epitopes in the HIV envelope (HIVenv). T cells expressing the antitumoral Ag BCIR lysed both CEA- and TAG-72-expressing ta rgets and did not kill Ag-negative targets or target cells Expressing other members of the CEA family. Similarly, T cells expressing the anti-HIVenv B CIR lysed target cells expressing both the wild-type HIVenv and a mutant HI Venv that lacked the epitopes recognized by the monospecific CIRs. This app roach permits the generation of T cells with a broader spectrum of activity capable of killing virus-infected cells and malignant cells and reduces th e potential of progression of disease due to Ag loss variants.