Abstract: Methods for developing engineered T-cells for immunotherapy that are both non-alloreactive and resistant to immunosuppressive drugs. The present invention relates to methods for modifying T-cells by inactivating both genes encoding target for an immunosuppressive agent and T-cell receptor, in particular genes encoding CD52 and TCR. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.

Abstract: Meganuclease variants which cleave at least one target in the provirus of a retrovirus and in particular which cleave the genomic insertion of the provirus. The present invention in particular relates to meganuclease variants which cleave the provirus of the Human Immunodeficiency Virus genome following genomic insertion. Vector encoding such variants, as well as to a cell or multi-cellular organism modified by such a vector and use of said meganuclease variants and derived products for genome engineering and for in vivo and ex vivo (gene cell therapy) genome therapy.