The present invention relates to methods for developing engineered T cells for immunotherapy and more specifically to methods for modifying T cells by inactivating at immune checkpoint genes preferably at least two selected from different pathways to increase T cell immune activity. 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 highly efficient adoptive immunotherapy strategies for treating cancer and viral infections.
