The present disclosure is in the field of genome engineering, particularly targeted modification of the genome of a cell.

The method entails modification of non-malignant cells for transplantation or therapy to avoid recognition and attack by monoclonal antibodies and antibody-derived therapeutics. Many therapies that use monoclonal antibodies or antibody-derived therapeutics not only bind to the intended target epitope on malignant cells, but also to the same target epitope on healthy non-malignant cells that express the target antigen. This phenomenon is termed on-target off-tumor effect. This can cause rejection, immune cell attack or opsonization of non-malignant cells, which in turn can cause severe side effects which often hampers the therapeutic effect. Similarly, cytokines in cytokine therapy can bind to receptors on bystander cells and cause unintended effects. The methods of the present invention change the antigen epitope or the cytokine receptor on non-malignant and bystander cells for adoptive cell therapy, thereby disrupting the binding of the therapeutic agentantibody or cytokineto the target antigen or receptor on non-malignant cells.