Chimeric proteins and methods of immunotherapy

A system capable of inducing death of a target cell, comprising:

• (a) a chimeric transmembrane receptor polypeptide (receptor) comprising a ligand binding domain, an immune cell signaling domain, and a gene modulating polypeptide (GMP), the GMP comprising an actuator moiety linked to a cleavage recognition site, wherein the actuator moiety modulates expression and/or activity of an immune regulatory protein of the lymphocyte, and wherein the immune regulatory protein enhances lymphocyte cytotoxicity and/or reduces a side effect of lymphocyte activation;
• and
• (b) a chimeric adaptor polypeptide (adaptor) comprising a receptor binding moiety linked to a cleavage moiety, wherein the cleavage moiety is capable of cleaving the cleavage recognition site on the receptor when the receptor binding moiety of the adaptor binds the immune cell signaling domain of the receptor in response to binding of the ligand binding domain of the receptor to a ligand present on the target cell, and wherein the adaptor does not bind a ligand present on the target cell,
• wherein the receptor is activatable upon binding to the ligand present on the target cell to recruit the adaptor to the receptor, and wherein the recruited adaptor releases the actuator moiety from the GMP of the receptor by action of the cleavage moiety at the cleavage recognition site to induce death of the target cell.