CA2-IL15 fusion proteins for tunable regulation

A method of treating a disease or disorder responsive to regulated IL 15 in a subject in need thereof, said method comprising:

• (a) administering to the subject a therapeutically effective amount of a cell comprising a nucleic acid molecule comprising a polynucleotide encoding a recombinant protein comprising a drug responsive domain (DRD) operably linked to an IL15 payload, wherein the DRD is derived from human carbonic anhydrase II (CA2) and comprises the amino acid sequence of SEQ ID NO:4 and wherein the IL15 payload is a membrane-bound IL15 polypeptide, wherein the cell is a tumor infiltrating lymphocyte (TIL), a human T cell or a human NK cell;
• and
• (b) administering a therapeutically effective amount of a stimulus to the subject, wherein the DRD is stabilized by the stimulus to enable expression of the IL15 payload, wherein the stimulus is acetazolamide, and wherein the disease or disorder is a cancer.