Drug-Resistant Immune Cells and Methods of Use Thereof

A method for generating a modified regulatory T (Treg) cell, comprising:

• (a) inserting an exogenous NR3C1 gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous NR3C1 gene in a Treg cell to render the modified Treg cell resistant to a steroid;
• and at least one of (b)-(f) as follows:
• (b) inserting an exogenous calcineurin A (CNa) gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous CNa gene in a Treg cell to render the modified Treg cell resistant to calcineurin inhibitors (CNIs), tacrolimus and cyclosporin;
• (c) inserting an exogenous calcineurin B (CNb) gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous CNa gene in a Treg cell to render the modified Treg cell resistant to the CNIs, tacrolimus and cyclosporin;
• (d) inserting an exogenous FKBP12 gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous FKBP12 gene in a Treg cell to render the modified Treg cell resistant to the CNIs, tacrolimus and sirolimus;
• (e) inserting an exogenous mammalian target of rapamycin (mTOR) gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous mTOR gene in a Treg cell to render the modified Treg cell resistant to sirolimus;
• and/or
• (f) inserting an exogenous inosine monophosphate dehydrogenase (IMPDH) gene comprising a mutation into the genome of a Treg cell or introducing a mutation into an endogenous IMPDH gene in a Treg cell to render the modified Treg cell resistant to mycophenolate.