Regulatable cell surface receptors and related compositions and methods
Provided herein are cell surface receptors that include an extracellular binding domain, a transmembrane domain, an intracellular signaling domain, and a protease cleavage site disposed between the extracellular binding domain and the intracellular signaling domain. In certain aspects, the cell surface receptors are engineered cell surface receptors, such as chimeric antigen receptors (CARs). Also provided are cells that include such receptors (e.g., where the cells express the receptors on their surface) and pharmaceutical compositions including such cells. Nucleic acids that encode the cell surface receptors, cells including such nucleic acids, and pharmaceutical compositions including such cells, are also provided. Also provided are methods for regulating signaling of a cell surface receptor, and methods of using the cells of the present disclosure, including methods of using such cells to administer a regulatable cell-based therapy to an individual.
1. An expression vector comprising a nucleic acid encoding a cell surface receptor, wherein the cell surface receptor comprises:
an extracellular binding domain;
a transmembrane domain;
an intracellular signaling domain; and
a cleavage site for a protease, wherein the cleavage site is disposed between the transmembrane domain and the intracellular signaling domain,
wherein the cell surface receptor is a chimeric antigen receptor (CAR) or an engineered T cell receptor (TCR),
wherein the cell surface receptor does not comprise the protease, and
wherein the cell surface receptor does not comprise a domain that dimerizes with the protease.
2. A cell comprising the expression vector of claim 1 .
3. The cell of claim 2 , wherein the cell is an immune cell.
4. The cell of claim 3 , wherein the immune cell is a T cell or a natural killer (NK) cell.
5. The cell of claim 4 , wherein the cell surface receptor is a CAR.
6. The cell of claim 4 , wherein the cell is T cell and the cell surface receptor is a CAR.
7. A pharmaceutical composition comprising the cell of claim 6 .
8. A pharmaceutical composition, comprising:
the cell of claim 2 ; and
a pharmaceutically-acceptable carrier.
9. The expression vector of claim 1 , wherein the cell surface receptor is a chimeric antigen receptor (CAR).
10. The expression vector of claim 1 , wherein the cell surface receptor is an engineered TCR.
11. The expression vector of claim 1 , wherein the extracellular binding domain specifically binds an antigen on the surface of a cancer cell.