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.

The present disclosure concerns dosages for the treatment of human patients susceptible to or diagnosed with a disease, such as cancer. Provided are methods for administering chimeric antigen receptor (CAR)-T cells. Also provided are compositions and articles of manufacture for use in the methods.

We provide compositions and methods to enhance the anti-cancer specificity of chimeric antigen receptor natural killer cells (CAR-NK) by activating them against cancer antigens while inhibiting them against human leukocyte antigen DR (HLA-DR). HLA-DR is reportedly lost or downregulated in a substantial proportion of hematologic malignancies. An anti-HLA-DR inhibitory CAR (iCAR) is provided to effectively suppress NK cell activation against HLA-DR-expressing cells. Dual CAR-NK cells, which co-express the anti-CD19 or anti-CD33 activating CAR and the anti-HLA-DR iCAR, can preferentially target HLA-DR-negative cells over HLA-DR-positive cells in vitro. The HLA-DR-mediated inhibition is positively correlated with both iCAR and HLA-DR densities. Surrounding cells that express HLA-DR do not affect the target selectivity of the dual CAR-NK cells. We have confirmed that HLA-DR-positive cells are resistant to dual CAR-NK cell-mediated killing in a xenograft mouse model. This can be used for enhancing CAR-NK and CAR-T cell specificity against malignancies with HLA-DR loss.