The present disclosure provides adoptive T cell therapies that have improved architectures for targeting antigens and recruiting multimeric immune signaling complexes for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.

The present disclosure is directed to leucine zipper-based sorting systems adapted to facilitate the expression and coordination of polypeptide sequences capable of improving the function of CAR T cells. The systems enable the generation of T cells engineered to express multiple combinations of CARs (multi-CAR), safety-switches, switch receptors, and/or cytokines.

The invention provides methods of treating CD-19 positive malignancies in human subjects with suitable doses of switchable CAR-T cells and complementary switch molecules.

Aspects of the disclosure include compositions and methods for treatment of a wide variety of diseases/conditions with engineered host cells, where the engineered host cells comprise a chimeric adaptor (CAD) polypeptide comprising DAP10 and at least one chimeric receptor. The CAD polypeptide may comprise substitution mutations and/or additional protein domains that function in conjunction with associated receptors to enhance cell survival and proliferation of the host cells, and to enhance cell killing activities of non-host cells.

In one embodiment, the invention provides a chimeric antigen receptor (CAR) T cell which is conjugated to a bi-functional molecule which is specific for both an extracellular binding domain of the chimeric antigen receptor (CAR) T cell and prostate-specific membrane antigen (PSMA). The chimeric antigen receptor (CAR) T cell contains a T cell signaling domain and the extracellular binding domain of the chimeric antigen receptor (CAR) T cell is not specific for prostate-specific membrane antigen (PSMA). Compositions and methods of treatment using these CAR T cells are also disclosed.

The invention relates to heterodimeric inactivatable chimeric antigen receptors (CARs) and their use for treatment.