The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an intracellular signaling molecule in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. One aspect includes a modified T cell and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.

Provided herein are modified T lymphocytes comprising chimeric receptors and methods of use thereof.

The present invention provides compositions and methods for regulating the specificity and activity of immune effector cells for use in immunotherapy. In one embodiment, the invention provides a type of chimeric antigen receptor (CAR) wherein the CAR is termed a NKR-CAR which is a CAR design comprising a component of a receptor naturally found on natural killer (NK) cells. In one embodiment, the NK receptor includes but is not limited to a naturally occurring activating and inhibitory receptor of NK cells known as a killer cell immunoglobulin-like receptor (KIR).

Disclosed herein are methods and compositions for cell-based immunotherapies that simultaneously target the tumor microenvironment (TME) via NKG2D ligands and tumor cells via tumor-associated antigens, specifically using immune effector cells as the platform due to their reduced toxicity against normal tissue. In some embodiments, immune effector cells co-express an NKG2D cytotoxic CAR and a CAR directed against a tumor-associated antigen that provides costimulatory signals to the immune effector cell, thus killing only in the presence of both antigens specifically within the TME. In contrast, within normal tissue that might express the tumor-associated antigen, but where self-HLA is also expressed, the costimulatory signal by itself is insufficient for immune effector cell activation, thereby preventing off-tumor toxicity.

Provided herein are recombinant nucleic acids encoding chimeric priming receptors that bind ALPG/P, chimeric antigen receptors that bind MSLN, and shRNA that target FAS, PTPN2, and/or TOX. Also provided are systems of chimeric priming receptors that bind ALPG/P, chimeric antigen receptors that bind MSLN, and shRNA that target FAS, PTPN2, and/or TOX, cells expressing such proteins and shRNA, and methods of use thereof.

Engineered T cell receptor (TCR) sequences, cells expressing such sequences and methods of use thereof are provided. The engineered receptors are mutagenized in vitro, and selected for target activation potency in combination with selection for a pMHC affinity that is sufficiently low to reduce off-target cross-reactivity. In some embodiments the engineered TCR recognizes the tumor associated antigen (TAA), human MAGE-A3

Provided herein are anti-CD72 nanobodies and methods of using such nanobodies for diagnostic and therapeutic purposes.

The presently disclosed subject matter provides uses of a chimeric costimulatory receptor (CCR) targeting CD38, and cells comprising a CD38 CCR and an antigen-recognizing receptor, and uses of such cells.

Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill IL13Ra2-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with an IL13Ra2-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Provided herein are IL-2 reporter systems comprising nucleic acid constructs comprising a nucleotide sequence encoding a reporter molecule operably linked to a minimal nuclear factor of activated T cells (NFAT)-responsive promoter. Also provided herein are vectors, cells, and cell lines comprising such nucleic acids. Also provided herein are methods of making and using such cells, for example to measure the ability of a chimeric antigen receptor (CAR) to induce nuclear factor of activated T cells (NFAT)-signaling in a cell.