The present invention provides compositions and methods for inducing a CAR mediated trans-signal in a T cell. The trans-signaling CAR T cells comprise a first CAR having a first signaling module and a second CAR having a distinct second signaling module. The present invention also provides cells comprising a plurality of types of CARs, wherein the plurality of types of CARs participate in trans-signaling to induce T cell activation.

The present invention provides, in some embodiments, methods of promoting an immune response in a subject in need thereof, comprising administering to the subject a population of immune cells that express an enzyme that facilitates immune cell function in a nutrient-poor environment. The invention also provides, in other embodiments, compositions comprising an ex vivo population of immune cells expressing an enzyme that enhances immune cell function in a nutrient-poor environment.

Cancer therapy comprising both a population of genetically engineered T cells expressing a chimeric antigen receptor (CAR) and a population of antigen-presenting cells (APCs), which enhances efficacy of the CAR-expressing T cells.

Provided herein are nucleic acids, expression cassettes, modified lymphocytes and compositions comprising the same which include a sequence encoding a fusion protein, TCR or CAR that includes a domain of LTBR. In certain embodiments, the cell is a T cell. Methods of treatment using the provided compositions are also described.

In certain embodiments, this disclosure provides methods to generate DNA, RNA and/or DNA-peptide nanostructures based chimeric antigen receptor (CAR) T cell (engineered T cell) for cancer immunotherapy, and compositions made by these methods.

The invention provides compositions and methods for treating diseases such as cancer. The invention also relates to a method of administering a therapy comprising a chimeric antigen receptor, an IL-15R molecule and an IL-15 molecule.

The invention provides compositions and methods for treating cancer by using immune effector cells (e.g., T cells, NK cells) engineered to conditionally express an agent which enhances the immune effector response of an immune effector cell that expresses a Chimeric Antigen Receptor (CAR). The conditional agents described herein include agents that target a cancer associated antigen, e.g., a CAR, agents that inhibit one or more checkpoint inhibitors of the immune response, and a cytokine.

The present disclosure provides binding-triggered transcriptional switch polypeptides, nucleic acids comprising nucleotide sequences encoding the binding-triggered transcriptional switch polypeptides, and host cells genetically modified with the nucleic acids. The present disclosure also provides chimeric Notch receptor polypeptides, nucleic acids comprising nucleotide sequences encoding the chimeric Notch receptor polypeptides, and host cells transduced and/or genetically modified with the nucleic acids. The present disclosure provides transgenic organisms comprising a nucleic acid encoding a binding triggered transcriptional switch polypeptide and/or a chimeric Notch receptor polypeptide of the present disclosure. Binding triggered transcriptional switch polypeptides and chimeric Notch receptor polypeptides of the present disclosure are useful in a variety of applications, which are also provided.

The present disclosure provides a heterodimeric, conditionally active chimeric antigen receptor (CAR), and a nucleic acid comprising a nucleotide sequence encoding the CAR. The present disclosure provides cells genetically modified to produce the CAR. A CAR of the present disclosure can be used in various methods, which are also provided.

The present disclosure relates, in general, to methods for generating engineered antigen-specific T cell receptors, cells and non-human animals comprising such engineered T cell receptors and methods of making engineered T cell receptors. The engineered T cell receptors can be specific for cancer or immunology targets, such as mesothelin, and are useful in developing therapies for cancer, autoimmune diseases, infectious diseases and other conditions or disorders.