The invention provides compositions and methods for treating diseases associated with expression of a tumor antigen as described herein. The invention also relates to nucleic acids comprising a truncated PGK promoter operably linked to a chimeric antigen receptor (CAR) specific to a tumor antigen as described herein, vectors encoding the same, and recombinant T cells comprising the CARs of the present invention. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an antigen binding domain that binds to a tumor antigen as described herein.

The present application provides constructs comprising an antibody moiety specifically recognizing Glypican 3 (GPC3), such as a cell surface-bound GPC3. Also provided are methods of making and using these constructs.

The invention provides an isolated and purified nucleic acid sequence encoding a chimeric antigen receptor (CAR) directed against B-cell Maturation Antigen (BCMA). The invention also provides host cells, such as T-cells or natural killer (NK) cells, expressing the CAR and methods for destroying multiple myeloma cells.

The invention provides novel light-switchable CAR T-cells that can be remotely controlled through NIR-light-converting upconvension nanoparticles, and related CAR T constructs, nanoparticles, compositions and methods thereof for optogenetic therapy.

Methods and compositions are provided related to therapeutic receptors, including chimeric antigen receptors (CARs), capable of specifically binding TYRP-1. The disclosed compositions include, for example, cells (e.g., immune cells) expressing TYRP-1 specific CARs, nucleic acids encoding TYRP-1 specific CARs, and TYRP-1 specific CAR polypeptides. Certain aspects relate to methods of treating cancer, including melanoma, using compositions comprising TYRP-1 specific CARs, for example cells expressing TYRP-1 specific CARs. In some embodiments, provided herein are chimeric polypeptides comprising a TYRP-1 binding domain, a hinge region, a transmembrane domain, and an intracellular signaling domain.

The present disclosure provides methods and compositions for enhancing the immune response toward cancers and pathogens. The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to cells comprising a c-Kit mutant, e.g., a c-Kit mutant comprising an activating mutation. The cells can further comprise an antigen-recognizing receptor (e.g., a chimeric antigen receptors (CAR) or a T cell receptors (TCR)). The presently disclosed subject matter relates to the use of cells for treatment, e.g., treating cancers.

Methods of culturing embryonic stem cells, induced pluripotent stem cells and/or differentiated cells in culture medium comprising activin are described. In one aspect, the disclosure features a pluripotent human stem cell, wherein the stem cell comprises: (i) a genomic edit that results in loss of function of Cytokine Inducible SH2 Containing Protein (CISH) and (ii) a genomic edit that results in a loss of function of an agonist of the TGF beta signaling pathway, or a genomic edit that results in a loss of function of adenosine Ata receptor.

The present disclosure provides methods of promoting a persistent effector function of immune cells, comprising modifying the cells to overexpress c-Jun and reduced levels of a NR4A gene and/or protein. Also provided are modified cells, e.g., immune cell, which have been modified to overexpress c-Jun and express reduced levels of NR4A gene and/or protein. Overexpressing c-Jun and simultaneously reducing expression levels of a NR4A gene and/or protein leads to exhaustion/dysfunction resistant cells, which are apoptosis resistant and also immune checkpoint resistant, and also to the maintenance of anti-tumor function in tumor microenvironments.

Methods for manufacturing genetically engineered T cells expressing a chimeric antigen receptor (CAR), such as a CAR that binds human CD19, BCMA, or CD70, and having multiple additional gene edits, for example, a disrupted Regnase-1 gene, a disrupted TGFBRII gene, a disrupted TRAC gene, a disrupted β2M gene, or a combination thereof, using CRISPR/Cas gene editing systems.

The present invention relates to methods for developing engineered T-cells for immunotherapy that are non-alloreactive. The present invention relates to methods for modifying T-cells by inactivating both genes encoding T-cell receptor and an immune checkpoint gene to unleash the potential of the immune response. This method involves the use of specific rare cutting endonucleases, in particular TALE-nucleases (TAL effector endonuclease) and polynucleotides encoding such polypeptides, to precisely target a selection of key genes in T-cells, which are available from donors or from culture of primary cells. The invention opens the way to standard and affordable adoptive immunotherapy strategies for treating cancer and viral infections.