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 invention relates to engineered T-cell(s) and methods for using the same as a therapeutic with a potent and selective ability to target an antigen of choice. Engineered T-cells of the disclosure are useful in the treatment of various cancers, infectious diseases, and immune disorders. Also disclosed are methods for expanding engineered and non-engineered T-cell(s) populations to therapeutically useful quantities. An engineered T-cell of the disclosure can be a universal donor, and can be administered to a subject with any MHC haplotype.

An immunotherapeutic composition is contemplated that comprises subject-derived peripheral blood mononuclear cells (PBMC) and at least one recombinant adenovirus subtype 5 (Ad5) comprising a deletion in an E1 gene region, a deletion in an E2b gene region, and a nucleic acid sequence encoding a peptide antigen, wherein the PBMC are exposed ex-vivo to the at least one Ad5 vector. Advantageously, the same PBMC composition may also be used to prepare modified NK cells, and especially modified NK include CIML NK cells, CENK cells and mCENK cells.

Provided herein are compositions comprising T cells modified to overexpress FOXO1 and methods of use thereof. Methods are provided to treat a disease or disorder in a subject comprising administration of the modified T cells. Also provided are methods for preventing exhaustion of engineered T cells comprising introducing a nucleic acid that overexpresses FOXO1 into the T cells.

Compositions and methods for making and using engineered NK cells, T cells and B cells that express a chimeric antigen receptor.

The present disclosure relates generally to T cells, e.g., CAR T cells, which have been engineered to express immunomodulatory factors in a tumor-site specific manner. The engineered T cells and pharmaceutical compositions comprising the engineered T cells exhibit improved therapeutic efficacy and reduced toxicity when used for the treatment of cancer. In other embodiments contemplated herein, the present disclosure relates to genome editing systems for engineering T cells to express immunomodulatory factors in a tumor-site specific manner.

Provided are genetically modified NK cells expressing a chimeric antigen receptor targeting an EGFR superfamily receptor. The CAR can comprise an intracellular domain of FcRI and further recombinant proteins expressed by the genetically modified NK cells are CD16, autocrine growth stimulating cytokines, and optionally one of IL-12, a TGF-beta trap, or a homing receptor. Also described are methods for treating a patient having or suspected of having a disease that is treatable with NK-92 cells, such as cancer, comprising administering to the patient the genetically modified NK cells.

The instant disclosure provides chimeric polypeptides which modulate various cellular processes following a cleavage event induced upon binding of a specific binding member of the polypeptide with its binding partner. Methods of using chimeric polypeptides to modulate cellular functions, including e.g., induction of gene expression, are also provided. Nucleic acids encoding the subject chimeric polypeptides and associated expression cassettes and vectors as well as cells that contain such nucleic acids and/or expression cassettes and vectors are provided. Also provided, are methods of treating a subject using the described components and methods as well as kits for practicing the subject methods.

Provided methods of obtaining a plurality of T cell receptors specifically recognizing a target tumor antigen peptide from an individual that has clinically benefitted from an immunotherapy, such as Multiple Antigen Specific Cell Therapy. Also provided tumor-specific TCRs, engineered immune cells expressing the TCRs and methods of treating a disease using the engineered immune cells.

Provided are chimeric antigen receptors (CAR) specific to a selected tumor antigen. Also provided are structure designs and function profiles of provided CAR candidates.