The invention is directed to a bispecific chimeric antigen receptor, comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific single chain Fv (scFv) fragment, and binds a different antigen, and wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control. The invention also provides methods and uses of the bispecific chimeric antigen receptors.

Provided are compositions and methods relating to regulatable chimeric antigen receptors (RCARs), natural killer cell receptor CARs (NKR-CARs), and regulatable NKR-CARs (RNKR-CARs), where the intracellular signaling or proliferation of the RCAR or RNKR-CAR can be controlled to optimize the use of an RCAR/NKR-CAR- or RNKR-CAR-expressing cell to provide an immune response. Cells can be engineered to express a RNKR-CAR or to express a RCAR and a NKR-CAR (e.g., inhibitory NKR-CAR). For example, a RCAR or RNKR-CAR can comprise a dimerization switch that, upon the presence of a dimerization molecule, can couple an intracellular signaling domain to an extracellular recognition element, e.g., an antigen binding domain, an inhibitory counter ligand binding domain, or costimulatory ECD domain. An RCAR or RNKR-CAR can be engineered to include an appropriate antigen binding domain that is specific to a desired antigen target and used in the treatment of a disease.

Disclosed herein are genome-edited chimeric antigen receptor T cells (CAR-T), which can be derived from a cytotoxic T cells, a viral-specific cytotoxic T cell, memory T cells, or gamma delta () T cells, and comprise one or more chimeric antigen receptors (CARs) targeting one or more antigens, wherein the CAR-T cell is deficient in one or more antigens to which the one or more CARs specifically binds. In particular, the present disclosure relates to engineered mono, dual, and tandem chimeric antigen receptor (CAR)-bearing T cells (CAR-T) and methods of immunotherapy for the treatment of cancer.

The present disclosure pertains to a method of construction and use of a novel bispecific chimeric antigen receptor (CAR) within the field of immunotherapy. The CAR described herein comprises an antigen-binding domain, a connecting peptide (C-peptide), a hinge region, a transmembrane domain, a 4-1BB co-stimulatory signaling domain, and a CD3 signaling domain. The antigen-binding domain is composed of either an anti-CD19 scFv and an anti-CD22 nanobody, or an anti-Her2 scFv paired with a ligand capable of recognizing IGF1R. The bispecific CAR-T cell provided by the present disclosure is constructed based on the ligation design involving an antiparallel -stranded loop (BS Loop) linker.

This invention is directed to engineered cells and methods for using the same. In embodiments, the engineered cell comprises a nucleic acid encoding a chimeric antigen receptor and a polypeptide, wherein the chimeric antigen receptor is specific for two or more antigens on the surface of a cancer cell, and wherein the polypeptide comprises an antibody or fragment thereof that can be secreted from the engineered cell.

Provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing mono- and/or bi-specific chimeric antigen receptors (CAR) with anti-CD133 and anti-EGFR antigen binding domains, and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.

The disclosure provides synthetic immune receptors (SIRs), nucleic acids encoding the SIRs, methods of making and using the SIRs, in, for example, adoptive cell therapy.

A humanized antibody specific for CD22 and a chimeric antigen receptor using the same, and, in some aspects, a chimeric antigen receptor including the antibody or a CD19CD22 antibody, a CAR-T cell expressing the chimeric antigen receptor, and a pharmaceutical composition including the same for preventing or treating a disease mediated by B cells.

Provided herein are antibodies and antigen-binding fragment thereof targeting CLL1, and chimeric antigen receptors (e.g., monovalent CAR, and multivalent CAR including bi-epitope CAR) having one or more anti-CLL1 antigen-binding fragments thereof. Further provided are engineered immune effector cells (e.g., T cells) expressing the chimeric antigen receptors and methods of use thereof.

Provided herein are antibodies and antigen-binding fragment thereof targeting CD33, and chimeric antigen receptors (e.g., monovalent CAR, and multivalent CAR including bi-epitope CAR) having one or more anti-CD33 antigen-binding fragments thereof. Further provided are engineered immune effector cells (e.g., T cells) expressing the chimeric antigen receptors and methods of use thereof.