The disclosure relates to immune cells comprising systems of two engineered receptors each having a ligand binding domain, collectively designed to target cells identified by loss of heterozygosity and used to treat a disease or disorder, for example, cancer. The disclosure provides immune cells expressing two engineered receptors, methods of making same, and polynucleotides and vectors encoding same.

In various embodiments, the present disclosure provides chimeric antigen receptors (CARs) which bind to mesothelin. The mesothelin CARs comprise an extracellular region comprising a binding domain that specifically binds to at least a portion of mesothelin, a transmembrane region, and an intracellular region comprising an effector domain or a portion or variant thereof and a costimulatory domain or a portion or variant thereof. Recombinant host cells expressing the mesothelin CARs are also provided, as well as compositions and methods of treatment, prevention, and manufacture comprising the same.

The present invention relates to an antigen composition comprising at least one mesothelioma cancer cell associated antigen and a pharmaceutically acceptable carrier for use in the treatment of cancer, in particular mesothelioma, wherein dendritic cells are loaded with said antigen composition and wherein said loaded dendritic cells are administered in combination with one or more checkpoint inhibitors, to patients. The present invention also relates to an antigen composition comprising at least two mesothelioma cancer cell associated antigens and a pharmaceutically acceptable carrier. The present invention further relates to an antigen composition comprising at least two mesothelioma cancer cell associated antigens and a pharmaceutically acceptable carrier, for use as a pharmaceutical, in particular for use in the treatment of mesothelioma.

Novel anti-effector moiety antibodies or antigen binding domains thereof and CARs that contain such effector moiety antigen binding domains, either with or without one or more booster elements, and host cells expressing the receptors, and nucleic acid molecules encoding the receptors are provided herein, as well as methods of use of same in a patient-specific immunotherapy that can be used to treat solid tumor cancers and other diseases and conditions.

The present invention provides compositions and methods for inhibiting one or more diacylglycerol kinase (DGK) isoform in a cell in order to enhance the cytolytic activity of the cell. In one embodiment, the cells may be used in adoptive T cell transfer. For example, in some embodiments, the cell is modified to express a chimeric antigen receptor (CAR). Inhibition of DGK in T cells used in adoptive T cell transfer increases cytolytic activity of the T cells and thus may be used in the treatment of a variety of conditions, including cancer, infection, and immune disorders.

Described herein are T cells engineered to express a chimeric antigen receptor (CAR), such as an anti-mesothelin CAR alone or in combination with a follicle-stimulating hormone receptor (FSHR) binding domain and/or a dominant negative transforming growth factor-? receptor II (dnTGF?RII) for the treatment of diseases associated with mesothelin expression. Also described are T cells engineered to express a modified T cell receptor (TCR).

The present invention discloses a novel switchable dual chimeric antigen receptor-T (sdCAR-T) cell and a construction method and use thereof, which fall within the field of cellular immunotherapy for tumors. The dual chimeric antigen receptor consists of a first chimeric antigen receptor for MSLN and a second chimeric antigen receptor for FITC. A dual-targeted functional T cells regulated by specific exogenous bifunctional molecules is constructed, and the exogenous molecules are used to preliminarily discuss the in vivo and in vitro activity of the dual chimeric antigen receptor-T cell. By means of in vitro and in vivo tests, it is confirmed that the activation mode of the constructed CAR-T cell is controlled by the combination of endogenous tumor antigens and exogenous bifunctional molecules, and this combined regulation mode can significantly improve the safe application of CAR-T cell immunotherapy.

Provided is a chimeric target factor receptor capable of activating an antigen-presenting cell such as a dendritic cell in a target-factor-specific manner. The chimeric target factor receptor contains a target factor-binding domain, a transmembrane domain, and an intracellular domain containing a TLR intracellular domain.

Provided herein are methods employing various fusion constructs in T cell therapy. The fusion constructs allow for one to reduce, to the point of full removal if desired, the use of IL-2 that would otherwise accompany an in vivo T cell therapy.

Disclosed herein are mesothelin (MSLN)-specific binding polypeptides. These binding polypeptides may be incorporated into chimeric antigen receptors (CARs). Also disclosed herein are methods of using these binding polypeptides and/or CARs for the treatment of, for example, a cancer.