Provided herein are compositions and methods for detecting and/or targeting dysfunctional tumor antigen-specific CD8.sup.+ T cells in the tumor microenvironment for diagnostic, therapeutic and/or research applications. In particular, dysfunctional tumor antigen-specific CD8.sup.+ T cells are detected and/or targeted via their expression of cell surface receptors described herein, such as 4-1BB,LAG-3, or additional markers that correlate with 4-1BB and LAG-3 expression, such as markers differentially expressed on the surface of the T cells.

The invention provides compositions and methods for generating improved T cells having increased Ezh2 activity and methods of use thereof in the treatment of cancer and chronic infection.

The present disclosure encompasses methods of cancer immunotherapy, and particularly methods of allogeneic cellular immunotherapy, using particular lymphodepletion regimens in combination with particular populations of chimeric antigen receptor T cells.

The present invention relates to a molecular switch regulation type chimeric antigen receptor polypeptide, containing a humanized anti-P329G mutant scFv sequence, a hinge region/spacer region, a transmembrane region, a costimulatory signal domain, and a stimulation signal domain; an immune effector cell engineered to express the molecular switch regulation type chimeric antigen receptor polypeptide; and a method for preparing the immune effector cell. The present invention further relates to a P329G mutant antibody capable of specifically binding CLDN18.2 molecules and a method for preparing the P329G mutant antibody. A pharmaceutical combination containing the immune effector cell and the P329G mutant antibody can be used for treating diseases related to CLDN18.2, such as cancer expressing or overexpressing CLDN18.2.

The disclosure relates generally to methods and compositions for performing bone marrow transplants using a non-myeloablative chemotherapeutic agent and chemotherapeutic-resistant cells. Using the methods and compositions described herein, a patient's bone marrow may be reconstituted and the patient avoids adverse side effects, including myeloablation and/or an impaired immune system.

Disclosed are compositions, kits, and methods for identifying genes that are involved in T-cell trafficking. In particular, the compositions, kits, and methods may be used to identify genes involved in T-cell trafficking and/or infiltration into tumors such as genes that encode immune checkpoint regulators and/or stimulatory agents. The disclosed compositions, kits, and methods utilize the Sleeping Beauty transposon system in a mouse tumor model to identify genes that are involved in T-cell trafficking and infiltration into tumors. The genes identified in the disclosed methods may provide immunotherapy targets in the tumor microenvironment. The identified genes may be utilized in order to develop therapies that enhance T-cell trafficking and infiltration into tumors and/or T-cell killing of tumors such as in chimeric antigen receptor (CAR) T cell therapies.

Provided herein are combination therapies involving administration of an immunotherapy involving a cell therapy, such as a T cell therapy, and an inhibitor of gamma secretase. Also provided are methods for engineering, preparing, and producing the cells, compositions containing the cells and/or gamma secretase inhibitor, and kits and devices containing and for using, producing and administering the cells and/or gamma secretase inhibitor, such as in accord with the provided combination therapy methods.

Provided herein are humanized mouse models and methods for determining whether administration of engineered immune cell therapies likely elicit cytokine release syndrome and/or determining the efficacy of an anti-disease therapy. Further, the models provided herein may be used to test the efficacy of different anti-CRS therapies.

Disclosed herein are engineered cells and/or hypoimmunogenic cells including engineered and/or hypoimmunogenic stem cells, engineered and/or hypoimmunogenic cells differentiated therefrom, engineered and/or hypoimmunogenic CAR-T cells (primary or differentiated from engineered and/or hypoimmunogenic stem cells) and related methods of their use and generation. Provided herein are engineered and/or hypoimmunogenic cells exhibiting reduced expression of MHC class I and/or MHC class II human leukocyte antigens and T-cell receptors. In some embodiments, such cells also exogenously express one or more tolerogenic factors such as CD47 and one or more chimeric antigen receptors (CAR)s.

The invention features multi-specific fusion protein complexes with one domain comprising IL-15 or a functional variant and a binding domain specific to IL-12 or IL-18.