The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward tumor and pathogen antigens. It relates to immunoresponsive cells comprising two or more chimeric antigen receptors (CARs), wherein the CARs comprise different intracellular signaling domains, in particular, the intracellular signaling domains of the CARs comprise different co-stimulatory molecules.

Provided are methods, compositions, uses and articles of manufacture of combination therapies involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and the use of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-di-hydro-isoindol-2-yl]-piperidine-2,6-dione, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for treating subjects with disease and conditions such as certain B cell malignancies, and related methods, compositions, uses and articles of manufacture. The cells generally express recombinant receptors such as chimeric antigen receptors (CARs). In some embodiments, the disease or condition is a non-Hodgkin lymphoma (NHL), such as relapsed or refractory NHL or specific NHL subtype.

Provided are methods, compositions, uses and articles of manufacture of combination therapies involving immunotherapies, such as adoptive cell therapy, e.g., T cell therapy, and the use of (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-di-hydro-isoindol-2-yl]-piperidine-2,6-dione, or an enantiomer or mixture of enantiomers thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, for treating subjects with disease and conditions such as certain B cell malignancies, and related methods, compositions, uses and articles of manufacture. The cells generally express recombinant receptors such as chimeric antigen receptors (CARs). In some embodiments, the disease or condition is a non-Hodgkin lymphoma (NHL), such as relapsed or refractory NHL or specific NHL subtype.

The present disclosure provides fusion proteins with improved signaling properties. Disclosed embodiments include fusion proteins that comprise an extracellular component comprising a target-binding domain, a transmembrane domain, and an intracellular component comprising a SH2 domain or a functional portion or variant thereof, and have improved signaling in response to antigen-binding, including of solid-tumor antigens with low levels of expression. Recombinant host cells expressing the fusion proteins, and polynucleotides encoding the fusion proteins, are also provided, as are compositions and methods comprising the same.

Embodiments of the disclosure encompass methods and compositions for producing engineered B cells. The disclosure concerns large-scale processes for producing B cells that are engineered to have disruption of expression of one or more genes using CRISPR and also express at least one heterologous antigen receptor. Specific embodiments include particular parameters for the process.

The present document describes compounds, or pharmaceutically acceptable salt thereof, of a core formula (I) where R.sub.1 features an amine group, particularly useful in the formulation of lipid particles including nucleic acid therapeutic agents, or proteins, or both, and for delivery of nucleic acid and protein therapeutics to cells in vivo or ex vivo, including anticancer and vaccine applications.

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A method for arterial endothelial-enhanced functional T cell generation is provided. In the method, arterial endothelial cells enhance functional T cell generation by promoting the generation of hematopoietic progenitor cells with T-lineage bias. The first stage of T cell differentiation from human pluripotent stem cells (hPSCs) is optimized, and it is found that hPSC-derived autologous arterial endothelial cells increase the T cell potential of hematopoietic progenitor cells. Moreover, the T cells generated by arterial endothelial cell priming share similar function to that of human peripheral blood T cells. hPSC-derived CD19-CAR-T cells have been verified to have tumor-killing effects both in vivo and in vitro. The established hPSC-T differentiation system would provide a valuable resource for chimeric antigen receptor T cell (CAR-T) therapy.

The invention provides compositions and methods for treating diseases associated with expression of CD20 or CD22. The invention also relates to chimeric antigen receptor (CAR) specific to CD20 or CD22, vectors encoding the same, and recombinant T or natural killer (NK) cells comprising the CD20 CAR or CD22 CAR. The invention also includes methods of administering a genetically modified T cell or NK cell expressing a CAR that comprises a CD20 or CD22 binding domain.

Provided is a modified immune cell, comprising a chimeric antigen receptor and/or a coding element therefor, or comprising a T cell receptor and/or a coding element therefor. The immune cell further comprises: leptin and/or a functional fragment thereof; and/or, a leptin receptor and/or a functional fragment thereof, and the expression quantity of the leptin receptor and/or the functional fragment thereof in the immune cell is increased compared with that in an immune cell without the corresponding modification. In addition, also provided is another modified immune cell, comprising leptin and/or a functional fragment thereof, and/or, a leptin receptor and/or a functional fragment thereof, and a low-density lipoprotein-receptor-related protein or a fragment thereof.

Provided herein are methods for preparing, producing, processing, culturing, isolating, or making cells suitable for immune or cell therapy, and for their use in cell therapy.