Provided herein are compositions and methods for improving immune system function. In particular, provided herein are compositions, methods, and uses of YY1 and EZH2 inhibitors for preventing and reversing T-cell exhaustion (e.g., for use in immunotherapy).

Embodiments of the disclosure encompass immunotherapy for Hepatitis B viral (HBV) infection in an individual in need thereof. The immunotherapy comprises one or more chimeric antigen receptors (CAR) that target a HBV antigen, including CAR molecules that utilize specific scFv antibodies. In certain cases, the CAR comprises one or more mutations to reduce binding to Fc receptors. In specific aspects, cells that express the CAR(s) have reduced cytotoxicity that is safer and/or beneficial to individuals that are immunocompromised.

The present invention provides novel uses and methods for T cell based immunotherapies. Specifically, the invention relates to novel ligands, targets and nucleic acids and vectors encoding said targets that are useful for modulating T cell responses.

The present invention relates to a method for obtaining stable pseudotyped lentiviral particles including a heterologous gene of interest, comprising the following steps: a) transfecting at least one plasmid in appropriate cell lines, wherein said at least one plasmid comprises the gene of interest, the rev. gag and pol genes, and a sequence coding for an ERV syncytin, wherein the rev, gag and pol genes are retroviral genes; b) incubating the transfected cells obtained in a), so that they produce the stable pseudotyped lentiviral particles in the supernatant; and c) harvesting and concentrating the stable lentiviral particles obtained in b). The present invention also relates to a method to transduce immune cells using lentiviral vectors pseudotyped with an ERV syncytin glycoprotein. The method can be performed on non-stimulated blood cells or on cells stimulated briefly with IL7, and the cells can be expanded. The stable pseudotyped lentiviral particles obtained are particularly useful in gene therapy.

The present invention provides Listeria vaccine strains that express a heterologous antigen and a metabolic enzyme, and methods of generating same.

Described herein are methods and compostions relating to breaking or inhibiting T cell exhaustion by increasing TMEM16F levels and/or activity. The methods and compositions can thereby further relate to treatment of viral infections or cancer, treatment of a chronic disease, vaccine administration, administering a CAR-T therapy, or increasing the number of T-bet+ T cells in a subject. In some embodiments, the methods relate to treatment of an autoimmune or inflammatory disease by inhibiting TMEM16F levels and/or activity.

Provided are methods and compositions for the treatment of cancer. The methods comprise administering to a subject an HDAC inhibitor and an immunotherapeutic agent. In certain instances the immunotherapeutic is an NK cell or a chimeric antigen receptor NK cell.

Embodiments herein described provide antigen-presenting cell-mimetic scaffolds (APC-MS) and use of such scaffolds to manipulating T-cells. More specifically, the scaffolds are useful for promoting growth, division, differentiation, expansion, proliferation, activity, viability, exhaustion, anergy, quiescence, apoptosis, or death of T-cells in various settings, e.g., in vitro, ex vivo, or in vivo. Embodiments described herein further relate to pharmaceutical compositions, kits, and packages containing such scaffolds. Additional embodiments relate to methods for making the scaffolds, compositions, and kits/packages. Also described herein are methods for using the scaffolds, compositions, and/or kits in the diagnosis or therapy of diseases such as cancers, immunodeficiency disorders, and/or autoimmune disorders.

The present disclosure relates to artificial antigen presenting cells (aAPCs), in particular engineered erythroid cells and enucleated cells (e.g. enucleated erythroid cells and platelets), that are engineered to activate or suppress T cells.

The invention provides an isolated, purified population of human cells comprising CD8.sup.+ T cells with reduced Cbl-b activity. The invention provides uses of such cells in methods for inducing or enhancing an anti-tumor immune response in a subject. These methods comprise: (a) providing a cell population, from a subject or from another source, which comprises CD8.sup.+ T cells, (b) reducing Cbl-b activity in the CD8.sup.+ T-cells, (c) administering the cells of step (b) to the subject. The invention provides methods for making CD8.sup.+ T cells that do not require stimulation through a co-receptor in order for the cell to become activated or proliferated in response to contact via its T cell receptor. Such methods are based upon reducing function of Cbl-b. The invention also provides methods for identifying agents which affect Cbl-b expression or activity.