The present disclosure relates to methods for expanding and increasing the cytotoxic activity of natural killer cells comprising co-culturing, as feeder cells, a population of myeloid leukemia cells engineered to express one or more of membrane-bound IL-21 (mb IL-21) or membrane-bound IL-15 (mbIL-15) in the presence of cytokine support. The present disclosure also relates to a population of acute myeloid leukemia cells engineered to express one or more of membrane-bound IL-21 (mbIL-21) or membrane-bound IL-15 (mbIL-15). The present disclosure also relates to methods of treating cancer employing the step of expanding natural killer cells using feeder cells engineered to express one or more of membrane-bound IL-21 (mbIL-21) or membrane-bound IL-15 (mbIL-15).

The present disclosure relates to identifying novel tumor immune evasion targets. A CRISPR activation screen was employed to identify novel checkpoint inhibitor targets, where upon upregulation, conferred tumor resistance to cytotoxic T cells in model cancer cell lines. Using MAGeCK and FDR analyses to identify candidate genes that were enriched in cancer cells, B3GNT2, MCL1, BCL2A1 and JUNB were identified as the most enriched after a pathway analysis of the top 576 genes prioritized by MAGeCK. Currently, these four genes have not been identified or suggested as possible checkpoint inhibitor targets. Provided herein are methods of targeting the expression or activity of B3GNT2, MCL1, BCL2A1 and JUNB using small molecule agents and/or gene editing methods with the aim of enhancing anti-tumor immunity in subjects in need thereof.

Methods are provided for enhancing immunization strategies by manipulation, e.g. in vitro manipulation, of phagocytic antigen presenting cells. In the methods of the invention, phagocytic antigen presenting cells (phAPC) are incubated with a particulate antigen in the presence of an anti-CD47 agent in a dose and for a period of time sufficient to allow the phAPC to phagocytose the particulate antigen, which process generates a loaded phAPC. The loaded phAPC is contacted with a population of T cells matched for at least one major histocompatibility locus with the phAPC, where the T cells are stimulated after contacting to generate an effector response against an epitope or epitopes present on the particulate antigen.

The present disclosure provides compositions and methods for treating a peritoneal cancer in a subject. The methods include administering a T cell which is genetically modified to express a chimeric T cell receptor protein. The chimeric T cell receptor protein may include a T cell receptor signaling domain fused to the tumor associated antigen-binding fragment of an antibody or a T cell receptor signaling domain fused to a naturally occurring ligand which specifically binds to a tumor cell surface protein. The compositions and methods disclosed herein are therapeutically effective to reduce, for example, tumor burden, abdominal ascites, peritoneal mucin, or serum tumor marker levels.

Modulators of syndecan-2, such as an antibody to syndecan-2 that cross-links syndecan-2 on the cell surface or a syndecan-2 polypeptide that interferes with syndecan-2 receptor binding, is used to regulate a Th17 mediated disease such as an autoimmune disease, fibrosis or cancer.

Immunomodulating polynucleotides are disclosed. The immunomodulating polynucleotides may contain 5-modified uridine, 5-modified cytidine, a total of from 6 to 16 nucleotides, and/or one or more abasic spacers and/or internucleoside phosphotriesters. Also disclosed are conjugates containing a targeting moiety and one or more immunomodulating polynucleotides. The immunomodulating polynucleotides and conjugates may further contain one or more auxiliary moieties. Also disclosed are compositions containing the immunomodulating polynucleotides or the conjugates containing one or more stereochemically enriched internucleoside phosphorothioates. Further disclosed are pharmaceutical compositions containing the immunomodulating polynucleotides or the conjugates and methods of their use.

A method for producing natural killer cells is disclosed. The method comprises isolating peripheral blood mononuclear cells (PBMCs) from a blood sample; isolating at least one of CD56+ cells and/or CD3?/CD56+ cells from the PBMCs; and co-culturing the at least one of CD56+ cells and/or CD3?/CD56+ cells with a combination of feeder cells in the presence of a cytokine. A composition for treating cancer is also disclosed. The composition comprises the CD56+ natural killer cells produced by the disclosed method and a cytokine.

The present disclosure relates to IL2 agonists with improved therapeutic profiles.

Provision of a chimeric antigen receptor (CAR) comprising a disialoganglioside (GD2)-binding domain which comprises?a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences:?b) a light chain variable region (VL) having CDRs with the following sequences: T cells expressing such a CAR are useful in the treatment of some cancers.

The present invention provides a universal, yet adaptable, anti-tag chimeric antigen receptor (AT-CAR) system which provides T cells with the ability and specificity to recognize and kill target cells, such as tumor cells, that have been marked by tagged antibodies. As an example, ?FITC-CAR-expressing T cells have been developed that specifically recognize various human cancer cells when those cells are bound by cancer-reactive FITC-labeled antibodies. The activation of ?FITC-CAR-expressing T cells is shown to induce efficient target lysis, T cell proliferation, and cytokine/chemokine production. The system can be used to treating subjects having cancer.