Provided is an effective amount of a desialylation agent and an effective amount of an anti CD38 antibody for use in the treatment of multiple myeloma. This results in potentiated primary NK cell activity against the multiple myeloma cell. Also envisaged is a method of treating multiple myeloma in a subject in need thereof.

In one embodiment, the present disclosure provides an engineered cell having a first chimeric antigen receptor polypeptide including a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain; and a second chimeric antigen receptor polypeptide including a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain; wherein the first antigen recognition domain is different than the second antigen recognition domain.

The present invention relates to a therapeutic combination of immune cells, preferably allogeneic non-alloreactive TCR-KO immune T cells, wherein a gene coding an antigen marker X present on both T-cells and pathological cells is inactivated and a corresponding therapeutic antibody specific for said antigen marker X, method for preparing the same and use in immunotherapy.

The invention provides compositions and methods improved CAR T cell therapies. Specifically, the invention provides cells with reduced Tet, e.g., Tet2 function or expression, and methods of use therefore. The invention further provides Tet2 inhibitors and methods of use therefore in connection with CAR T cells.

The present disclosure provides activatable masked antigen binding proteins comprising an antigen binding protein attached to universal masking moieties by peptide linkers. The universal masking moieties dimerize with each other to form a dimerized masking complex that blocks binding between the antigen binding domain and its target antigen. The individual masking moieties and the dimerized masking complex do not bind specifically to the antigen binding domain. The masking moieties form stable dimers because their association with each other mimics homodimers or heterodimers found in naturally-occurring immunoglobulin or cell receptor molecules. The dimerization of the masking moieties does not involve covalent bonding and can be optimized by engineering interchain association through structure complementarity such as knob-in-hole.

The invention provides compositions and methods for treating diseases associated with expression of a cancer associated antigen as described herein. The invention also relates to chimeric antigen receptor (CAR) specific to a cancer associated antigen as described herein, vectors encoding the same, and recombinant T cells comprising the CARs of the present invention. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises an antigen binding domain that binds to a cancer associated antigen as described herein.

The present disclosure provides transgenic cells that express memory dimeric antigen receptors (mDARs), where the mDAR constructs comprise a JAK-STAT intracellular region having a cytokine receptor intracellular region which includes Box 1 and Box 2 motifs for binding a Janus kinase (JAK) which can play a role in JAK-STAT cellular signaling pathway to induce effector cell activation and proliferation. In one embodiment, the JAK-STAT intracellular region further comprises a CD3zeta intracellular signaling region having an intact ITAM region, or having ITAM 1 and 3, or having only ITAM 3 with a partial deletion. Transgenic cells expressing the mDAR constructs exhibit potent cytotoxicity, and release reduced levels of cytokines, compared to traditional DARs that lack a cytokine receptor intracellular region. The mDAR constructs have antibody-like properties as they bind specifically to a target antigen. Transgenic cells expressing the mDAR constructs can be used for directed cell therapy.

Embodiments of the disclosure include compositions and methods effective for immunotherapy, such as for cancer. The embodiments include cells that recognize a combination of two signals or three signals present at the tumor microenvironment. In certain embodiments, the signals for antigen stimulation, co-stimulation, and cytokine signaling act through separate molecules, although in certain embodiments the signals for antigen stimulation and co-stimulation are transmitted through the same molecule.

Disclosed herein are cells that are immune cells or precursor cells thereof, which cells recombinantly express a chimeric antigen receptor (CAR), and a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell, wherein the CAR binds to a cancer antigen. Also disclosed herein are T cells that recognize and are sensitized to a cancer antigen, which T cells recombinantly express a dominant negative form of an inhibitor of a T cell-mediated immune response. Additionally provided are methods of using such cells to treat cancer in a subject in need thereof.

Polynucleotide constructs and engineered natural killer (NK) cells expressing such constructs are provided for the treatment of cancer and other adenosine-overexpressing disease states. The constructs are a fusion of at least an antigen binding domain specific to an adenosine producing (or adenosine-intermediary producing) cell surface protein and a receptor for promoting cytotoxic or cytolytic activity of the NK cell upon activation, where activation occurs upon the antigen binding domain binding its target cell. Pharmaceutical compositions of the engineered NK cells are also provided, as well as methods of treating an adenosine overexpressing cancer using such pharmaceutical compositions.