Provided herein are genetically modified hematopoietic cells with reduced expression or activity of: (i) one or more CRL5 complex genes, and/or (ii) one or more genes orthogonal to the CRL5 complex, that exhibit improved therapeutic potential compared to wild-type hematopoietic cells, as well as methods of generating and using genetically modified hematopoietic cells for the treatment of a disease, such as cancer.

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 (mbIL-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).

Provided herein are antibodies and antigen binding fragments thereof specific for endomucin (EMCN). Also provided herein are cells, nucleic acids, vectors, compositions, and methods directed to antibodies or antigen-binding domains thereof specific for EMCN.

Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in combination therapies and lack of efficacy in monotherapies. NK cells have effector activity within the TME, under continuous ligand exposure. NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. We created NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3 to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PDL1+ target cells.

The invention provides recombinant CD47 engager receptor proteins comprising an intracellular domain that enhances an immune response in a cell when the CD47 engager receptor protein binds to CD47 on a target cell. The invention also provides cells comprising the CD47 engager receptor proteins. The CD47 engager receptor protein may be a switched Signal Regulatory Protein Alpha (SIRP) receptor (SIRP switch receptors) and cells that comprise them (SIRP switch cells). SIRP switch receptors recognize CD47 on target tumor cells and transmit an intracellular signal within the SIRP switch cells that upregulates natural killer cell (NK), T cell, and macrophage activity. The result is increased tumor cell killing.

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

A method of manipulating allogeneic cells for use in allogeneic cell therapy providing a composition of highly activated allogeneic T-cells which are infused into immunocompetent cancer patients to elicit a novel anti-tumor immune mechanism, or Mirror Effect. In contrast to current allogeneic cell therapy protocols where T-cells in the graft mediate the beneficial graft vs. tumor (GVT) and detrimental graft vs. host (GVH) effects, the allogeneic cells of the present invention stimulate host T-cells to mediate the mirror of these effects. The mirror of the GVT effect is the host vs. tumor (HVT) effect. The mirror of the GVH effect is the host vs. graft (HVG) effect The anti-tumor HVT effect occurs in conjunction with a non-toxic HVG rejection effect. The highly activated allogeneic cells of the invention can be used to stimulate host immunity in a complete HLA mis-matched setting in a patient.

The present invention relates to a chimeric receptor capable of signaling both a primary and a co-stimulatory pathway, thus allowing activation of the co-stimulatory pathway without binding to the natural ligand. The cytoplasmic domain of the receptor contains a portion of the 4-1BB signaling domain. Embodiments of the invention relate to polynucleotides that encode the receptor, vectors and host cells encoding a chimeric receptor, particularly including T cells and natural killer (NK) cells and methods of use.

The present disclosure is generally related to methods for combining chemotherapy and immunotherapy for the treatment of a cancer. The methods also relate to generating a drug-resistant cytotoxic immune cell line and uses thereof in conjunction with cytotoxic drugs

The application provides new compositions and methods for stimulating the production of natural killer (NK) cells in a subject. NK cells can be selectively expanded with a combination of stimulating ligands. Methods and compositions for the administration of stimulatory ligands modified to self-insert into tumor cells, thereby stimulating an increase in the number of NK cells in proximity to a tumor, are also described.