Abstract: Embodiments of the disclosure include methods and compostions in which NK cells are modified by the hand of man to express a heterologous a) polypeptide comprising a CD16 Fc binding domain, b) a T Cell Receptor (TCR, e.g., an invariant T Cell Receptor (iTCR), and c) a CD3 co-receptor on NK cells that do not naturally express them. Such modified NK cells work effectively (with monospecific, bispecific, or multi-specific antibodies, that may have modified or non-modified Fc domains.

Abstract: Embodiments of the disclosure include methods and compositions in which NK cells are modified by the hand of man to express a heterologous a) polypeptide comprising a CD16 Fc binding domain, b) a T Cell Receptor (TCR, e.g., an invariant T Cell Receptor (iTCR)), and c) a CD3 co-receptor on NK cells that do not naturally express them. Such modified NK cells work effectively with monospecific, bispecific, and/or multi-specific antibodies, that may have modified or non-modified Fc domains.

Abstract: Provided herein are methods for producing immune cells with disruption of multiple genes. Further provided are methods for inserting a chimeric antigen receptor at a gene locus of an immune cell.

Abstract: Provided herein are methods for producing immune cells with disruption of multiple genes. Further provided are methods for inserting a chimeric antigen receptor at a gene locus of an immune cell.

Abstract: Provided herein are methods for expanding populations of regulatory B cells comprising engineering a population of B cells to express CD40 ligand. Also provided herein are methods of treating immune disorders with the regulatory B cells.

Abstract: Embodiments of the disclosure encompass methods and compositions that utilize an anti-CD70 chimeric antigen receptor (CAR) that lacks an antibody or antibody fragment as part of the receptor, including as part of the antigen binding region of the CAR. In particular embodiments, instead of the CAR employing an antibody to bind CD70, the CAR molecule utilizes CD27, the receptor for the ligand CD70. In specific embodiments, the CAR comprises a truncated version of CD27 rather than full length CD27. In specific cases, the CAR lacks the CD27 transmembrane domain.

Abstract: The present application provides BCMA targeting chimeric antigen receptor (CAR) comprising a BCMA binding region and an intracellular costimulatory domain derived from DAP10. Further provided are engineered immune effector cells (such as NK cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.

Abstract: Provided herein are methods for deactivation of effector cells, such as NK cells, including cells for adoptive cell therapy that are off-the-shelf cells. The deactivated cells may be cryopreserved following deactivation. The deactivated and cell may be expanded and/or activated prior to deactivation, and may or may not comprise a transgene, which may optionally encode a chimeric antigen receptor and/or T cell receptor. In certain embodiments, disclosed are methods for deactivation of NK cells comprising treatment with a kinase inhibitor, for example an mTOR inhibitor and/or a tyrosine kinase inhibitor, for example rapamycin and/or Dasatinib. Also provided herein are deactivated and cryopreserved NK cells, and methods of preparing and/or using the same for treatment of a subject in need thereof, for example treatment of a subject with cancer.

Abstract: Embodiments of the disclosure concern methods and compositions related to preparation and use of combinatorial immunotherapies. In specific embodiments, compositions comprising engineered NK cells prepared in a particular manner also include certain antibodies. These compositions are utilized for treatment, such as for cancer treatment. In particular embodiments, the compositions include complexes of the engineered NK cells and the antibodies in which the antibody is bound to the engineered NK cells and may also bind to another antigen, such as on a cancer cell.

Abstract: The present application provides BCMA targeting chimeric antigen receptor (CAR) comprising a BCMA binding region and an intracellular costimulatory domain derived from DAP10. Further provided are engineered immune effector cells (such as NK cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.

Abstract: Aspects of the present disclosure include methods and compositions related to therapeutic immune cells having enhanced metabolic fitness. In certain aspects, polynucleotides encoding one or more viral, bacterial, and/or fungal genes capable of manipulating cell metabolism and, optionally, one or more antigen-specific receptors, are disclosed. In some aspects, disclosed are methods for enhancing the metabolic fitness of an immune cell comprising introducing into the immune cell a polynucleotide encoding one or more viral, bacterial, and/or fungal genes capable of manipulating cell metabolism. Cells (e.g., NK cells, T cells) expressing polynucleotides encoding one or more viral, bacterial, and/or fungal genes capable of manipulating cell metabolism and, optionally, one or more antigen-specific receptors are described. Also described are therapeutic methods using polynucleotides of the disclosure.

Abstract: Embodiments of the disclosure encompass particular chimeric antigen receptor constructs that comprise optionally a hinge, one of the CD28 transmembrane domain or the DAP10 transmembrane domain, DAP10 costimulatory domain, and CD3zeta. In particular embodiments, the chimeric antigen receptor is expressed by natural killer (NK) cells, and in some cases the NK cells are further modified, such as to express one or more cytokines and optionally a suicide gene.

Abstract: Aspects of the present disclosure are directed to immune cells comprising polynucleotides encoding genetically engineered receptors (e.g., chimeric antigen receptors, T-cell receptors) and having anti-CD20 antibodies (or fragments thereof) attached to their surface. Certain aspects are directed to preactivated and/or expanded natural killer cells having anti-CD20 antibodies (or fragments thereof) attached to their surface. Also disclosed are compositions comprising such cells, and methods for using such compositions to treat an individual having CD20-positive cancer. Further aspects encompass methods for cell preparation comprising culturing natural killer cells with cytokines (e.g., IL-12, IL-15, and/or IL-18) and incubating the cells with an anti-CD20 antibody.

Abstract: The present application provides BCMA targeting chimeric antigen receptor (CAR) comprising a BCMA binding region and an intracellular costimulatory domain derived from DAP10. Further provided are engineered immune effector cells (such as NK cells) comprising the chimeric antigen receptors. Pharmaceutical compositions, kits and methods of treating cancer are also provided.

Abstract: Embodiments of the disclosure include methods and compositions in which NK cells are modified by the hand of man to express the T-cell receptor and CD3 co-receptor on NK cells that do not naturally express them. Such modified NK cells work effectively with bispecific or multi-specific antibodies that are tailored to comprise anti-CD3 antibodies that bind the modified NK cells, thereby triggering signaling, activation, and cytotoxicity of target cells to which the antibodies also bind. Thus, the NK cells are specifically configured to be able to work effectively with Bispecific NK cell engagers (BiKEs) as well as Bispecific T cell Engagers (BiTEs).

Abstract: Embodiments of the disclosure include methods and compositions related to targeting of TROP-2-expressing cells with particular engineered receptors. In specific embodiments, NK cells are specifically engineered to bind TROP-2 using particular chimeric antigen receptor constructs. In certain embodiments, vectors that express the TROP-2-targeting CARs also express a particular suicide gene and/or one or more particular cytokines.

Abstract: Embodiments of the present disclosure include methods and compositions related to CD70-targeting polypeptides. In certain aspects, anti-CD70 antibodies are disclosed. In some aspects, disclosed are chimeric receptors engineered to bind to CD70. Also disclosed are immune cell engagers comprising a CD70-binding region and one or more immune cell binding regions. Cells (e.g., NNK cells, T cells) expressing CD70-targeting peptides are described. Also described are therapeutic methods using polypeptides of the disclosure.

Abstract: Embodiments of the disclosure include methods and compositions related to targeting of HLA-G-expressing cells with particular engineered receptors. In specific embodiments, NK cells are specifically engineered to bind HLA-G using particular chimeric antigen receptor constructs. In certain embodiments, vectors that express the HLA-G-targeting CARs also express particular a suicide gene and/or one or more particular cytokines.

Abstract: Embodiments of the disclosure include methods and compositions related to targeting of CD5-expressing cells with particular engineered receptors. In specific embodiments, NK cells are specifically engineered to bind the CD5 antigen using particular chimeric antigen receptor constructs. In certain embodiments, vectors that express the CD5-targeting CARs also express particular a suicide gene and/or one or more particular cytokines.

Abstract: Embodiments of the disclosure concern methods and compositions related to preparation and use of combinatorial immunotherapies. In specific embodiments, compositions comprising NK cells prepared in a particular manner also include certain antibodies. These compositions are utilized for treatment, such as for cancer treatment. In particular embodiments, the compositions include complexes of the NK cells and the antibodies in which the antibody is bound to the NK cells and may also bind to another antigen, such as on a cancer cell.