Abstract: Provided are nucleic acids encoding CD47 polypeptides. In some embodiments, the nucleic acids encode a CD47 polypeptide comprising a mutant CD47 Ig-like domain that reduces binding of a therapeutic anti-CD47 binding agent to the CD47 polypeptide as compared to binding of the therapeutic anti-CD47 binding agent to a wild-type CD47 polypeptide, and where the CD47 polypeptide retains binding to SIRP?. In certain embodiments, the mutant CD47 Ig-like domain comprises a mutant BC loop. Therapeutic immune cells (e.g., CAR-T cells, etc.) comprising the nucleic acids and expressing the CD47 polypeptides on their surface are also provided, as are therapeutic methods comprising administering such cells to subjects receiving an anti-CD47 therapy, e.g., to treat cancer.

Abstract: Provided are polypeptides that include, from N-terminus to C-terminus, a chimeric antigen receptor (CAR), a protease, and a degron, where the polypeptide further includes a cleavage site for the protease disposed between the CAR and the degron. Also provided are cells that include such polypeptides (e.g., where the cells express the CAR on their surface) and pharmaceutical compositions including such cells. Nucleic acids that encode the polypeptides, cells including such nucleic acids, and pharmaceutical compositions including such cells, are also provided. Also provided are methods for controlling the expression of a CAR on the surface of a cell, and methods of using the cells of the present disclosure, including methods of using such cells to administer a regulatable CAR cell-based therapy (e.g., a regulatable CAR T cell therapy) to an individual.

Abstract: The invention relates to immunotherapeutic treatment of cancer. In particular, the invention relates to methods of treating cancer carrying a histone H3 K27M (H3K27M) mutation (e.g., diffuse midline glioma with H3K27M mutation) using immunotherapeutic compositions comprising immune cells engineered to express GD2-specific chimeric antigen receptors.

Abstract: Provided herein are cell surface receptors that include an extracellular binding domain, a transmembrane domain, an intracellular signaling domain, and a protease cleavage site disposed between the extracellular binding domain and the intracellular signaling domain. In certain aspects, the cell surface receptors are engineered cell surface receptors, such as chimeric antigen receptors (CARs). Also provided are cells that include such receptors (e.g., where the cells express the receptors on their surface) and pharmaceutical compositions including such cells. Nucleic acids that encode the cell surface receptors, cells including such nucleic acids, and pharmaceutical compositions including such cells, are also provided. Also provided are methods for regulating signaling of a cell surface receptor, and methods of using the cells of the present disclosure, including methods of using such cells to administer a regulatable cell-based therapy to an individual.

Abstract: Provided are methods of manufacturing cells. The methods comprise expanding cells in the presence of inosine, and harvesting the cells after expansion. In certain embodiments, the cells are genetically modified. For example, the cells may be genetically modified to express an engineered receptor, non-limiting examples of which are chimeric antigen receptors (CARs), engineered T cell receptors (TCRs), and the like. According to some embodiments, the cells are immune cells, e.g., T cells or natural killer cells. Also provided are populations of cells manufactured according to the methods of the present disclosure. Also provided are methods comprising administering an effective amount of a population of cells manufactured according to the methods of the present disclosure to a subject in need thereof. In certain embodiments, the subject has cancer, and the cells express an engineered receptor that binds to a tumor antigen on the surface of cells of the cancer.

Abstract: Provided are polypeptides that include, from N-terminus to C-terminus, a chimeric antigen receptor (CAR), a protease, and a degron, where the polypeptide further includes a cleavage site for the protease disposed between the CAR and the degron. Also provided are cells that include such polypeptides (e.g., where the cells express the CAR on their surface) and pharmaceutical compositions including such cells. Nucleic acids that encode the polypeptides, cells including such nucleic acids, and pharmaceutical compositions including such cells, are also provided. Also provided are methods for controlling the expression of a CAR on the surface of a cell, and methods of using the cells of the present disclosure, including methods of using such cells to administer a regulatable CAR cell-based therapy (e.g., a regulatable CAR T cell therapy) to an individual.

Abstract: Provided herein are cell surface receptors that include an extracellular binding domain, a transmembrane domain, an intracellular signaling domain, and a protease cleavage site disposed between the extracellular binding domain and the intracellular signaling domain. In certain aspects, the cell surface receptors are engineered cell surface receptors, such as chimeric antigen receptors (CARs). Also provided are cells that include such receptors (e.g., where the cells express the receptors on their surface) and pharmaceutical compositions including such cells. Nucleic acids that encode the cell surface receptors, cells including such nucleic acids, and pharmaceutical compositions including such cells, are also provided. Also provided are methods for regulating signaling of a cell surface receptor, and methods of using the cells of the present disclosure, including methods of using such cells to administer a regulatable cell-based therapy to an individual.

Abstract: The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides T cells that are modified (e.g., genetically and/or functionally) to maintain functionality under conditions in which unmodified T cells display exhaustion. Compositions and methods disclosed herein find use in preventing exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as non-engineered T cells thereby enhancing T cell function (e.g., activity against cancer or infectious disease).

Abstract: Provided herein are compositions comprising T cells modified to overexpress FOXO1 and methods of use thereof. Methods are provided to treat a disease or disorder in a subject comprising administration of the modified T cells. Also provided are methods for preventing exhaustion of engineered T cells comprising introducing a nucleic acid that overexpresses FOXO1 into the T cells.

Abstract: Antigen binding domain polypeptides (ABD) specific for human CD93 are provided, which ABD may be formatted as antibodies, as chimeric antigen receptors, and the like. T cells comprising an anti-CD93 CAR are useful in the treatment of cancer, e.g. hematologic malignancies.

Abstract: Provided are methods of selecting for cells that comprise two or more separate expression constructs. In certain embodiments, the methods comprise contacting a population of cells with two or more separate expression constructs under conditions in which the two or more expression constructs are delivered to cells of the population of cells. The two or more separate expression constructs comprise a first expression construct that encodes a fusion protein comprising a selection marker, a protein localization tag, and a protease cleavage site disposed between the selection marker and the protein localization tag. The second expression construct encodes a protein required for cell surface expression of the selection marker. Such methods further comprise selecting for cells exhibiting cell surface expression of the selection marker. Related cells, compositions, kits and therapeutic methods are also provided.

Abstract: The present disclosure generally relates to compositions and methods useful for an adoptive cell therapy. Some embodiments of the disclosure relates to methods for producing a population of lymphocytes enriched in T stem cell memory cells (TSCM cells). Further provided are compositions containing a substantially pure population of TSCM cells that are therapeutically effective in treating various cancers, and kits containing such compositions. Methods for treating a subject having or suspected of having a cancer using the compositions and kits as disclosed herein are also provided.

Abstract: The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides chimeric antigen receptor (CAR) T cells that are modified to maintain functionality under conditions in which unmodified CAR T cells display exhaustion. Compositions and methods disclosed herein find use in inhibiting or reversing CAR T cell exhaustion (e.g., by modulating CAR surface expression) thereby enhancing CAR T cell function. Compositions and methods of the invention find use in both clinical and research settings, for example, within the fields of biology, immunology, medicine, and oncology.

Abstract: The present disclosure generally relates to compositions and methods useful for an adoptive cell therapy. Some embodiments of the disclosure relates to methods for producing a population of lymphocytes enriched in T stem cell memory cells (TSCM cells). Further provided are compositions containing a substantially pure population of TSCM cells that are therapeutically effective in treating various cancers, and kits containing such compositions. Methods for treating a subject having or suspected of having a cancer using the compositions and kits as disclosed herein are also provided.

Abstract: Provided herein are engineered lymphocytes which overexpress one or more anti-phagocytic signaling proteins, and methods of using same to induce an immune response against cancer cells by inhibiting immune clearance of the engineered T cells. Also provided is a method of depleting engineered T cells in a subject by administering to the subject an agent that inhibits the activity of one or more anti-phagocytic signaling proteins expressed by the engineered T cells.

Abstract: The present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides chimeric antigen receptor (CAR) T cells that are modified to maintain functionality under conditions in which unmodified CAR T cells display exhaustion. Compositions and methods disclosed herein find use in inhibiting or reversing CAR T cell exhaustion (e.g., by modulating CAR surface expression) thereby enhancing CAR T cell function. Compositions and methods of the invention fmd use in both clinical and research settings, for example, within the fields of biology, immunology, medicine, and oncology.

Abstract: Provided are recombinant polypeptides that comprise a protein of interest, a protein localization tag, and a protease cleavage site disposed between the protein of interest and the protein localization tag. In certain embodiments, the recombinant polypeptides further comprise a protease, where the protease cleavage site is a cleavage site for the protease. Also provided are nucleic acids that encode the recombinant polypeptides, cells that comprise such nucleic acids, and compositions (e.g., pharmaceutical compositions) that comprise such cells. Methods of regulating cellular localization of a protein of interest, and methods of administering a regulatable cell-based therapy to an individual in need thereof, are also provided.

Abstract: An immunotherapy delivery system includes a hydrogel with an immunomodulatory cargo including cells encapsulated in the hydrogel, a cell adhesion motif in the hydrogel configured to reversibly adhere to and release the cells, and an immunomodulatory cargo encapsulated in the hydrogel. The hydrogel includes a polymer non-covalently crossed-linked with a plurality of nanoparticles.

Abstract: The present disclosure generally relates to methods that utilize cell-free DNA from a liquid biopsy of an individual to track DNA from both the tumor and the chimeric antigen receptor (CAR) T-cells. The present disclosure further relates to methods of predicting individuals' response to therapy, e.g., CAR T-cell therapies. Additionally, the present disclosure relates to methods of treating individuals with cancer, such as lymphoma.

Abstract: The invention relates to immunotherapeutic treatment of cancer. In particular, the invention relates to methods of treating cancer carrying a histone H3 K27M (H3K27M) mutation (e.g., diffuse midline glioma with H3K27M mutation) using immunotherapeutic compositions comprising immune cells engineered to express GD2-specific chimeric antigen receptors.