The present invention provides a method for producing a cell culture for promoting angiogenesis or axon outgrowth, particularly for the treatment of a cerebrovascular disease, an ischemic cardiac disease or traumatic brain injury and spinal cord injury, which comprises culturing a cell population containing microglia and/or monocytes under conditions of low oxygen concentration and/or low sugar concentration to produce the culture, a cell preparation obtained by the method, and a method for treating a cerebrovascular disease, an ischemic cardiac disease or traumatic cerebrospinal neuropathy by using the cell preparation.

Embodiments of the invention employ methods and compositions for enhancing potency of immune cells that express one or more therapeutic proteins. In certain cases, the methods modulate expression of a CAR transgene in an immune cell, such as a T cell. Specific embodiments employ the exposure of cells and/or individuals to be treated with the cells with an effective amount of at least one agent that upregulates expression of the therapeutic protein, such as a mitogen, histone deacetylase inhibitor, and or DNA methyltransferase inhibitor.

A heterodimeric Fc-fused protein and a pharmaceutical composition comprising the heterodimeric Fc-fused protein are disclosed. The heterodimeric Fc-fused protein comprises first and second Fc regions of an immunoglobulin heavy chain constant region (Fc) pair and in which IL-21 is bound to at least one of the N-terminus or the C-terminus of the first Fc region and/or the second Fc region, wherein CH3 domains of the first Fc region and the second Fc region are mutated such that the formation of a heterodimer is promoted.

When the heterodimeric Fc-fused protein according to the present invention is used, an in vivo half-life of IL-21 included in the heterodimeric Fc-fused protein may be significantly increased.

Cell loss by apoptosis is a common feature in certain conditions, including cancer. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that are designed to restore tissue homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. To remove inhibitory signals in the homeostatic clearance pathway a fusion protein comprising a phosphatidylserine binding domain and an immunostimulatory domain can restore immune responses to dead tumor cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific immune effector cells into tumors. These effects combine to elicit anti-tumor immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T cells.

The present invention relates generally to immunization and immunotherapy for the treatment or prevention of HIV. In particular, the methods include in vivo and/or ex vivo enrichment of HIV-specific CD4+ T cells.

Provided are methods and compositions for the treatment of cancer. The methods comprise administering to a subject an HDAC inhibitor and an immunotherapeutic. In certain instances the immunotherapeutic is a chimeric antigen receptor T cell, an antibody or polypeptide that binds a checkpoint inhibitor, or a vaccine.

The disclosure provides methods of treating cancer in a subject or preventing a relapse or reducing the incidence of relapse of cancer in a subject in remission, comprising administering to the subject: (a) a therapeutically effective amount of an immunotherapeutic agent, e.g., an immune checkpoint blockade therapy, an adoptive cellular therapy, a marrow-infiltrating lymphocytes, an adenosine A2aR inhibitor, or an antibody; and (b) a compound having formula (1):

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and the pharmaceutically acceptable salts thereof, wherein R.sub.1, R.sub.2, R.sub.2, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON).

Compositions, e.g., therapeutic agents, and methods are provided for modulating gene and protein expression of Forkhead Box protein 1 (Foxp1). The therapeutic agents include short nucleic acid molecules that modulate gene and protein expression of Forkhead Box protein 1 (Foxp1) expression, viral vectors containing such molecules, T cells transduced with these viruses for adoptive therapies, and any small molecules that bind to and inactivate Foxp1. These compounds and methods have applications in cancer therapy either alone or in combination with other therapies that stimulate the endogenous immune system in the environment of the cancer, e.g., tumor.

The inventive subject matter relates to methods for treating a T-cell deficiency in a subject in need thereof, comprising administering to said subject a T-cell precursor isolated from an allogeneic donor, provided that said allogeneic donor is not MHC-matched to said subject. The inventive methods can be further enhanced by genetic engineering for targeted immunotherapy.

T-cells useful in T-cell immunotherapy comprise a CAR, TCR and/or nucleic acid sequence(s) encoding a CAR and/or a TCR. The T-cells also comprise HP-NAP, an immunological equivalent fragment thereof and/or nucleic acid sequence(s) encoding HAP-NAP and/or an immunological equivalent fragment thereof. The T-cells have improved effects in immunotherapy including improved cytotoxicity, stimulation of chemokine and cytokine secretion, promoting dendritic cell maturation and recruitment and activation of innate immune cells.