The present disclosure relates to methods and agents for enhancing the effect of T cells engineered to express chimeric antigen receptors (CARs). These methods and agents are, in particular, useful for the treatment of diseases characterized by diseased cells expressing an antigen the CAR is directed to. Specifically, the present disclosure relates to methods comprising providing to a subject T cells genetically modified to express a chimeric antigen receptor (CAR) and administering to the subject IL2 or a polynucleotide encoding IL2. The methods of the disclosure may comprise administering IL2 or a polynucleotide encoding IL2 and a further cytokine or a polynucleotide encoding a further cytokine, wherein the further cytokine may be IL7 or IL21. The T cells genetically modified to express a CAR may be provided to the subject by administering the T cells genetically modified to express a CAR or by generating the T cells genetically modified to express a CAR in the subject. The methods of the disclosure may further comprise administering to the subject an antigen or a variant thereof, or a polynucleotide encoding an antigen or a variant thereof, wherein the T cells genetically modified to express a CAR are targeted to the antigen. In one particularly preferred embodiment, the polynucleotides administered according to the present disclosure are RNA.

The present disclosure relates to a method of improving cognitive function in a subject. The method includes implanting group-2 innate lymphoid cells (ILC2) in a cranium of a subject, where the ILC2 was treated with an ILC2 activator. The present disclosure further relates to a method including selecting a subject having aging-associated cognitive decline and administering to the subject an activator of innate lymphoid cell activity under conditions effective to promote innate lymphoid cell activity. The present disclosure further relates to a method of improving cognition in a subject. The method includes selecting a subject having aging-associated cognitive decline and administering to the subject a cytokine selected from the group consisting of IL-33, IL-5, IL-7, IL-25, and thymic stromal lymphopoietin.

The present invention concerns compositions and methods related to approaches to render ineffective Th1 T cells resistant to the inhibitory cytokine milieu present in a cancer microenvironment. In particular embodiments, tumor-specific T cells are modified to employ a chimeric receptor that binds inhibitory/suppressive cytokines and converts their intracellular consequences to a Th1 immunostimulaotyr/activating signal. In specific embodiments, the T cells employ a chimeric antigen receptor having exodomains for IL10, IL13 and/or IL4 fused with the signal transducing endodomains for IL2 and/or IL7.

The present disclosure provides rAAV vectors and rAAV virions that specifically express exogenous nucleic acid sequences in CD14.sup.+ cells. The rAAV vectors or virions are useful for specifically expressing exogenous nucleic acid sequences encoding, for example, cancer antigens, viral antigens, and/or bacterial antigens in monocytes and dendritic cells. The rAAV transduced CD14.sup.+ cells can be used as antigen presenting cells that induce antigen-specific T cell responses. The present disclosure further provides methods producing rAAV virions and methods of immunotherapy.

The present invention relates to a method for ex vivo generating and expanding γδ Foxp3.sup.+ regulatory T cells, and therapeutic uses thereof. The inventors performed the induction of Foxp3+ expression in ex vivo human induced tumor-antigen specific CD4− TCRγδ unrestricted T cells and the induction of autologous CD8-mediated T-cell responses against tumor-antigen specific FOXP3 expressing CD4+ TCRγδ unrestricted T cells. The inventors developed a method to ex vivo generated and expanded antigen specific Foxp3 expressing CD3+ TCRγδ+ unrestricted T cells, committed to exclusively exert regulatory activity, whichever culture condition of stimulation is. In particular, the present invention relates to a method for generating ex vivo γδ Foxp3+ regulatory T cells having the following phenotype: CD3+ TCRγδ+ Foxp3+.

The present invention relates to an in vitro cell culture method comprising a step of contacting T-cells with an MPC inhibitor, and further to a cell population comprising T-cells with a memory phenotype obtained by said method, preferably, wherein the T-cells are human cells. The present invention also relates to a method for generating and/or maintaining T-cells and/or B-cells with a memory phenotype comprising the steps of culturing T-cells and or B-cells in vitro and adding an MPC inhibitor to the culture. The invention furthermore relates to a population of T-cells and/or B-cells obtained by the methods of the invention. Also provided are immunotherapies using the cells of the invention. Furthermore, provided is an MPC inhibitor for use in immunotherapy and/or as a vaccine co-adjuvant.

The present disclosure provides rAAV vectors and rAAV virions that specifically express exogenous nucleic acid sequences in CD14.sup.+ cells. The rAAV vectors or virions are useful for specifically expressing exogenous nucleic acid sequences encoding, for example, cancer antigens, viral antigens, and/or bacterial antigens in monocytes and dendritic cells. The rAAV transduced CD14.sup.+ cells can be used as antigen presenting cells that induce antigen-specific T cell responses. The present disclosure further provides methods producing rAAV virions and methods of immunotherapy.

The present invention in general relates to a method of differentiating human hematopoietic stem cells (HSC) into mature natural killer (NK) cells; wherein said method is in particular characterized in that mature NK cells are obtainable very early during the differentiation method, and that these NK cells display increased CD16 expression and antibody-dependent cellular cytotoxicity (ADCC) (FIG. 11). The method of the invention specifically encompasses transfecting and/or transducing HSCs with at least one transcription factor selected from T-Box expressed in T cells (T-BET) and Eomesodermin (EOMES); or a combination thereof.

An isolated cell having a central memory T-lymphocyte (Tcm) phenotype, the cell being tolerance-inducing cell and capable of homing to the lymph nodes following transplantation, the cell being transduced to express a cell surface receptor comprising a T cell receptor signaling module is disclosed. Methods of generating same and using same are also disclosed.

Provided herein are methods of treating acute myeloid leukemia (AML) and multiple myeloma (MM) by administering an effective amount of a cell population comprising natural killer cells, wherein the cell population comprising natural killer cells is produced by a three-stage method comprising culturing a population of hematopoietic stem or progenitor cells in media comprising stem cell mobilizing factors, e.g., three-stage methods of producing NK cells in media comprising stem cell mobilizing factors starting with hematopoietic stem or progenitor cells from cells of the placenta, for example, from placental perfusate (e.g., human placental perfusate) or other tissues, for example, umbilical cord blood or peripheral blood. Further provided herein are methods of using the NK cells produced by the three-stage methods provided herein to suppress the proliferation of acute myeloid leukemia cells. In certain embodiments, the NK cells produced by the three-stage methods described herein are used in combination with IL-2.