The present invention relates to the field of immunology, molecular biology and therapeutics. In particular, the invention relates to novel artificial feeder cells for activation and expansion of natural killer (NK) cells. The artificial feeder cell expresses endogenous ligands (HLA C1, C2, 5 and Bw4 type) for killer cell immunoglobulin-like receptors (KIRs), non-KIR binding Bw6 ligand, endogenous HLA-E-ligand for inhibitory NKG2A receptor, and comprises at least one stimulatory cytokine either membrane bound or secreted or at least one co-stimulatory ligand where those ligands and cytokines each specifically bind to a cognate receptor on a NK cell of interest, thereby mediating expansion of the NK cell. The invention can be used as an “off the 10 shelf” artificial feeder cell that can be readily designed to expand a NK cell or a NK subset of interest and also specifically expand NK cells modified with a chimeric antigen receptor (CAR). By genetically introducing or knockdown of candidate genes, the artificial feeder cell of the invention can be used to identify the stimulatory, co-stimulatory, and any other factors that mediate growth, expansion and cytotoxicity of a NK cell. Thus, the present invention provides 15 powerful tools for development of novel therapeutics where activation and expansion of the NK cell and of the CAR-NK cell can provide a benefit.

A method for producing CD4/CD8 double-positive T cells, comprising the steps of: (1) culturing pluripotent stem cells in a medium to induce hematopoietic progenitor cells; and (2) culturing the hematopoietic progenitor cells obtained in the step (1) in a medium containing a p38 inhibitor and/or SDF-1 to induce CD4/CD8 double-positive T cells.

The present invention relates to T cells, in particular a non-activated T cell, comprising an exogenous nucleic acid encoding a T cell Receptor (TCR) specific for a virus. An embodiment of the invention is directed to a non-activated (resting) T cell expressing Hepatitis B virus (HBV) envelope s183-191 TCR capable of inhibiting viral replication and which shows reduced expression of perforins and/or granzymes in response to stimulation as compared to an activated T cell expressing the said TCR. Also encompassed are methods for producing such cells, compositions, pharmaceutical compositions and kits comprising such cells and medical uses thereof.

There is provided a chimeric antigen receptor (CAR) comprising a CD19-binding domain which comprises a) a heavy chain variable region (VH) having complementarity determining regions (CDRs) with the following sequences: CDR1—GY-AFSSS (SEQ ID No. 1); CDR2—YPGDED (SEQ ID No. 2) CDR3—SLLYGDYLDY (SEQ ID No. 3); and b) a light chain variable region (VL) having CDRs with the following sequences: CDR1—SASSSVSYMH (SEQ ID No. 4); CDR2—DTSKLAS (SEQ ID No. 5) CDR3—QQWNINPLT (SEQ ID No. 6). There is also provided a cell comprising such a CAR, and the use of such a cell in the treatment of cancer, in particular a B cell malignancy.

Described herein are methods for producing and utilizing an alternative signal 1 domain to construct an optimally signaling CAR. Alternative signal 1 domains of the present technology are based on alternatives to CD3ζ, including mutated ITAMs from CD3ζ (which contains 3 IT AM motifs), truncations of CD3ζ, and alternative splice variants known as CD3s, CD3 theta, and artificial constructs engineered to express fusions between CD3s or CD30 and CD3ζ. CAR polypeptides comprising alternative signal 1 domains are utilized to engineer CAR T cells. Further, this technology related to methods of treating cancer by administering to a subject in need thereof CAR T cells comprising alternative signal 1 domains.

Systems and methods to genetically modify B cells to express selected antibodies are described. The systems and methods can be used to: obviate the need for classical vaccinations; provide protection against infectious agents for which no vaccinations are currently available; provide protection against infectious agents when patients are otherwise immune-suppressed; and/or provide a benefit provided by a therapeutic antibody, such as in the treatment of autoimmune disorders.

Genetically modified cells that are compatible with multiple subjects, e.g., universal donor cells, and methods of generating said genetic modified cells are provided herein. The universal donor cells comprise at least one genetic modification within or near a gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or a component or a transcriptional regulator of a MHC-I or MHC-II complex, wherein genetic modification comprises an insertion of a polynucleotide encoding a tolerogenic factor and/or survival factor. The universal donor cells may further comprise at least one genetic modification within or near a gene that encodes a survival factor, wherein said genetic modification comprises an insertion of a polynucleotide encoding a second tolerogenic factor and/or a different survival factor.

The present invention relates to an isolated T cell receptor (TCR) specific for a MAGEA1-derived peptide and to a polypeptide comprising a functional portion of the TCR. Further implicated are a multivalent TCR complex, a nucleic acid encoding a TCR, a cell expressing the TCR and a pharmaceutical composition comprising the TCR. The invention also refers to the TCR for use as a medicament, in particular to the TCR for use in the treatment of cancer.

The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.

Embodiments of the disclosure encompass methods and compositions for producing engineered mesenchymal stem/stromal cells (MSCs). The disclosure concerns large-scale processes for producing MSCs that are engineered to have disruption of expression of one or more genes using CRISPR and also express at least one heterologous antigen receptor. Specific embodiments include particular parameters for the process.