The present invention is related to an isolated guide ribonucleic acid (gRNA) including a guide sequence targeting an inhibitory receptor (IR), a TCR (TRAC) constant region or a chain (TRBC1/2) constant region target sequence, wherein the guide sequence is selected from the group consisting of SEQ ID NOs: 1-27, 122-126 and combinations thereof.

Provided herein are methods and compositions for editing the genome of a human T cell. In some embodiments, a heterologous T cell receptor (TCR)- chain and a heterologous TCR- chain are inserted into exon 1 of a TCR subunit constant gene in the genome of the T cell.

The present disclosure relates in general to the field of genetic engineering of immune cells, specifically to mucosal-associated invariant T (MAIT) cells genetically engineered to express an exogeneous T cell receptor (TCR) and uses thereof. More specifically, the invention in embodiments thereof relates to cell compositions adapted for adoptive transfer cell therapy (ACT) providing for improved therapeutic modalities.

Disclosed are nucleic acid constructs comprising a promoter; a nucleic acid sequence encoding a single-chain variable fragment (scFv); a nucleic acid sequence encoding a notch transmembrane domain; and a nucleic acid sequence encoding a transcription factor. Disclosed are vectors comprising any of the disclosed nucleic acid constructs. Disclosed are proteins comprising a scFv; a notch transmembrane domain; and a transcription activator. Disclosed are methods of increasing human leukocyte antigen class I (HLA-I) on the surface of a tumor cell in a subject comprising administering to the subject one or more of the recombinant cells or compositions comprising a recombinant cell disclosed herein.

The instant disclosure provides chimeric polypeptides which modulate various cellular processes following a cleavage event induced upon binding of a specific binding member of the polypeptide with its binding partner. Methods of using chimeric polypeptides to modulate cellular functions, including e.g., induction of gene expression, are also provided. Nucleic acids encoding the subject chimeric polypeptides and associated expression cassettes and vectors as well as cells that contain such nucleic acids and/or expression cassettes and vectors are provided. Also provided, are methods of treating a subject using the described components and methods as well as kits for practicing the subject methods.

The presently disclosed subject matter provides for methods and compositions for treating cancer (e.g., breast cancer). It relates to mutant PIK3CA-targeted TCRs that specifically target a mutant PIK3CA peptide (e.g., a human mutant PIK3CA peptide), and immunoresponsive cells comprising such TCRs. The presently disclosed mutant PIK3CA peptide-specific TCRs have enhanced immune-activating properties, including anti-tumor activity.

The present invention encompasses methods and compositions for the generation and use of cytotoxic T lymphocytes that target multiple viruses or that are specific for multiple tumor antigens. In specific embodiments, the generation methods employ use of certain cytokines to promote proliferation and reduce cell death in an activated T cell population and/or that employ a particular bioreactor having a gas permeable membrane.

The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or b) MAGE-A12 in the context of HLA-Cw7. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention.

The present disclosure provides engineered immune cells and methods for their creation and use. The immune cells comprise activating and blocking receptors, that exhibit cross-talk between the receptors.

Provided is a method for preparation of a composition comprising activated human CD8.sup.+ lymphocytes with phenotype of stem cell-like memory cells and natural killer (NK) lymphocytes. The method entails use of short-term activation of lymphocytes by CD3/CD28 activating agents followed by treatment with DNA-demethylating agent. The invention also provides a version of the method where addition of a CD3/CD28 activating agent is made a few days after initiation of CD4.sup.+ mediated activation of the CD8.sup.+ cells; this step is also disclosed as an improvement of related methods where autologous dendritic cells have been used to activate the lymphocytes. Also provided is a method for treatment of cancer using the cells obtained from the process.