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.

There is provided a single variable domain T-cell receptor (svd-TCR) comprising a first TCR variable domain, the first TCR variable domain specifically binding to an epitope, that is not a superantigen, in the absence of a second TCR variable domain. Also provided are compositions and cells comprising the svd-TCR as well as methods of identifying the svd-TCR.

Provided herein is a composition comprising, a cell, comprising nucleic acids encoding a chimeric antigen receptor (CAR) and one or more of signaling proteins selected from K13-vFLIP, MC159-vFLIP, cFLIP-L, cFLIP-p22, HTLV1-Tax and HTLV2-Tax, wherein the CAR comprises an a) extracellular antigen specific domain, b)a transmembrane domain and c) an intracellular signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM); wherein c) is located at the C-terminus of the chimeric receptor. In some embodiments, the CAR further comprises one or more co-stimulatory domains. Also provided herein are methods for treating diseases using the compositions described herein.

The present disclosure provides gene edited modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising an exogenous T cell receptor (TCR) and/or a chimeric antigen receptor (CAR) having specificity for a target antigen, and an insertion and/or deletion in one or more endogenous gene loci, wherein the endogenous gene loci encode regulators of T cell function, thereby resulting in immune cells having enhanced function. Compositions and methods of treatment are also provided. The present invention provides methods of screening for TCR- or CAR-T cells with enhanced immune function (e.g., T cell efficacy, T cell memory, and/or T cell persistence).

Disclosed are compositions and methods for targeted treatment of cancer. The present disclosure provides chimeric antigen receptors and cells expressing such chimeric antigen receptors. In certain embodiments, engineered cells expressing the chimeric antigen receptors are specific for a low density cancer antigen or peptide in groove antigen.

Provided is a genetically engineered ??T cell, which is characterized in that a high-affinity ??TCR gene is transferred into the ??T cell, and the affinity of the high-affinity ??TCR to the specific pMHC thereof is at least two times of that of a wild-type ??TCR corresponding thereto. Further provided are a use of and a preparation method for the ??T cell.

The present invention provides methods for increasing the sensitivity of tumor cells to a TCR-engineered T cells (TCR-T) therapy comprising genetically modifying the tumor cells to express an haplotype, for example an HLA haplotype, different from the haplotype endogenous to the tumor cells.

The present disclosure provides modified immune cells or precursors thereof (e.g., gene edited modified T cells) comprising a modification in an endogenous gene locus encoding SOX and/or ID3. Methods for assessing and treating T cell dysfunction are also provided.

The present application provides antibody-TCR chimeric constructs comprising an antibody moiety that specifically binds to a target antigen fused to a TCRM capable of recruiting at least one TCR-associated signaling module. Also provided are methods of making and using these constructs.

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.