Disclosed are compositions and methods related to the construction and use of conditional universal synthetic notch (synNotch) receptors and conditional chimeric antigen receptor (CAR) T cells. Also disclosed herein are methods of using said synNotch receptors in the construction of engineered cells. It is contemplated herein that the disclosed synNotch receptors and engineered cells can be used in regenerative medicine. Additionally disclosed herein are methods of using the disclosed synNotch, CAR T cells, and engineered cells in the treatment of cancer, autoimmune disease, autoinflammatory disease, and infectious disease.

The invention relates to agents and methods for targeted delivery of payloads to cells. The agents and methods are useful for delivering therapeutic or diagnostic agents to target cells. In one embodiment, the invention involves administering RNA encoding a peptide or polypeptide (docketing compound) comprising a binding moiety (primary targeting moiety) binding to target cells and a further binding moiety (secondary target) binding to an agent that comprises a payload (effector probe). Following expression of the RNA, the primary targeting moiety may bind to a target antigen such as a cancer antigen on cancer cells and then a secondary targeting moiety comprised in the effector probe may target the secondary target to thereby precisely deliver a payload to the target cells such as cancer cells.

The present invention relates to chimeric receptors capable of facilitating cross-presentation (XP) of antigens, and methods of doing the same.

Chemically induced dimerizers (AbCIDs) have emerged as one of the most powerful tools to artificially regulate signaling pathways in cells; however, no facile method to identify or design these systems currently exists. The present invention provides a methodology to rapidly generate antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. Success of this strategy is demonstrated by generating ten chemically-inducible antibodies against the BCL-xL/ABT-737 complex. Three of the antibodies are highly selective for the BCL-xL/ABT-737 complex over BCL-xL alone. Two exemplary important cellular applications of AbCIDs are demonstrated by applying them intracellularly to induce CRISPRa-mediated gene expression and extracellularly to regulate CAR T-cell activation with the small molecule, ABT-737. ABT-737 is not toxic at the concentrations used to activate AbCIDs in cells. AbCIDs provided by this invention are new and orthogonal AbCIDs, expanding the limited toolbox of available CIDs.

A CD7-targeted engineered immune cell, a chimeric antigen receptor, a CD7 blocking molecule and the use thereof. A natural ligand of human CD7 is used for substituting for an antibody sequence to serve as an antigen recognition domain of a CD7-specific CAR-T or CAR-NK cell. The advantage of using human CD7 as the antigen recognition domain in the CD7-specific CAR is that cellular and humoral reactions produced by a host can be prevented, to achieve long-term durability and better efficacy of the CAR-T cell.

The invention provides therapeutic humanized anti-HERV-K antibodies, CAR, or a fusion thereof consisting of a hispecific T ceil engager (BiTE) FOR CD3 and CDS, a DNA-encoded BiTE (DBiTE), or an antibody-drug conjugate (ADC). The invention also relates to peptides, proteins, nucleic acids, and cells for use in immunotherapeutic methods. In particular, the invention relates to the immunotherapy of cancer peptides bound to molecules of the MHC, or peptides as such, which can also be targets of antibodies and other binding molecules.

A polypeptide comprising a chimeric antigen receptor (CAR) comprising (i) an extracellular domain capable of binding to a first antigen, (ii) a transmembrane domain, and (iii) an intracellular domain; and a domain capable of binding to a second antigen expressed on the surface of a cell that can interact with a T cell, wherein the CAR and the domain are fused by a peptide linker.

The present invention relates to compositions and methods for enhancing T cell metabolism and activity for more effective adoptive T cell therapy. By expressing an chimeric antigen receptor and bispecific antibodies in T cells, the T cells are metabolically enhanced with improved cytotoxicity and resistance to immunosuppression imposed by tumor microenvironments. Certain aspects include modified T cells and pharmaceutical compositions comprising the modified cells for adoptive cell therapy and treating a disease or condition associated with enhanced immunity.

Provided herein are recombinant nucleic acids encoding a T cell receptor (TCR) fusion protein (TFP) and an interleukin-15 (IL-15) polypeptide and/or an interleukin-15 receptor alpha (IL-15R?) polypeptide, modified T cells expressing the encoded molecules, and methods of use thereof for the treatment of diseases, including cancer.

Disclosed are off-the-shelf immune effector cells that are engineered to express anti-CD3 antibodies disclosed herein that are configured to autoactivate the immune effector cells, thereby decreasing expression of T cell receptors (e.g. TCR??) that could result in GVHD. Also disclosed are methods for modifying donor immune effector cells to make them suitable for off-the-shelf treatment of allogeneic subjects. These methods involve engineering the cells to express an anti-CD3 antibody configured to activate the cells. In some embodiments, the antibody is a bi-specific antibody that binds the CD3 complex on the immune effector cells. In other embodiments, the antibody is a membrane bound anti-CD3 antibody that autoactivates the immune effector cell.