Isolated antibodies that bind to human TIGIT (T-cell immunoreceptor with Ig and ITIM domains) are provided. In some embodiments, the antibody has a binding affinity (K.sub.D) for human TIGIT of less than 5 nM. In some embodiments, the anti-TIGIT antibody blocks binding of CD155 and/or CD112 to TIGIT. In some embodiments, the antibodies are afucosylated.

The present disclosure provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to chimeric antigen receptors (CARs) comprising a mutated CD28 intracellular motif, and cells comprising such CARs. The presently disclosed subject matter further relates to the use of said cells for treating diseases, e.g., for treating cancers.

The invention provides novel light-switchable CAR T-cells that can be remotely controlled through NIR-light-converting upconvension nanoparticles, and related CAR T constructs, nanoparticles, compositions and methods thereof for optogenetic therapy.

The disclosure is directed to dual variable domain immunoglobulin double-stranded RNA conjugates that are advantageous for inhibition of target gene expression, as well as compositions suitable for therapeutic use. The dual variable domain immunoglobulin comprises a first variable domain that binds to a binding target, and a second variable domain that comprises a reactive residue, where the linker is covalently conjugated to the reactive residue. The dsRNA is linked to the linker and is capable of inhibiting the expression of the target gene by RNA interference. The disclosure also provides pharmaceutical compositions comprising these conjugate and methods of inhibiting the expression of a target gene by administering these conjugates, e.g., for the treatment of various disease conditions.

The present disclosure provides a system that enables precise temporal control of the serum half-life a therapeutic moiety by inducing the association or disassociation of the therapeutic moiety with an Fc domain by a small molecule. The present disclosure also provides a system that enables precise control of the serum half- life a T cell engager domain by incorporating a chemically induced dimerizer (CID). One half of the CID is fused to a T cell engager, and the other half of the CID is fused to a HSA binding domain. Addition or removal of a small molecule induces association or dissociation of the T cell engager with HSA, thereby enabling precise temporal control of the serum half-life the T cell engager.

Methods and compositions are provided related to therapeutic receptors, including chimeric antigen receptors (CARs), capable of specifically binding TYRP-1. The disclosed compositions include, for example, cells (e.g., immune cells) expressing TYRP-1 specific CARs, nucleic acids encoding TYRP-1 specific CARs, and TYRP-1 specific CAR polypeptides. Certain aspects relate to methods of treating cancer, including melanoma, using compositions comprising TYRP-1 specific CARs, for example cells expressing TYRP-1 specific CARs. In some embodiments, provided herein are chimeric polypeptides comprising a TYRP-1 binding domain, a hinge region, a transmembrane domain, and an intracellular signaling domain.

Provided herein are methods of treating cancer (e.g., NSCLC), which comprise administering to a human patient in need thereof: (a) a PD-1 antagonist; (b) an ILT4 antagonist; and (c) one or more chemotherapeutic agents. Also provided are pharmaceutical compositions and kits containing such agents for the treatment of cancer.

Regulatory T cells (T.sub.reg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4.sup.+ T.sub.reg cells have been described—naturally occurring T.sub.reg cells and adaptive T.sub.reg cells. Disclosed herein are methods for producing efficacious CAR T.sub.reg cells in a GMP-scalable system.

The present disclosure provides methods of promoting a persistent effector function of immune cells, comprising modifying the cells to overexpress c-Jun and reduced levels of a NR4A gene and/or protein. Also provided are modified cells, e.g., immune cell, which have been modified to overexpress c-Jun and express reduced levels of NR4A gene and/or protein. Overexpressing c-Jun and simultaneously reducing expression levels of a NR4A gene and/or protein leads to exhaustion/dysfunction resistant cells, which are apoptosis resistant and also immune checkpoint resistant, and also to the maintenance of anti-tumor function in tumor microenvironments.

Methods for manufacturing genetically engineered T cells expressing a chimeric antigen receptor (CAR), such as a CAR that binds human CD19, BCMA, or CD70, and having multiple additional gene edits, for example, a disrupted Regnase-1 gene, a disrupted TGFBRII gene, a disrupted TRAC gene, a disrupted β2M gene, or a combination thereof, using CRISPR/Cas gene editing systems.