The disclosure describes T cells that express chimeric antigen receptors (CARs), as well as pharmaceutical compositions comprising T cells and methods of making and using such T cells. Particularly, this disclosure describes T cells expressing a first CAR that binds to a first antigen and a second CAR comprising a LAT intracellular signaling domain that binds to a second antigen, and methods of use in treating cancers, such as solid tumors and hematological malignancies.

The present disclosure provides chimeric antigen receptors, compostions, and methods thereof. In one embodiment the present disclosure provides a method of treating autoimmune diseases, asthma, and preventing or mediating organ rejection in a subject.

The present invention provides nucleic acid sequences encoding chimeric antigen receptors (CAR), wherein the CAR comprises an antigen binding domain, an extracellular domain, a transmembrane domain, intracellular stimulatory and co-stimulatory domains. The present invention also provides chimeric DNA comprising a first DNA segment encoding a single-chain variable fragment (scFv) of an antibody comprising a heavy chain variable region (VH) linked to a light chain variable region (VL) by a flexible linker. The present invention also provides a chimeric DNA wherein the endogenous protein is expressed on the surface of a lymphocyte or macrophage and triggers the activation of the lymphocyte or macrophage. The present invention also provides an expression vector comprising a chimeric DNA. The present invention also provides a lymphocyte or macrophage transformed with an expression vector or chimeric DNA wherein expression of the expression vector or chimeric DNA endows the lymphocyte or macrophage with antibody specificity.

Provided are polycistronic vectors for co-expression of one or more tolerogenic factors, one or more CARs, and optionally one or more safety switches, as well as compositions comprising the same, cells comprising the same and methods of generating those cells, and methods of using the disclosed vectors, compositions, and cells to treat diseases such as cancer, diabetes, and neurological diseases.

The present disclosure relates generally to compositions and methods for robustly improving fitness and function of CAR T cells. More particularly, the present disclosure relates to novel chimeric polypeptides capable of anchoring adenosine deaminase activity to the surface of T cells, nucleic acids encoding the chimeric polypeptides, engineered T cells comprising the chimeric polypeptides or the nucleic acids encoding the chimeric polypeptides. Also provided herein are methods of generating the engineered T cells, methods of administering the engineered T cells, and methods of treating individuals of relevant health conditions.

Compositions and methods for improved ACT are provided. Compositions of CAR-T cells including CAR modified by fusion with one or more copies of a polypeptide including from 20 to 44 amino acids from the transmembrane and/or cytosolic domain of CTLA-4 (CT) are described. CAR-CT-T cells have reduced trogocytosis, reduced T-cell fratricide, enhanced tumor antigen presentation and overall enhanced anti-tumor efficacy as compared with CAR-T cells lacking the CT domain(s). In preferred embodiments, CAR-TC fusion peptides include a CT domain having 2 copies of the YVKM motif. The compositions and methods provide enhanced CAR-T cell therapy for cancer, auto-immune disease as well as other disease and disorders. Also disclosed are genetically modified cells and pharmaceutical compositions and methods of use thereof for treating subjects having diseases or disorders.

Provided herein are humanized mouse models and methods for determining whether administration of engineered immune cell therapies likely elicit cytokine release syndrome and/or determining the efficacy of an anti-disease therapy. Further, the models provided herein may be used to test the efficacy of different anti-CRS therapies.

New synthetic expression cassettes comprising a minimal promoter and a cell-specific enhancer for expression of a nucleic acid of interest in one or more specific cell subtypes are disclosed. Vectors and host cells comprising such synthetic expression cassettes are also disclosed. The application also discloses methods for expressing a nucleic acid of interest, such as a nucleic acid encoding a chimeric antigen receptor (CAR), in a cell and for treating diseases or conditions such as cancers and genetic diseases using the synthetic expression cassettes, vectors and cells.

The method entails modification of non-malignant cells for transplantation or therapy to avoid recognition and attack by monoclonal antibodies and antibody-derived therapeutics. Many therapies that use monoclonal antibodies or antibody-derived therapeutics not only bind to the intended target epitope on malignant cells, but also to the same target epitope on healthy non-malignant cells that express the target antigen. This phenomenon is termed on-target off-tumor effect. This can cause rejection, immune cell attack or opsonization of non-malignant cells, which in turn can cause severe side effects which often hampers the therapeutic effect. Similarly, cytokines in cytokine therapy can bind to receptors on bystander cells and cause unintended effects. The methods of the present invention change the antigen epitope or the cytokine receptor on non-malignant and bystander cells for adoptive cell therapy, thereby disrupting the binding of the therapeutic agentantibody or cytokineto the target antigen or receptor on non-malignant cells.

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.