Compositions and methods for efficient cellular genomic engineering that transduce diverse cell types with minimal toxicity, leading to efficient and stable genomic modifications are described. The compositions and methods are applicable to development of chimeric antigen receptor engineered T cell therapy (CAR-T). An exemplary method introduces a gene of interest into cells by introducing to the cell a viral vector including a transposon encoding the gene of interest and mRNA including a sequence that encodes transposase enzymes configured to mediate targeted integration of the transposon into the cellular genome, whereby the mRNA is introduced to the cell via electroporation. Also disclosed are genetically modified cells and pharmaceutical compositions and methods of use thereof for treating subjects having diseases or disorders.

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 invention pertains to the field of adaptive cell immunotherapy. It provides with the genetic insertion of exogenous coding sequence(s) that help the immune cells to direct their immune response against infected or malignant cells. These exogenous coding sequences are more particularly inserted under the transcriptional control of endogenous gene promoters that are sensitive to immune cells activation. Such method allows the production of safer immune primary cells of higher therapeutic potential.

The present invention provides a cell which co-expresses a first chimeric antigen receptor (CAR) and second CAR at the cell surface, each CAR comprising an antigen-binding domain, wherein the antigen-binding domain of the first CAR binds to CD19 and the antigen-binding domain of the second CAR binds to CD22.

There is provided method for making a cell composition which comprises step of transducing a population of cells with a mixture of at least two viral vectors, wherein at least one vector comprises a nucleic acid sequence which encodes a chimeric antigen receptor (CAR); and wherein at least one vector comprises a nucleic acid encoding an activity modulator which modulates the activity of the CAR, of a cell expressing the CAR, or of a target cell. There is also provided a cell composition made by such a method and its use in the treatment of diseases such as cancer.

Disclosed herein are engineered cells comprising one or more CARs directed to a first therapeutic target and one or more CARs directed to a second therapeutic target, as well as methods of using such engineered cells. Also provided herein are methods of treating a disease or disorder in a patient that has previously been administered one or more targeted therapies, the method comprising administering a population of engineered CAR-T cells to the patient. In some embodiments, one or more targeted therapies comprised administration of a first therapeutic agent, wherein the first therapeutic agent is directed to a first therapeutic target. In some embodiments, engineered CAR-T cells of the population comprise one or more chimeric antigen receptors (CARs), wherein at least one CAR encoded by the one or more exogenous polynucleotides is directed to a second therapeutic target, wherein the first therapeutic target and the second therapeutic target are different.

Disclosed herein are engineered cells and/or hypoimmunogenic cells including engineered and/or hypoimmunogenic stem cells, engineered and/or hypoimmunogenic cells differentiated therefrom, engineered and/or hypoimmunogenic CAR-T cells (primary or differentiated from engineered and/or hypoimmunogenic stem cells) and related methods of their use and generation for use in the treatment of autoimmune diseases/disorders and/or inflammatory diseases/disorders. Provided herein are engineered and/or hypoimmunogenic cells exhibiting reduced expression of MHC class I and/or MHC class II human leukocyte antigens and T-cell receptors for use in the treatment of autoimmune diseases/disorders and/or inflammatory diseases/disorders. In some embodiments, such cells also exogenously express one or more tolerogenic factors such as CD47 and one or more chimeric antigen receptors (CARS).

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 present invention relates to T cell compositions and methods of using the same in the context of therapy and treatment. In particular, the invention provides T cells that are modified (e.g., genetically and/or functionally) to maintain functionality under conditions in which unmodified T cells display exhaustion. Compositions and methods disclosed herein find use in preventing exhaustion of engineered (e.g., chimeric antigen receptor (CAR) T cells) as well as non-engineered T cells thereby enhancing T cell function (e.g., activity against cancer or infectious disease).

The present invention provides an anti-CD22 antibody molecule and a CD22-targeted chimeric antigen receptor (CAR) constructed using the anti-CD22 antibody molecule. The present invention also provides an application of the anti-CD22 antibody molecule and the CAR in the preparation of drugs for treating CD22-related diseases.