The method disclosed herein describes a novel technology offering unparalleled efficiency, flexibility, utility and speed for the stable integration of transgenes into lymphocytes and other mammalian cells. The novel method is based on the use of an mRNA-encoded transposase (e.g. sleeping beauty transposase) in combination with a minicircle DNA-encoded transposable element. The novel method enables higher gene-transfer rates and is at the same time less toxic than the conventional approach, which is the use of plasmid DNA-encoded transposase in combination with a plasmid DNA-encoded transposable element. Applications of the invention include but are not limited to the stable integration of a transgene encoding an immune receptor (e.g. a T-cell receptor or synthetic chimeric antigen receptor) into human T lymphocytes, with the immune receptor conferring specificity for a molecule expressed by a tumor cell. The transposase mRNA and transposon minicircle DNA may be introduced into lymphocytes by methods including but not limited to electrotransfer such as electroporation and nucleofection.

The invention provides compositions and methods for treating diseases associated with expression of an antigen, e.g., a solid tumor antigen or antigen expressed on a tumor associated with TAMs and/or MDSCs, by administering a recombinant T cell comprising a CAR binding to said antigen, as described herein, in combination with an inhibitor of a pro-M2 macrophage molecule, e.g., described herein. The invention also provides kits and compositions described herein.

The present invention relates generally to proteins which bind to human epidermal growth factor receptor variant III (EGFRvIII). The present invention also relates to chimeric antigen receptors (CARs) comprising the EGFRvIII binding proteins, nucleic acids and vectors encoding the CARs, as well as cells comprising the CARs. The present invention also relates to methods of treating and diagnosing diseases such as cancer.

The present invention relates to an artificially manipulated immune system having an improved immune effect. More particularly, the present invention relates to an immune system having functions artificially altered which comprises artificially manipulated immunoregulatory elements and cells containing the same. Contemplated according to a particular embodiment is an immune system comprising artificially manipulated immunoregulatory genes such as PD-1, CTLA-4, A20, DGK?, DGK?, FAS, EGR2, PPP2R2D, PSGL-1, KDM6A, and TET2, and/or expression products thereof.

The present disclosure provides engineered immune cells and methods for their creation and use. The immune cells comprise activating and blocking receptors. The signals of the activating and blocking receptors can be modulated via the identity of a hinge.

The present invention provides a universal, yet adaptable, anti-tag chimeric antigen receptor (AT-CAR) system which provides T cells with the ability and specificity to recognize and kill target cells, such as tumor cells, that have been marked by tagged antibodies. As an example, ?FITC-CAR-expressing T cells have been developed that specifically recognize various human cancer cells when those cells are bound by cancer-reactive FITC-labeled antibodies. The activation of ?FITC-CAR-expressing T cells is shown to induce efficient target lysis, T cell proliferation, and cytokine/chemokine production. The system can be used to treating subjects having cancer.

The present disclosure provides novel cell compositions engineered to express at least a chimeric antigen receptor and a survival factor. Methods of using such cell compositions are also described.

Provided are CCT5-binding molecules, including anti-CCT5 antibodies and antigen-binding fragments thereof such as heavy chain variable (VH) regions and single-chain antibody fragments, and conjugates comprising the anti-CCT5 binding molecules such as immunoconjugates and antibody-drug conjugates, and chimeric receptors comprising the anti-CCT5 binding molecules such as chimeric antigen receptors (CARs). In some embodiments, the anti-CCT5 antibodies or antigen-binding fragments thereof specifically bind to CCT5. Also provided are genetically engineered cells expressing the CARs or CCT5-binding molecules and uses thereof such as in adoptive cell therapy.

The present disclosure generally relates to, among other things, a new class of receptors engineered to modulate transcriptional regulation in a ligand-dependent manner. In particular, the new receptors contain a heterologous stop-transfer-sequence and a ?-secretase cleavable transmembrane domain. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating an activity of a cell and/or for the treatment of various diseases such as cancers.

The present invention provides recombinant TIM-4 fusion proteins comprising an extracellular domain of TIM-4 and at least one co-stimulatory domain. Also provided are cells comprising the fusion protein and methods of making and using the same.