Provided are compositions and methods for treating diseases associated with expression of mesothelin. Also provided are a chimeric antigen receptor (CAR) specific to mesothelin, vectors encoding the same, and recombinant T cells comprising the mesothelin CAR. Further provided are methods of administering a genetically modified T cell expressing a CAR that comprises a mesothelin binding domain.

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.

A method of treating cancer in a subject includes contacting an enriched population of T-cells obtained from cancer or tumor draining lymph nodes ex-vivo with: an anti-CD3 antibody, an anti-CD28 antibody, and/or functional fragments thereof, and optionally a VEGF inhibitor and/or an IL-2 receptor agonist, at amounts effective to activate and expand the T-cells and administering the activated and expanded T-cells to the subject.

Disclosed herein are chimeric antigen receptors (CARs) that target MUC1*. In some embodiments, the CARs have been optimized to reduce T cell exhaustion.

Provided herein is a method of expanding clinically-relevant quantities of polyclonal ?? T cells that have anti-tumor, anti-viral, and anti-bacterial reactivity. Polyclonal ?? T cells can target a variety of tumors, including solid tumors as well as other conditions, such as viral and bacterial infections.

Masked chimeric antigen receptor (CAR) constructs comprising an extracellular antigen binding domain specific tyrosine-protein kinase-like 7 (PTK7), which is linked to a mask peptide that blocks binding of masked CAR from binding to PTK7. Also provided herein are genetically engineered T cells expressing a masked CAR specific to PTK7 and therapeutic uses thereof.

Disclosed herein are isolated nucleic acid molecules comprising a polynucleotide encoding a chimeric antigen receptor (CAR) comprising an antibody that specifically recognizes human mesothelin, a CD8 hinge region, a CD8 transmembrane region, a 4-1BB intracellular region and a CD3 intracellular region; a polynucleotide encoding IL-7; and a polynucleotide encoding CCL19. Also disclosed herein include vectors, modified immune cells, and pharmaceutical compositions comprising the nucleic acid molecules and methods of use.

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 is a cytotoxic immune cell that is primed by and/or whose cytotoxicity within the tumor microenvironment is enhanced by binding to a stromal marker, e.g., Fibroblast Activation Protein Alpha (FAP). In some embodiments, the cells may contain a protein circuit that contains at least two components, wherein one of the components binding-triggered transcriptional switch that is activated by binding to the stromal marker. The second component may be a nucleic acid encoding an immune receptor (e.g., a chimeric antigen receptor or TCR) that is activated by binding to a cancer-specific antigen and/or a pro-inflammatory cytokine.

What is described is a method for treating cancer in a patient in need of such treatment through the use of an antagonist to CXCR1 and/or CXCR2 receptors by administering a therapeutically effective amount of an antagonist of CXCR1 and/or CXCR2, or pharmaceutical compositions thereof, either alone as monotherapy, or in combination with at least one other anticancer therapy.