The present invention provides a nucleic acid construct comprising the following structure: A-X-B in which A and B are nucleic acid sequences encoding a first and a second polypeptide of interest (POI); and X is a nucleic acid sequence which encodes a cleavage site, wherein either the first or second POI is a transmembrane protein which comprises an intracellular retention signal.

The present invention provides a nucleic acid construct comprising the following structure: A-XB in which A is nucleic acid sequence encoding a first polypeptide which comprises a first signal peptide; B is nucleic acid sequence encoding a second polypeptide which comprises a second signal peptide and X is a nucleic acid sequence which encodes a cleavage site, wherein the first signal peptide or the second signal peptide comprises one or more mutation(s) such that it has fewer hydrophobic amino acids.

The application pertains to pharmaceutical combinations of orally administered paclitaxel, a P-gp inhibitor, and a checkpoint inhibitor. The pharmaceutical combinations are suitable for the treatment of a cancer (e.g., lung cancer) in a subject.

This invention provides an isolated or purified T-cell receptor (TCR) having antigenic specificity for the mutated human CTNNB1S37F. The inventive TCR can recognize the HLA-A2 restricted mutant CTNNB1S37F peptide (YLDSGIHFGA) but cannot recognize the wild-type CTNNB1S37 peptide (YLDSGIHSGA). The inventive TCR can also be activated by tumor cells harboring a mutated human CTNNB1S37F in the context of HLA-A2. The invention further provides related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells and pharmaceutical compositions relating to the TCR of the invention. Methods of treating or preventing cancer in a mammal are further provided by the invention.

The present invention relates to chimeric antigen receptors (CARs), particularly CARs expressed in immune cells (e.g. Tregs) and their use in therapy. In particular, the invention provides a CAR comprising an antigen recognition domain that specifically binds to TREM2.

Embodiments of the disclosure include methods and compositions related to targeting of antigen-expressing cells with particular engineered antigen receptors expressed by immune cells. In specific embodiments, immune cells specifically engineered to express particular antigen receptor constructs are cultured in the presence of kinase inhibitors and exhibit reduced fratricidal activity compared to immune cells cultured in the absence of kinase inhibitors. In some embodiments, the genetically engineered immune cells having reduced fratricidal activity are used to treat diseases in subjects, and the fratricidal activity of the genetically engineered immune cells is restored in vivo after substantial elimination of the diseased cells, resulting in elimination of the genetically engineered immune cells.

Anaplastic large cell lymphoma (ALCL) is a rare and aggressive peripheral T-cell lymphoma affects lymph nodes and extra-nodal sites with characteristic skin lesions. Approximatively half of the tumors express the NPM1-ALK fusion from the translocation t(2;5)(p23;q32). In the present study, the inventors identify ROR2 as progressively up regulated thought tumorigenesis. Patient samples show a significantly high ROR2 expression (transcriptomic data) as well as a strong ROR2 protein expression (IHC) with some tumors displaying a clear membrane signal. ROR2 mRNA expression level is also positively correlated to NPM-ALK expression level in tumor cells and is not expressed in normal T cells. In addition, ROR2 protein level is significantly increased in resistant cells to the ALK inhibitor, crizotinib, used in clinical trials for children with refractory tumors. This result opens the road to ROR2 specific therapies: ROR2 inhibitors, monoclonal antibodies therapies or even ROR2 specific CAR cells, including for ALCL ALK(+) resistant tumors.

The present disclosure relates to polynucleotides encoding a chimeric polypeptide comprising a c-Jun polypeptide, a ROR1-binding protein, and a truncated EGF receptor. Also provided are cells (e.g., T cells) expressing CARs comprising a ROR1-binding protein and overexpressing a c-Jun polypeptide. Overexpression of c-Jun in CAR T cells confers improved properties, e.g., reducing or preventing exhaustion.

The present invention refers immune cells expressing a TCR and a co-stimulatory receptor which are poly functional, i.e. secreting 2 or more proteins. Exemplary immune cells express a(i) T cell receptor (TCR) specific for the PRAME peptide SLLQHLIGL or a TCR specific for NY-ESO-1 peptide SLLMWITQC and (ii) a chimeric co-stimulatory receptor comprising an extracellular domain derived from PD-1 (CD279) and an intracellular domain derived from 4-1BB (CD137).

A BAG6 specific chimeric antigen receptor, a nucleic acid, a BAG6 specific chimeric antigen receptor expression plasmid, a BAG6 specific chimeric antigen receptor expressing cell, a pharmaceutical composition for treating cancer, and use of the BAG6 specific chimeric antigen receptor expressing cell are provided. The BAG6 specific chimeric antigen receptor specifically binds to BCL2 associated athanogene 6 (BAG6). The nucleic acid encodes the BAG6 specific chimeric antigen receptor. The BAG6 specific chimeric antigen receptor expression plasmid expresses the BAG6 specific chimeric antigen receptor. The BAG6 specific chimeric antigen receptor expressing cell is obtained by transducing the BAG6 specific chimeric antigen receptor into an immune cell. The pharmaceutical composition for treating cancer includes the BAG6 specific chimeric antigen receptor expressing cell and a pharmaceutically acceptable carrier.