The disclosure provides immune cells comprising a first activator receptor specific to mesothelin and a second inhibitory receptor specific to a ligand that has been lost in a mesothelin-positive cancer cell, and methods of making and using same for the treatment of cancer.

The present disclosure provides a CAR comprising a tumor antigen binding domain, a transmembrane domain, and an intracellular domain comprising an intracellular signaling domain of an interleukin-9 receptor alpha (IL9Ra), and modified cell(s), i.e., immune cell(s) or precursor cell(s) thereof, engineered to express the CAR. Also provided are methods and uses of the modified cells, e.g., for treating at least one sign and/or symptom of cancer. Related nucleic acids, vectors, and pharmaceutical compositions are also provided.

Disclosed herein are methods for treatment of a mesothelin (MSLN)-expressing cancer in a human subject comprising administration of, e.g., a plurality of anti-MSLN T cell receptor fusion protein (TFP)-expressing T cells. A ratio of CD4+ to CD8+ T cells in a sample from the human subject may have been determined before the administration of the plurality of anti-MSLN TFP-expressing T cells. The plurality of anti-MSLN TFP-expressing T cells may comprise a pre-determined ratio of CD4+ to CD8+ T cells.

The disclosure provides immune cells comprising a first activator receptor specific to mesothelin and a second inhibitory receptor specific to a ligand that has been lost in a mesothelin-positive cancer cell, and methods of making and using same for the treatment of cancer.

The present disclosure provides chimeric cytokine receptors comprising an intracellular signaling domain of an interleukin-9 receptor alpha (IL9Ra). The present disclosure also provides modified cell(s), i.e., immune cell(s) or precursor cell(s) thereof, wherein the cell(s) are engineered to express a) interleukin-9 receptor alpha (IL9Ra), or a chimeric cytokine receptor disclosed herein; and b) a chimeric antigen receptor (CAR). The present disclosure further provides a vector (e.g., an oncolytic adenoviral vector) comprising a nucleic acid sequence encoding a cytokine, as well as methods of using the modified cells and the vector for treating cancer in a subject in need thereof. Also provided are modified immune cell(s) or precursor cell(s) thereof which are engineered to express a chimeric antigen receptor (CAR), wherein expression of Cullin 5 in the cell(s) is reduced and/or eliminated. Also provided are methods and uses of the modified cells, e.g., for treating at least one sign and/or symptom of cancer. Related nucleic acids, vectors, and pharmaceutical compositions are also provided.

The present invention provides an anti-human MSLN-specific antibody and an MSLN-targeting immune effector cell. Also provided is an MSLN-targeting chimeric antigen receptor modified T-cell prepared using the antibody and a use thereof.

The present invention provides a use of IFN-γ in preparing an anti-tumor adjuvant drug, wherein the IFN-γ enhances killing effect of the T cell preparation on tumor cell by sensitizing the tumor cell; the T cell preparation comprises non-genetically engineered T cell and/or genetically engineered T cell; and the IFN-γ comprises full-length or fragment of wild-type or mutant IFN-γ. The present invention revises the current understanding of IFN-γ in the prior art and finds that the IFN-γ inhibits the acquired immune resistance mediated by PD-L1-PD-1 and enhances the anti-tumor effect of immunotherapy by activating the IFN-γ signaling pathway in tumor cell.

The disclosure provides immune cells comprising a first activator receptor specific to mesothelin and a second inhibitory receptor specific to a ligand that has been lost in a mesothelin-positive cancer cell, and methods of making and using same for the treatment of cancer.

The present disclosure provides methods of producing a modified immune cell responsive to orthogonal cytokine signaling and a modified immune cell produced by said method. The present disclosure further provides a modified immune cell responsive to orthogonal cytokine signaling and methods for treating cancer comprising the modified immune cell.

The present invention is directed to a chimeric antigen receptor (CAR), comprising an antigen binding domain specific for MSLN in combination with one or more antigen binding domains specific for an antigen selected from the group consisting of CLA, CD66c, TSPAN8 and CD318; cell populations expressing such CARs and the use of the cell populations for cancer therapy.