The present invention is directed to genome editing systems, reagents and methods for immunooncology.

The technology relates in part to binding molecules that specifically bind to a polypeptide that is the Isoform 2 of mesothelin, or that specifically bind to an antigenic determinant (epitope) of the isoform 2 of mesothelin, or that specifically bind to polypeptides containing an antigenic determinant (epitope) of the isoform 2 of mesothelin, chimeric PD1 receptors that bind to PD ligands such as PDLs, to polynucleotides including vectors that encode such binding molecules, to ceils presenting such binding molecules and to methods of making such cells, to humanized forms of the binding molecules, and to methods of using such binding molecules, such as for treating cancers (e.g., ovarian cancers and mesotheliomas), including cancers in which the Isoform 2 of mesothelin is specifically expressed and/or upregulated relative to normal tissues.

Provided herein are acute myeloid leukemia antigen targets for chimeric receptors and methods of using same.

The present disclosure relates to chimeric Tim receptors, host cells modified to include chimeric Tim receptor molecules, and methods of making and using such receptor molecules and modified cells.

Provided herein are chimeric antigen receptors that binds specifically to B-cell maturation antigen (BCMA) and CD307e, nucleic acids that encode these chimeric antigen receptors, and methods of making and using these chimeric antigen receptors.

Disclosed herein are chimeric antigen receptor (CAR) polypeptides, which can be used with adoptive cell transfer to target and kill cancers, that comprise a co-stimulatory signaling region having a mutated form of a cytoplasmic domain of CD28 that enhances CAR-T cell function, e.g. by reducing CAR-T cell exhaustion. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a tumor associated antigen-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

The present invention generally relates to heterodimeric Fc domain antibodies as well as to combination with antigen binding receptors capable of specific binding to such antibodies comprising the amino acid mutation P329G according to EU numbering. The present invention also relates to T cells, transduced with such antigen binding receptor and kits comprising the transduced T cells and tumor targeting antibodies comprising such heterodimeric Fc domains.

Single-domain shark variable new antigen receptor (V.sub.NAR) monoclonal antibodies that specifically bind programmed death-ligand 1 (PD-L1) are described. The PD-L1-specific V.sub.NAR antibodies are capable of binding PD-L1-expressing tumor cells from human, mouse and canine origin. Immune cells expressing chimeric antigen receptors (CARs) developed using the V.sub.NAR antibodies can be used to kill PD-L1-positive tumor cells, for example in animal models of liver cancer and breast cancer.

Provided herein are TILs that are genetically modified to silence or reduce expression of endogenous PD-1. In some embodiments, the subject TILs are produced by genetically manipulating a population of TILs that have been selected for PD-1 expression (i.e., a PD-1 enriched TIL population). Also provided herein are expansion methods for producing such genetically modified TILs and methods of treatment using such TILs.

The present application relates to an antigen-binding polypeptide that specifically binds to B7H3, comprising at least one complementarity-determining region (CDR) of an antibody heavy chain variable region (VH), wherein the VH comprises an amino acid sequence set forth in SEQ ID NO: 25. The present application further relates to a chimeric antigen receptor comprising the antigen-binding polypeptide and a universal CAR-T cell comprising the chimeric antigen receptor. The CAR-T cell recognizes a surface antigen of a tumor cell and knocks out TCR and HLA-A genes expressed by the cell at the same time, so that the immune rejection caused by an allogeneic CAR-T therapy is reduced, the survival time of the cell is prolonged, and the anti-tumor effect is improved.