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 is directed to chimeric antigen receptor (CAR) compositions and methods of their use in cancer and anti-viral immunotherapy. In particular, the CAR of the invention comprises a costimulatory signal (CSS) domain comprising herpes virus entry mediator protein (HVEM) or a functional fragment or variant thereof. CARs comprising such a HVEM CSS exhibit enhanced effector function.

Provided is a bispecific chimeric antigen receptor targeting CD19 and CD22, which comprises extracellular antigen binding domains of heavy-chain variable regions and light-chain variable regions of anti-CD19 and anti-CD22 antibodies. Further provided is a bispecific CAR-T cell targeting CD19 and CD22.

Compositions and methods for cellular genome engineering that permit simple and efficient targeted knock-in of a CAR and simultaneous knockout of individual genes are described. The compositions and methods are especially applicable to massively parallel engineering, selection, and identification of CAR T cell variants exhibiting a desired phenotype. AAV vectors containing crRNA and CAR expression cassettes and homology arms for targeted genomic integration thereof are provided. Also provided are libraries containing a plurality of AAV vectors and methods of use thereof in screens for identifying desirable CAR T cell variants. Methods of treatment using CAR T cell variants exhibiting improvements in one or more phenotypes are also provided.

Aspects of this disclosure relate generally to the use of biomaterials for the in vivo generation of CAR expressing cells. In some embodiments, the biomaterials comprise one or more of a cell recruitment composition, a viral vector, and/or a cell activation agent.

Described herein is a therapeutic cell that expresses a fusion protein comprising: (a) a target-binding domain; and (b) a degradation domain, e.g., a degron or E3 ligase-recruiting domain, that is heterologous to the target-binding domain. In the therapeutic cell, binding of the fusion protein to a target protein via the target-binding domain induces degradation of the target protein. The therapeutic cell can be an immunostimulatory cell, an immunoinhibitory cell or a stem cell, for example. Methods of treatment using the cell are also provided.

The present disclosure provides modified immune cells or precursors thereof (e.g. T cells) comprising a chimeric antigen receptor (CAR) capable of binding human PSCA. CARs capable of binding human PSCA, and nucleic acids encoding the same are also provided. Provided herein are bispecific CARs capable of binding human PSCA and human PSMA, nucleic acids encoding the same, and modified immune cells comprising the same. Modified immune cells comprising a PSMA CAR and a PSCA CAR are also provided. Compositions and methods of treatment are also provided.

The disclosure relates to methods of diagnosis and prognosis, compositions for immunotherapies, methods of improving said compositions, and immunotherapies using the same (e.g., T cells, non-T cells, TCR-based therapies, CAR-based therapies, bispecific T-cell engagers (BiTEs), and/or immune checkpoint blockade).

Provided for herein are fusogenic rhabdovirus glycoproteins and uses thereof, compositions comprising the same, and methods of using the same. Also provided for herein are pseudotyped viral particles comprising rhabdovirus glycoproteins as provided for herein and targeting moieties as provided for herein. Also provided are methods of generating and using the pseudotyped viral particles as provided for herein.

Provided herein are a recombinant chimeric antigen receptor (CAR) fusion protein, a method of modifying an immune cell into a CAR immune cell by treating the immune cell with the recombinant CAR fusion protein, and a method of treating cancer by administering the CAR immune cell to a subject in need thereof.