This disclosure describes, generally, a modified form of CD16, genetically-modified cells that express the modified CD16, and methods that involve the genetically-modified cells. The modified form of CD16 can exhibit increased anti-tumor and/or anti-viral activity due, at least in part, to reduced susceptibility to ADAM17-mediated shedding upon NK cell stimulation.

Disclosed are methods of identifying immunosuppressive T.sub.R1 regulatory T cells, including methods of diagnosing the presence of immune tolerance, methods of producing immunosuppressive regulatory T cells, and methods of eliciting immune tolerance in a subject. These methods include screeing T cells to detect Eomes .sup.+IL-10.sup.+ T cells or expressing recombinant Eomes in T cell populations to generate immunosuppressive regulatory T cells.

An in vitro or ex vivo method for producing and isolating a cell subpopulation including T cells specific for an antigen linked to a disease of interest, which includes steps of obtaining, from an isolated human biological sample, a population of mononuclear cells including T cells specific for the antigen with a high proliferative capacity, culturing these mononuclear cells in a suitable cell culture medium containing the antigen, and isolating T cells specific to the antigen which do not express the CD45RO and CD27 markers at their surface. The cell subpopulation thus obtained and isolated finds application in particular for the treatment of the disease of interest.

Provided herein are methods and compositions for treating chordoma by preferentially targeting cancer stem cells than non-cancer stem cells in chordoma to effectively treat chordoma. In some embodiments, the chordoma tumors cells (preferentially the cancer stem cells in chordoma) are targeted by modified NK-92 cells (i.e., haNK cells) that express CARs that comprise means for binding to the PD-L1 and another tumor-specific antigen (e.g., EGFR). In some embodiments, the chordoma tumor cells are targeted by using NK cells in combination with a means for binding to means for binding to the PD-L1 and/or a means for binding another tumor antigen (e.g., EGFR). Each of the treatment methods disclosed above may be implemented prior to, and/or concurrent with radio- and/or chemotherapy, and/or may be employed with immune therapy as is discussed in more detail below.

Provided in the present invention is a method for treating tumor. An immune effector cell and a second treatment agent are applied to individual suffering from tumor, wherein the immune effector cell expresses a receptor for recognizing tumor antigen, and wherein the second treatment agent is a compound of formula I or a pharmaceutically acceptable salt thereof.

Camel single-domain monoclonal antibodies that specifically bind human and mouse mesothelin are described. Chimeric antigen receptor (CAR) T cells and antibody conjugates based on the mesothelin-specific antibodies are also described. The disclosed CAR T cells, mesothelin-specific antibodies and conjugates thereof can be used, for example, in the diagnosis or treatment of mesothelin-positive cancers.

In one embodiment, the present disclosure provides an engineered cell having a first chimeric antigen receptor polypeptide including a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain; and a second chimeric antigen receptor polypeptide including a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain; wherein the first antigen recognition domain is different than the second antigen recognition domain.

Embodiments of the disclosure include methods and compositions for enhancing expansion of immune cells for immunotherapy. In particular embodiments, immune cells, such as T-cells, express a constitutively active cytokine receptor in which the transmembrane and endodomains are able to provide an activating signal separately from any input to the corresponding exodomain to which they are operably linked. In specific embodiments, the transmembrane and endodomain from IL-7R is utilized with the exodomain of CD34.

The invention is directed to modified T cells, methods of making and using isolated, modified T cells, and methods of using these isolated, modified T cells to address diseases and disorders. In one embodiment, this invention broadly relates to TOR-deficient T cells, isolated populations thereof, and compositions comprising the same. In another embodiment of the invention, these TOR-deficient T cells are designed to express a functional non-TOR receptor. The invention also pertains to methods of making said TCR-deficient T cells, and methods of reducing or ameliorating, or preventing or treating, diseases and disorders using said TOR-deficient T cells, populations thereof, or compositions comprising the same.

The invention is directed to modified T cells, methods of making and using isolated, modified T cells, and methods of using these isolated, modified T cells to address diseases and disorders. In one embodiment, this invention broadly relates to TCR-deficient T cells, isolated populations thereof, and compositions comprising the same. In another embodiment of the invention, these TCR-deficient T cells are designed to express a functional non-TCR receptor. The invention also pertains to methods of making said TCR-deficient T cells, and methods of reducing or ameliorating, or preventing or treating, diseases and disorders using said TCR-deficient T cells, populations thereof, or compositions comprising the same.