The invention provides improved T cell compositions and methods for manufacturing T cells. More particularly, the invention provides methods of T cell manufacturing that result in adoptive T cell immunotherapies with improved survival, expansion, and persistence in vivo.

Methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject, the method comprising a step of administering a recombinant hGM-CSF antagonist to the subject, wherein said administering inhibits or reduces the incidence or the severity of immunotherapy-related toxicity in said subject, are provided. An hGM-CSF antagonist for use in methods of inhibiting or reducing the incidence or the severity of immunotherapy-related toxicity in a subject also are provided.

Engineered orthogonal cytokine receptor/ligand pairs, and methods of use thereof, are provided.

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.

Methods for preparing T cell populations useful for a variety of purposes requiring a highly active, long-lived T cell population. The T cell populations are enriched for: nave T cells (TN), memory stem cells (TSCM) and central memory T cells (TCM). These cell populations can be derived from peripheral blood mononuclear cells (PBMC) by both: 1) depleting unwanted cell populations such as CD14 expressing myeloid cells and CD25 expressing cells; and 2) enriching for CD62L expressing memory and nave T cells.

Compositions disclosed herein, and methods of use thereof included those for inhibiting or reducing the incidence of cytokine release syndrome or cytokine storm in a subject undergoing CAR T-cell therapy, wherein the subjects are administered compositions comprising apoptotic cells or apoptotic cell supernatants. In certain instances compositions and methods of use thereof disclosed herein do not reduce the efficacy of the CAR T-cell cancer therapy. Disclosed herein are also compositions and methods of use thereof for decreasing or inhibiting cytokine production in a subject experiencing cytokine release syndrome or cytokine storm comprising administration of a composition comprising apoptotic cells or an apoptotic cell supernatant.

The invention provides compositions and methods for treating diseases associated with expression of an antigen, e.g., a solid tumor antigen or antigen expressed on a tumor associated with TAMs and/or MDSCs, by administering a recombinant T cell comprising a CAR binding to said antigen, as described herein, in combination with an inhibitor of a pro-M2 macrophage molecule, e.g., described herein. The invention also provides kits and compositions described herein.

The invention provides compositions and methods for treating diseases associated with expression of an antigen, e.g., a solid tumor antigen or antigen expressed on a tumor associated with TAMs and/or MDSCs, by administering a recombinant T cell comprising a CAR binding to said antigen, as described herein, in combination with an inhibitor of a pro-M2 macrophage molecule, e.g., described herein. The invention also provides kits and compositions described herein.

Immunotherapies, particularly chimeric antigen receptors targeting IL-13R?2 and their use for treating cancer are provided. A single chain fragment variable (scFv) that specifically binds IL-13R?2, chimeric antigen receptors (CARs) including the IL-13R?2 scFv, nucleic acids encoding the CARs, vectors including the nucleic acids encoding the CARs, and immune cells expressing the CARs are provided. Also provided are methods of treating a subject with cancer, including administering to the subject an immune cell expressing an IL-13R?2 scFv-CAR alone or in combination with other cancer therapies.

The present disclosure provides novel cell compositions engineered to express at least a chimeric antigen receptor and a survival factor. Methods of using such cell compositions are also described.