The present invention relates to compositions and methods for generating RNA Chimeric Antigen Receptor (CAR) transfected T cells. The RNA-engineered T cells can be used in adoptive therapy to treat cancer.

The present disclosure provides methods for expanding T cells (e.g., v1 T cells), wherein the cells are contacted with IL-15. In some aspects, the cells are not contacted with IL-4. In some aspects, the cells are engineered, e.g., to express a chimeric antigen receptor. Further provided are populations of expanded and/or engineered T cells and methods of using the same.

The present disclosure provides compositions and methods for engineering T cells (e.g., v1 T cells and v2 T cells) with an IL-15 receptor subunit (IL-15R), e.g., by transduction with a viral vector, to restore IL-15 responsiveness. Further provided are populations of engineered T cells and methods of using the same.

Compositions and methods for treating diseases associated with expression of a cancer associated antigen are disclosed. The invention also relates to chimeric antigen receptor (CAR) specific to a cancer associated antigen as described herein, SHP inhibitory molecules, vectors encoding the same, and recombinant immune effector cells comprising the CARs and SHP inhibitory molecules. Methods of administering a genetically modified immune effector cell expressing a CAR that comprises an antigen binding domain that binds to a cancer associated antigen and a SHP inhibitory polypeptide are also disclosed.

Novel anti-effector moiety antibodies or antigen binding domains thereof and CARs that contain such effector moiety antigen binding domains, either with or without one or more booster elements, and host cells expressing the receptors, and nucleic acid molecules encoding the receptors are provided herein, as well as methods of use of same in a patient-specific immunotherapy that can be used to treat solid tumor cancers and other diseases and conditions.

The present invention refers to a bispecific in tandem receptor CAR, named RfuCAR, which includes a scFv that recognizes and ligates surface molecules on tumoral cells (CD33, CD123 or another tumoral target) and the IL-1 receptor type 2 (IL-1R2). According to this, the IL1-R2 was chosen as the ideal receptor to compose the RfuCAR construction, being able to capture the IL-1 with high affinity and specificity. These proprieties indicate it as a good candidate to reduce the neurotoxicity and CRS effects of CAR-T therapies. Additionally, the present invention deals with a method for modulating the tumoral microenvironment, for example, in case of acute myeloid leukemia, or other cancer type like but not restricted to acute lymbloblastic leukemia, pancreatic, lung and ovarian cancer.

Therapeutic modalities are provided for targeting adoptive cellular therapies to specific sites of disease, involving the use of specific repertoirs of PRR ligands. In effect, innate immune system signaling is provoked so as to facilitate the homing of adoptive immune cells to sites of disease, for example to the site of a solid tumor.

Provided are methods of producing an isolated T memory stem cell population, the method comprising a) isolating nave T cells from a mammal, wherein the mammal is not a mouse; b) activating the nave T cells and expanding the numbers of nave T cells in the presence of one or more non-specific T cell stimuli, one or more cytokines, and a GSK-3beta inhibitor. Also provided are methods of producing an isolated T memory stem cell population, the method comprising a) isolating lymphocytes from a mammal; b) sorting the lymphocytes using flow cytometry into a population comprising a phenotype comprising i) CD95+, CD45RO, and CCR7+; and ii) CD62L+ or one or more of CD27+, CD28+, CD45RA+, and CD127+ to produce an isolated T memory stem cell population. Further embodiments of the invention provide related cells, populations of cells, pharmaceutical compositions, and methods of treating or preventing cancer.

The present invention includes methods and compositions for treating cancer, whether a solid tumor or a hematologic malignancy. By expressing a chimeric antigen receptor in a monocyte, macrophage or dendritic cell, the modified cell is recruited to the tumor microenvironment where it acts as a potent immune effector by infiltrating the tumor and killing the target cells. One aspect includes a modified cell and pharmaceutical compositions comprising the modified cell for adoptive cell therapy and treating a disease or condition associated with immunosuppression.

Provided is an anti-mesothelin chimeric antigen receptor that has increased affinity for mesothelin and binds specifically to mesothelin. An anti-mesothelin chimeric antigen receptor according to one aspect has increased affinity for mesothelin and exhibits a specific binding ability to mesothelin, and accordingly, can be useful for the prevention or treatment of cancer in which mesothelin is overexpressed.