Disclosed are compositions and methods for targeted treatment of myeloid and B cell malignancies. In particular, chimeric antigen receptor (CAR) T cells are disclosed that can be used with adoptive cell transfer to target and kill myeloid and B cell malignancies with reduced antigen escape. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a myeloid and B cell malignancies that involves adoptive transfer of the disclosed CAR T cells.

Chimeric antigen receptors (CAR) that bind Preferentially Expressed Antigen in Melanoma (PRAME) ALY(SEQ ID NO: 94)/HLA-A2 are disclosed. The CAR can be used to treat PRAME/HLA-A2 expressing cancers such as the t(8;21), Inv(16), and KMT2A-r forms of acute myeloid leukemia (AML).

Provided herein are methods of treatment including methods of treating cancer and methods of enhancing an anti-tumoral activity of a bispecific T-cell engager (BiTE) or of a bispecific antibody. The methods disclosed herein include activating T-cells and contacting activated T-cells with BiTEs or bispecific antibodies for administration to a subject.

Compounds that either produced a higher proportion or greater absolute number of phenotypically identified naive, stem cell memory, central memory T cells, adaptive NK cells, and type I NKT cells are identified. Compositions and methods for modulating immune cells including T, NK, and NKT cells for adoptive cell therapies with improved efficacy are provided.

The presently disclosed subject matter provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to novel designs of chimeric antigen receptors (CARs) and engineered immunoresponsive cells comprising the same. The engineered immunoresponsive cells comprising the novel CARs are antigen-directed and have extended persistence without compromising function.

The invention provides methods of increasing the efficacy of a T cell therapy in a patient in need thereof. The invention includes methods of identifying a patient who would respond well to a T cell therapy or conditioning a patient prior to a T cell therapy so that the patient responds well to a T cell therapy. The conditioning involves administering one or more preconditioning agents prior to a T cell therapy and identifying biomarker cytokines prior to administering a T cell therapy.

Provided is a chimeric antigen receptor, comprising an antigen binding region, a transmembrane domain and an intracellular signaling region. The antigen binding region comprises an antibody specifically targeting CD7, and the intracellular signaling region consists of a co-stimulatory domain, a primary signal transduction domain, and a ?C chain or intracellular region thereof. Also provided are an engineered immune cell comprising the chimeric antigen receptor and a pharmaceutical composition thereof, and use of the engineered immune cell/pharmaceutical composition for treating cancers.

The present invention includes compositions and methods for treating AML utilizing bispecific CARs. In certain aspects, the invention includes a bispecific split CAR which binds CD13 and TIM-3 on AML cells. In one aspect, the invention provides a bispecific chimeric antigen receptor (CAR) comprising a first antigen binding domain capable of binding CD13, a first intracellular domain, a second antigen binding domain capable of binding TIM-3, a transmembrane domain, and a second intracellular domain.

This invention relates to methods and compositions comprising antibodies or fragments thereof comprising a targeting ligand and engineered cytotoxic cells comprising a targeting agent specific for the targeting ligand, for use in inducing cytotoxicity in a cancer cell, in delivering a cytotoxic cell to a cancer cell in a subject, and in treating cancer.

The present invention encompasses genetically-modified immune cells (and populations thereof) expressing a microRNA-adapted shRNA (shRNAmiR) that reduces the expression of a target endogenous protein. Methods for reducing the expression of an endogenous protein in an immune cell are also provided wherein the method comprises introducing a shRNAmiR that targets the endogenous protein. Using shRNAmiRs for knocking down the expression of a target protein allows for stable knockdown of expression of endogenous proteins in immune cells.