Disclosed are compositions and methods for targeted treatment of infections and cancers expressing cancers. In particular, tumor infiltrating lymphocytes (TILs) are genetically engineered to express chimeric antigen receptor (CAR) polypeptides to produce CAR-TILs that can be used with adoptive cell transfer to target, penetrate, and kill solid tumor masses. Therefore, also disclosed are methods of providing an immunotherapy in a subject with an infection or cancer that involves adoptive transfer of the disclosed CAR-TILs.

The present disclosure generally relates to, inter alia, a class of chimeric switch receptors containing an endodomain of an IL-9 receptor, engineered to modulate transcriptional regulation in a ligand-dependent manner. The disclosure also provides compositions and methods useful for producing such receptors, nucleic acids encoding same, host cells genetically modified with the nucleic acids, as well as methods for modulating gene expression, modulating an activity of a cell, and/or for the treatment of various health conditions or diseases.

The present invention provides a chimeric receptor comprising: a first polypeptide which has (i) a first extracellular region binding to a ligand, (ii) a first transmembrane region, and (iii) a first intracellular region derived from an IL-2 receptor chain, and in which a mutation is introduced to a tyrosine residue in the first intracellular region; and a second polypeptide which has (iv) a second extracellular region binding to a ligand, (v) a second transmembrane region, and (vi) a second intracellular region derived from an IL-2 receptor chain.

The application provides bispecific chimeric antigen receptors (CARs) targeting glucose-regulated-protein 78 (GRP78) and Cluster of Differentiation 123 (CD123) or GRP78 and B7-homolog 3 (B7H3). The application further provides polynucleotides and recombinant vectors encoding the CARs, as well isolated host cells and methods for preparing isolated host cells that express the CARs. The application further provides pharmaceutical compositions comprising the CAR modified cells and methods for treating a tumor using the CAR modified cells.

The present disclosure relates to methods for treating or preventing a leukemia or a myelodysplastic syndrome in a subject in need thereof, said method comprising administering to the subject an effective amount of a combination comprising: (i) a binding protein comprising a first antigen binding domain (ABD) with binding specificity to CD123 and a second (ABD) with binding specificity to NKp46; and one or both of: (ii) a BCL-2 inhibitor, and (iii) a DNA hypomethylating agent.

The invention provides compositions and methods for treating diseases associated with expression of CD33. The invention also relates to chimeric antigen receptor (CAR) specific to CD33, vectors encoding the same, and recombinant T cells comprising the CD33 CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a CD33 binding domain.

The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.

A truncated EGFR (tEGFR) cell surface molecule and its uses is provided herein. The tEGFR cell surface molecule includes an EGFR domain IV and does not include an EGFR domain III and may be used, inter alia, as an in vivo tracking marker for genetically modified human T cells. Furthermore, the tEGFR cell surface molecule has cellular depletion potential through mediated through specific anti-domain IV EGFR antibodies. Thus, the tEGFR cell surface molecules provided herein may, inter alia, be used as a non-immunogenic selection tool, tracking marker, a depletion tool or a suicide gene for genetically modified cells having therapeutic potential.

Dual-chimeric antigen receptor (CAR) cell systems are disclosed that can be used with adoptive cell transfer to target and kill cancers expressing tumor antigens (TA) that are also expressed on healthy hematopoietic cells. In some embodiments, the dual CAR cell expresses a first CAR polypeptide that contains in an ectodomain a binding agent that can selectively bind CD83 on CD83-expressing cancer cells (anti-CD83 binding agent), and a second CAR polypeptide that contains in an ectodomain an antigen-binding agent that can bind a second tumor antigen that is expressed on both the cancer and healthy hematopoietic cells (anti-TA binding agent), such as CD33, CLEC12A, CD123, or FLT3.

The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.