The present invention relates to a cell which co-expresses: (i) a first chimeric antigen receptor (CAR) at the cell surface, comprising an antigen-binding domain which binds to CD19; (ii) a second CAR at the cell surface, comprising an antigen-binding domain which binds to CD22; (iii) dominant negative SHP2 (dSHP2); and (iv) dominant negative TGF receptor II (dnTGFRII).

Disclosed are receptor cytokine switches, immune cells containing them, and uses thereof for controllable adoptive cell therapy.

Disclosed herein are recombinant polypeptides and recombinant nucleic acids encoding the same. According to some embodiments of the present disclosure, the recombinant polypeptide comprises a first bi-functional domain, and a first single-chain fragment variable (scFv) or a peptide linked to the N-terminus of the first bi-functional domain. Optionally, the recombinant polypeptide further comprises a second scFv linked to the N-terminus of the first scFv or peptide. Also disclosed herein are methods of treating cancers by using the immune cells expressing the recombinant polypeptides.

The current disclosure provides polypeptide constructs and cells comprising CDR3 regions of 9. 2 or both, that selectively bind a J-configuration of CD277 on a target cell. The disclosure also provides pharmaceutical compositions with the disclosed polypeptides or cells and methods of using these compositions in the treatment of cancer.

The presently disclosed subject matter provides cells comprising a Fas ligand (FasL) polypeptide and a cFLIP polypeptide. In certain embodiments, the cells further comprise an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR), or a TCR like fusion molecule). Also provided are uses of the cells for cell lysis of target cells expressing Fas, and for treating diseases or disorders, e.g., tumors.

Multiple myeloma (MM) is an incurable hematological cancer, in which immune checkpoint inhibition (ICI) with monoclonal antibodies (mAbs) has failed due to uncontrollable immune responses in combination therapies and lack of efficacy in monotherapies. NK cells have effector activity within the TME, under continuous ligand exposure. NK cell dysfunctionality may occur due to interaction of PD1 and its ligand PD-L1. We created NK cell specific PD1-based chimeric switch receptors (PD1-CSR) by employing signaling domains of DAP10, DAP12 and CD3 to revert NK cell inhibition and retarget ICI. PD1-CSR modified NK cells showed increased degranulation, cytokine secretion and cytotoxicity upon recognition of PDL1+ target cells.

A method of manipulating allogeneic cells for use in allogeneic cell therapy providing a composition of highly activated allogeneic T-cells which are infused into immunocompetent cancer patients to elicit a novel anti-tumor immune mechanism, or Mirror Effect. In contrast to current allogeneic cell therapy protocols where T-cells in the graft mediate the beneficial graft vs. tumor (GVT) and detrimental graft vs. host (GVH) effects, the allogeneic cells of the present invention stimulate host T-cells to mediate the mirror of these effects. The mirror of the GVT effect is the host vs. tumor (HVT) effect. The mirror of the GVH effect is the host vs. graft (HVG) effect The anti-tumor HVT effect occurs in conjunction with a non-toxic HVG rejection effect. The highly activated allogeneic cells of the invention can be used to stimulate host immunity in a complete HLA mis-matched setting in a patient.

GPC3 T cell antigen coupler (TAC) polypeptides having (i) an antigen-binding domain that binds GPC3, (ii) an antigen-binding domain that binds a protein associated with a TCR complex, and (iii) a T cell receptor signaling domain polypeptide are provided.

Provided are engineered cells for adoptive therapy, including NK cells and T cells. Also provided are compositions for engineering and producing the cells, compositions containing the cells, and methods for their administration to subjects. In some aspects, features of the cells and methods provide specificity and/or efficacy. In some embodiments, the cells contain genetically engineered antigen receptors that specifically bind to antigens, such as chimeric antigen receptors (CARs) and costimulatory receptors. In some embodiments, the cells include receptors targeting multiple antigens. In some embodiments, the cells include repression of one or more gene product, for example, by disruption of a gene encoding the gene product. In some embodiments, a gene encoding an antigen recognized by the engineered antigen receptor is disrupted, reducing the likelihood of targeting of the engineered cells.

Methods are disclosed for producing defective ribosomal products (DRiPs) in blebs (DRibbles) by contacting cells with a proteasome inhibitor, and in some examples also an autophagy inducer, thereby producing treated cells. DRibbles can be used to load antigen presenting cells (APCs), thereby allowing the APCs to present the DRiPs and antigenic fragments thereof. Immunogenic compositions that include treated cells, isolated DRibbles, or DRibble-loaded APCs are also disclosed. Methods are also provided for using treated cells, isolated DRibbles, or DRibble-loaded APCs to stimulate an immune response, for example in a subject. For example, DRibbles obtained from a tumor cell can be used to stimulate an immune response against the same type of tumor cells in the subject. In another example, DRibbles obtained from a pathogen-infected cell or cell engineered to express one or more antigens of a pathogen can be used to stimulate an immune response against the pathogen in the subject.