Abstract: Disclosed are compositions and methods for targeted treatment of CD123-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CD123-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CD123-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Abstract: Disclosed are off-the-shelf immune effector cells that are engineered to express anti-CD3 antibodies disclosed herein that are configured to autoactivate the immune effector cells, thereby decreasing expression of T cell receptors (e.g. TCR??) that could result in GVHD. Also disclosed are methods for modifying donor immune effector cells to make them suitable for off-the-shelf treatment of allogeneic subjects. These methods involve engineering the cells to express an anti-CD3 antibody configured to activate the cells. In some embodiments, the antibody is a bi-specific antibody that binds the CD3 complex on the immune effector cells. In other embodiments, the antibody is a membrane bound anti-CD3 antibody that autoactivates the immune effector cell.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer having endodomains with a customized number of immunoreceptor tyrosine-based activation motifs (ITAMs). In some embodiments, the endodomain has a backbone of a receptor endodomain, such as CD8, CD3?, CD3?, CD3?, CD3?, CD32 (Fc gamma RIIa), DAP10, DAP12, CD79a, CD79b, Fc?RI?, Fc?RIII?, Fc?RI? (FCERIB), and Fc?RI? (FCERIG). In particular embodiments disclosed herein, the backbone is a DAP12 backbone. The disclosed endodomain is engineered to express at least one heterologous ITAM, including 1, 2, 3, 4, 5, or 6 ITAMs.

Abstract: Disclosed are compositions and methods for targeted treatment of CLEC12A-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CLEC12A-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CLEC12A-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CLEC12A-expressing malignant cells.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides, which can be used with adoptive cell transfer to target and kill cancers, that comprise a co-stimulatory signaling region having a mutated form of a cytoplasmic domain of CD28 that enhances CAR-T cell function, a mutated form of a cytoplasmic domain of 41BB that enhances nuclear factor kappaB (NF?B) signaling, or a combination thereof. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Also disclosed are immune effector cells co-expressing a CAR and one or more TRAF proteins. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a tumor associated antigen-expressing cancer that involves adoptive transfer of the disclosed immune effector cells.

Abstract: Disclosed herein are compositions and methods for targeted treatment of cancers co-expressing CD99 and CLEC12A. In particular, disclosed herein are immune effector cells genetically modified to express at least two chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target cancers co-expressing CD99 and CLEC12A.

Abstract: Bi-specific CAR-T cells are disclosed for treating NSCLCs. The disclosed CAR-T cells contain CAR polypeptides that can bind EGFR/MUC1-expressing cells. Therefore, also disclosed is an immune effector cell genetically modified to express an anti-EGFR CAR binding agent and an anti-MUC1 binding agent. Also disclosed are methods of providing an anti-tumor immunity in a subject with a EGFR and MUC1-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Abstract: Disclosed are compositions and methods for targeted treatment of CD33-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CD33-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CD33-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CD33-expressing malignant cells.

Abstract: Regulatory T cells (Treg cells), formerly known as suppressor T cells, are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ Treg cells have been described—naturally occurring Treg cells and adaptive Treg cells. Disclosed herein are methods for producing efficacious CAR Treg cells in a GMP-scalable system.

Abstract: Relapse in adoptive cell transfer of CAR-T cells is often the result of CAR-T cells disappearance. Disclosed herein a method for enhancing CAR-T cell therapy in a subject, comprising administering to a subject undergoing adoptive cell transfer of therapeutic CAR-T cells an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells. As a consequence, a subject treated with a combination of CAR-T cells and an Akt inhibitor is less likely to relapse. Therefore, also disclosed herein is a method for treating a subject, comprising adoptively transferring to the subject an effective amount of a composition comprising a CAR-T cell, and administering to the subject an Akt inhibitor in an amount effective to increase the persistence of the CAR-T cells.

Abstract: Disclosed are compositions and methods for targeted treatment of CD123-expressing cancers. In particular, recombinant antibodies are disclosed that are able to engage T-cells to destroy CD123-expressing malignant cells.

Abstract: Disclosed are compositions and methods for targeted treatment of CD33-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CD33-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CD33-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CD33-expressing malignant cells.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill TIM3-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TIM3-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

Abstract: Disclosed herein are chimeric antigen receptor (CAR) polypeptides, which can be used with adoptive cell transfer to target and kill cancers, that comprise a co-stimulatory signaling region having a mutated form of a cytoplasmic domain of CD28 that enhances CAR-T cell function, a mutated form of a cytoplasmic domain of 41BB that enhances nuclear factor kappaB (NF?B) signaling, or a combination thereof. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Also disclosed are immune effector cells co-expressing a CAR and one or more TRAF proteins. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a tumor associated antigen-expressing cancer that involves adoptive transfer of the disclosed immune effector cells.

Abstract: Disclosed herein are therapeutic B lymphocytes engineered to express bispecific antibodies that are able to engage T-cells to destroy tumor cells. The B lymphocytes can be autologous, allogeneic, or syngeneic. Also disclosed is a pharmaceutical composition comprising a therapeutic B lymphocyte disclosed herein in a pharmaceutically acceptable carrier. Also disclosed herein is a method for treating cancer in a subject, comprising administering to the subject an effective amount of activated B lymphocytes engineered to express bispecific antibodies that are able to engage T-cells to destroy tumor cells.

Abstract: Disclosed herein are recombinant immune effector cells genetically modified to regulate expression of one or more transcription factors selected from T-bet, Eomes, and c-Myb. In some embodiments, the cells are modified to express recombinant T-bet, Eomes, c-Myb, or any combination thereof. In some embodiments, the cells are modified to express recombinant dominant negative forms of T-bet, Eomes, c-Myb, or any combination thereof to inhibit the activity of endogenous transcription factors. In some embodiments combinations of these approaches are used to increase expression of one or more of T-bet, Eomes, c-Myb while inhibiting the activity of one or more of T-bet, Eomes, and c-Myb.

Abstract: 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.

Abstract: Disclosed are compositions and methods for targeted treatment of CD99-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CD99-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CD99-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CD99-expressing malignant cells.

Abstract: Disclosed are compositions and methods for targeted treatment of CLEC12A-expressing cancers. In particular, chimeric antigen receptor (CAR) polypeptides are disclosed that can be used with adoptive cell transfer to target and kill CLEC12A-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a CLEC12A-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs. Also disclosed are multivalent antibodies are disclosed that are able to engage T-cells to destroy CLEC12A-expressing malignant cells.

Abstract: Disclosed are compositions and methods for detecting the cytokines upregulated in cytokine release syndrome and neurotoxicities associated with CAR-T cell toxicity and methods of targeted treatment of cytokines associated with the same.