Embodiments of the disclosure concern methods and compositions related to preparation and use of combinatorial immunotherapies. In specific embodiments, compositions comprising engineered NK cells prepared in a particular manner also include certain antibodies. These compositions are utilized for treatment, such as for cancer treatment. In particular embodiments, the compositions include complexes of the engineered NK cells and the antibodies in which the antibody is bound to the engineered NK cells and may also bind to another antigen, such as on a cancer cell.

Embodiments of the disclosure concern methods and compositions related to preparation and use of combinatorial immunotherapies. In specific embodiments, compositions comprising engineered NK cells prepared in a particular manner also include certain antibodies. These compositions are utilized for treatment, such as for cancer treatment. In particular embodiments, the compositions include complexes of the engineered NK cells and the antibodies in which the antibody is bound to the engineered NK cells and may also bind to another antigen, such as on a cancer cell.

In one embodiment, the present disclosure provides an engineered cell having a first chimeric antigen receptor polypeptide including a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain; and a second chimeric antigen receptor polypeptide including a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain; wherein the first antigen recognition domain is different than the second antigen recognition domain.

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. In various embodiments, the derivative cells provided herein have stable and functional genome editing that delivers improved or enhanced therapeutic effects. Also provided are therapeutic compositions and the use thereof comprising the functionally enhanced derivative effector cells alone, or with antibodies or checkpoint inhibitors in combination therapies.

Compositions and combination cellular therapies with natural killer (NK) cells and macrophages for treating disease such a leukemia are disclosed herein. The compositions and therapeutic methods of administration may optionally include antibodies, such as anti-CD47 or other SIRP signaling inhibitors. The NK and macrophage cells may be produced from stem cells, and may optionally be produced from induced pluripotent stem cells (iPSCs), where the NK and macrophage cells may have enhanced antibody-dependent cellular cytotoxicity (ADCC). These immune cells may also be incorporated into pharmaceutical compositions. Methods for making the immune cells and pharmaceutical compositions, and methods of use thereof, are also provided.

Aspects of the present disclosure are directed to INCENP-targeting polypeptides, including antibodies, antibody-drug conjugates, antibody fragments, antibody-like molecules, and chimeric receptors. Also disclosed herein are nucleic acids encoding for such INCENP-targeting polypeptides and cells comprising such nucleic acids. Described are methods for detection, diagnosis, and treatment of cancer using INCENP-targeting polypeptides.

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

Embodiments of the disclosure encompass particular chimeric antigen receptor constructs that comprise optionally a hinge, one of the CD28 transmembrane domain or the DAP10 transmembrane domain, DAP10 costimulatory domain, and CD3zeta. In particular embodiments, the chimeric antigen receptor is expressed by natural killer (NK) cells, and in some cases the NK cells are further modified, such as to express one or more cytokines and optionally a suicide gene.

Disclosed herein are modified NK cells, compositions comprising modified NK cells, and methods for treating a tumor or hyperproliferative disease in a subject. In some embodiments, the modified NK cells include NK cells including a heterologous nucleic acid molecule encoding a CD16 protein comprising a valine at amino acid position 158 (CD16-V158), a heterologous nucleic acid molecule encoding a CCR7 protein, or both. In some embodiments, methods include treating a subject with a tumor by administering a composition comprising an anti-cancer monoclonal antibody and administering a composition comprising the modified NK cells to the subject. Also disclosed are methods of making modified NK cells by obtaining a population of NK cells from a subject and transfecting the population of NK cells with a heterologous nucleic acid molecule encoding CD16-V158, a heterologous nucleic acid molecule encoding a CCR7 protein, or both.

Methods and compositions are provided herein for generating tumor targeted lymphocytes and/or tumor infiltrating lymphocytes and/or tumor targeted natural killer (NK) cells for use in the treatment of a cancer or an infectious disease. Also provided herein are methods of making and using the same.