Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. Also provided are derivative cells having stable and functional genome editing that delivers improved or enhanced therapeutic effects. Further 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.

Composition and methods for ex vivo expansion of natural killer (NK) cells, and methods for cell-based cancer immunotherapy are disclosed. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies, and certain embodiments with addition of PBMCs are used for in vivo administration for cancer treatment. Leukemic cell-derived dendritic cells and anti-PD-L1 antibodies are also used for ex vivo expansion of NK cells.

Provided herein, inter alia, are compositions and methods for reprogramming immune cells for treating or preventing immune disorders. The methods include contacting immune cells with antigens, and administering the resultant immune cells to a subject who has an immune disorder.

The present invention provides a method for treating a disease in a subject, which comprises the step of administering to the subject a plurality of cells which express: (a) a chimeric antigen receptor (CAR); and (b) a mutant version of calcineurin A and/or calcineurin B which is resistant to the calcineurin inhibitor. The subject may be receiving or have received treatment with a calcineurin inhibitor. The CAR-expressing cells may be administered prior to, following, simultaneously with or in combination with a calcineurin inhibitor.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

Provided are methods for isolating T-cells with T cell receptors (TCRs) optimized for reactivity to specific peptides and decreased cross-reactivity to non-target peptides. Advantageously, TCRs of the invention can be optimized to target cancer antigens and peptides while having reducing reactivity to healthy cells. Methods of the invention utilize a novel combination of culturing conditions that increase T-cell activation and allow for validation of TCR activity. Culturing conditions of the invention further reduce culturing times generally needed to achieve expanded reactive T-cells. Because of the robust nature of the activation and validation conditions of the present invention, variants of identified TCRs can also be optimized and validated for their response to peptides, including cancer peptides.

Provided herein are cells engineered to have improved protection against natural killer cell killing. The cells are engineered to comprise an insertion of a polynucleotide encoding SERPINB9. Also provided herein are methods of making the engineered cells and therapeutic uses of the engineered cells. The engineered cells can also comprise at least one genetic modification within or near at least one gene that encodes one or more MHC-I or MHC-II human leukocyte antigens or component or transcriptional regulator of the MHC-I or MHC-II complex, at least one genetic modification that increases the expression of at least one polynucleotide that encodes a tolerogenic factor, and optionally at least one genetic modification that increases or decreases the expression of at least one gene that encodes a survival factor. The engineered cells can be stem cells and the engineered stem cells can be differentiated into various lineages having protection against NK cell killing.

A bi-specific genetically modified immune cell, comprising a first antigen binding moiety that is specific to CD83 and a second antigen binding moiety that is specific to interleukin 6 receptor (IL-6R). Also provided herein are uses of such bi-specific genetically modified immune cells for suppressing alloreactive donor cells in cell transplantation.

Nucleic acid molecules encoding an IL-15 domain and a chimeric antigen receptor (CAR) that targets cells expressing prostate stem cell antigen are provided as well as polypeptides encoded thereby. Vectors and host cells such as immune cells containing the nucleic acid molecules also are disclosed, as well as methods for their use.

The disclosure is directed to methods and compositions relating to genetically engineered cells expressing chimeric antigen receptors, where the cells are mobilized lymphocytes.