Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are genetically edited, for example, using Crispr/Cas, to modulate, reduce or otherwise eliminate expression of one or more endogenous genes. In several embodiments, the edited cells are engineered to express a chimeric antigen receptor targeting a tumor antigen, for example CD19, ligands of the NKG2D receptor, CD70, and/or BCMA, among others. In several embodiments, the editing enhances one or more aspects of the efficacy of the immune cells in cellular immunotherapy including cytotoxicity (e.g., ADCC) and/or persistence.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors as well as genetically edited or otherwise engineered enhance the persistence the cells in immunotherapy. In several embodiments, the cells are edited to knock out a target gene that encodes a protein involved in antigen processing and presentation by major histocompatibility complex class I molecules. In several embodiments, a mixture of immune cell types is used, optionally in allogeneic therapy. The engineering and editing of the cells, such as NK cells and/or T cells exhibit enhanced cytotoxicity and/or persistence, as well as reduced risk of reduced graft versus host, host versus graft, and graft versus graft effects.

Abstract: Several embodiments disclosed herein relate to methods and compositions for enhanced expansion of NK cells in culture, through the repeated co-culturing of NK cells with feeder cells and the selective use of stimulatory interleukins. In several embodiments, the methods utilize one or more soluble interleukins as culture media supplements at one or more time points during expansion of the NK cell, or other immune cell, which results in a highly expanded and highly cytotoxic population of cells, for use in, for example allogeneic cellular immunotherapy.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors (CAR) and/or genetically modified to reduce potential side effects of cellular immunotherapy. Several embodiments relate to genetic modifications to the immune cells, such as Natural Killer (NK) cells, to reduce, substantially, reduce, or eliminate expression of a marker by the immune cells that would otherwise cause them to be self-targeted by the CAR. In several embodiments, the CAR targets CD70, and in some embodiments is used for renal cell carcinoma immunotherapy.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to Mexpress chimeric antigen receptors as well as genetically edited or otherwise engineered to alter the effectiveness with which another immune cell can target and induce cytotoxic effects on the engineered cells. In several embodiments, the methods and compositions disclosed herein reduce fratricide within a therapeutic cell population, which in some instances comprises mixture of immune cell types. Additionally, the methods and compositions disclosed herein enhance one or more aspects of the efficacy of the immune cells in cellular immunotherapy including cytotoxicity and/or persistence, as well as reduced graft versus host or host versus graft effects.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors (CAR) and/or genetically modified to reduce potential side effects of cellular immunotherapy. Several embodiments relate to genetic modifications to the immune cells, such as Natural Killer (NK) cells, to reduce, substantially, reduce, or eliminate expression of a marker by the immune cells that would otherwise cause them to be self-targeted by the CAR. In several embodiments, the CAR targets CD70, and in some embodiments is used for renal cell carcinoma immunotherapy.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors (CAR) and/or genetically modified to reduce potential side effects of cellular immunotherapy. Several embodiments relate to genetic modifications to the immune cells, such as Natural Killer (NK) cells, to reduce, substantially, reduce, or eliminate expression of a combination of genes and their corresponding proteins. In several embodiments, one edit is to reduce expression of a marker by the immune cells that would otherwise cause them to be self-targeted by the CAR and at least two additional gene edits to enhance the cytotoxicity and/or persistence of the resulting cells. In several embodiments, the CAR targets CD70, and in some embodiments is used for renal cell carcinoma immunotherapy.

Abstract: Several embodiments disclosed herein relate to methods and compositions for enhanced expansion of NK cells in culture. In several embodiments, the methods utilize one or more soluble interleukins as culture media supplements at one or more time points during expansion of the NK cell, or other immune cell, the expansion employing a feeder cell population.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors and/or genetically modified to enhance one or more aspects of the efficacy of the immune cells in cellular immunotherapy. Several embodiments relate to genetic modifications which reduce potential side effects of cellular immunotherapy. In several embodiments, combinations of cells are used to achieve both rapid and long-term tumor reduction with reduced or eliminated potential for graft versus host effects.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Several embodiments of the methods and compositions disclosed herein relate to immune cells that are engineered to express chimeric antigen receptors (CAR) and/or genetically modified to reduce potential side effects of cellular immunotherapy. Several embodiments relate to genetic modifications to the immune cells, such as Natural Killer (NK) cells, to reduce, substantially, reduce, or eliminate expression of a marker by the immune cells that would otherwise cause them to be self-targeted by the CAR. In several embodiments, the CAR targets CD70, and in some embodiments is used for renal cell carcinoma immunotherapy.

Abstract: Several embodiments provided for relate to methods of using of anti-CD19 CAR expressing immune cells in immunotherapy. Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence. Several embodiments include methods of using of the anti-CD19 CAR expressing immune cells in immunotherapy.

Abstract: Several embodiments provided for relate to methods of using of anti-CD19 CAR expressing immune cells in immunotherapy. Provided for herein in several embodiments are immune cell-based (e.g., natural killer (NK) cell) compositions comprising CD19-directed chimeric antigen receptors. In some, embodiments the anti-CD19 binder portion of the CAR is humanized. In several embodiments, the humanized anti-CD19 CAR expressing cells exhibit enhanced expression of the CAR as well as enhanced cytotoxicity and/or persistence.

Abstract: A system for controllably generating jitter in a serial data stream includes a frequency generator and first and second mixers. The frequency generator is configured to output in-phase and quadrature local oscillator signals with a local oscillator frequency of at least about 5 MHz. The local oscillator frequency varies between a selectable minimum frequency and a selectable maximum frequency. The first mixer is configured to mix a fixed frequency clock signal with the in-phase local oscillator signal to output a first mixer output. The second mixer is configured to mix the fixed frequency clock signal with the quadrature local oscillator signal to output a second mixer output. An adder is configured to add the first and second mixer outputs to produce a frequency-modulated clock signal with a frequency that is about the sum of the fixed frequency and the local oscillator frequency and includes a periodic jitter.