A composition and a method for generating clinically safe NK cells derived from non-fully differentiated stem cells are provided. The non-fully differentiated stem cells are co-cultured with endogenous NK cells isolated from adipocyte-containing tissue to generate a high percentage of clinically safe NK cells, where anti-tumor activity of the clinically safe NK cells in vitro is similar to that of endogenous NK cells. Optimized Production of the clinically safe autologous NK cells from stem cells provides platform for treating cancer patients by applying an effective adoptive immunotherapy ranging from the early to terminal stages.

The preset disclosure provides chimeric activation receptors comprising (i) a TGFβ-binding domain and (ii) a CD2 costimulatory domain. In some aspects, the TGFβ-binding domain comprises an extracellular domain of a TGFβ receptor. Other aspects of the disclosure are directed to nucleic acid molecules encoding a chimeric activation receptor, cells comprising the chimeric activation receptor and/or a nucleic acid molecule encoding the same, and methods of use thereof in the treatment of a disease or condition (e.g., a tumor) in a subject in need thereof.

An immunotherapy delivery system includes a hydrogel with an immunomodulatory cargo including cells encapsulated in the hydrogel, a cell adhesion motif in the hydrogel configured to reversibly adhere to and release the cells, and an immunomodulatory cargo encapsulated in the hydrogel. The hydrogel includes a polymer non-covalently crossed-linked with a plurality of nanoparticles.

An example genetically engineered natural killer (NK) cell comprises an exogenous polynucleotide sequence that includes a receptor element, an actuator element, and an effector element. The receptor element encodes a chimeric antigen receptor (CAR) comprising an extracellular antigen binding domain operably linked to a transmembrane domain, and an intracellular signaling domain, wherein the extracellular antigen binding domain recognizes a surface antigen of a target cell. The actuator element encodes a transcription factor binding site that upregulates synthesis of an effector protein. The effector element encodes the effector protein operably linked to a signal peptide, wherein, in response to the antigen binding domain of the CAR binding to the antigen of the target cell, the engineered NK cell is configured to activate and, to synthesize and secrete the effector protein.

A recombinant natural killer (NK) cell or T-cell composition is transfected with a nucleic acid encoding i) a homing receptor; ii) an antigen binding protein (ABP) or a chimeric antigen receptor (CAR) that specifically binds a target antigen; iii) an Fc Receptor; and/or iv) a secreted immune modulator selected from a TGFβ inhibitor and/or IL-12, where the recombinant cell is gamma (γ)-irradiated conferring inhibition of cell proliferation with transient activity of the transfected molecules including the secreted immune modulators for up to 72 hours.

Provided is a method of transducing and expanding a population of cells, the method comprising, in order: a cell selection step; a pre-transduction activation step; a cell transduction step; and a cell expansion phase. At least the cell transduction step and the expansion phase comprise incubation of the cells with IL-15. The methods of the invention are well suited to the transduction and expansion of populations of cells expressing chimeric antigen receptors (CARs), and in particular for the transduction and expansion of populations of invariant natural killer T (iNKT) cells expressing CARs. Also provided are populations of cells produced by the methods of the invention, and pharmaceutical compositions comprising populations of cells, as well medical uses of the pharmaceutical compositions and populations of cells. The cells and pharmaceutical composition are suitable for application in medical use and methods of treatment, including immunotherapy.

Provided are methods and compositions for obtaining functionally enhanced derivative effector cells obtained from directed differentiation of genomically engineered iPSCs. The iPSC-derived effector 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.

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.

Disclosed are invariant natural killer T (iNKT) cells engineered using hematopoietic stem and progenitor cells (HSPCs) and methods of making and using thereof. Specifically, the engineered cells iNKT are genetically modified to contain at least one exogenous invariant natural killer T cell receptor (iNKT TCR) nucleic acid molecule. Further disclosed are iNKT TCR nucleotide sequences and codon optimized sequences for expression.

Provided herein are methods and customized media compositions for culturing CIK NKT cells.