The present disclosure provides methods for genetically modifying lymphocytes and methods for performing adoptive cellular therapy that include transducing T cells and/or NK cells. The methods can include inhibitory RNA molecule(s) and/or engineered signaling polypeptides that can include a lymphoproliferative element, and/or a chimeric antigen receptor (CAR), for example a microenvironment restricted biologic CAR (MRB-CAR). Additional elements of such engineered signaling polypeptides are provided herein, such as those that drive proliferation and regulatory elements therefor, as well as replication incompetent recombinant retroviral particles and packaging cell lines and methods of making the same. Numerous elements and methods for regulating transduced and/or genetically modified T cells and/or NK cells are provided, such as, for example, those including riboswitches, MRB-CARs, recognition domains, and/or pH-modulating agents.

The disclosure provides immunogenic cells expressing LMP1, and use thereof in activating T cells and treating cancer. Also provided are methods of producing the immunogenic cells.

Engineered orthogonal cytokine receptor/ligand pairs, and methods of use thereof, are provided.

Embodiments herein provide specially designed synthetic BCL11A-targeting microRNAs for RNA polymerase II expression, and methods of use to treat hemoglobinopathies such as sickle cell disease or thalassemia by increasing the expression levels of fetal hemoglobin levels.

Recombinant AAV (rAAV) vectors comprising a rAVV genome comprising a heterologous nucleic acid encoding a signal peptide and optionally a IGF-2 sequence, fused to an acid alpha-glucosidase (GAA) polypeptide, enabling the GAA polypeptide to be secreted from the liver and targeted to the lysosomes. Particular embodiments relate to a recombinant AAV (rAAV) vector encoding an alpha-glucosidase (GAA) polypeptide, having a liver secretory signal peptide and a targeting IGF2 sequence that binds human cation-independent mannose-6-phosphate receptor (CI-MPR) or to the IGF2 receptor, permitting proper subcellular localization of the GAA polypeptide to lysosomes. Also encompassed are cells, and methods to treat a glycogen storage disease type II (GSD II) disease and/or Pompe Disease with the rAAV vector.

The present invention relates to vectors and their use to develop host cell lines for production of a protein of interest, and in particular to vectors which utilize a weak promoter to drive a selectable marker.

The present disclosure describes the role for miR-322(424)/503 in the differentiation of cardiac precursor cells. Thus, the use of these molecules in the programming of resident stem/progenitor cells into cardiomyocytes, both in vitro and in vivo. Such methods find particular use in the treatment of patients post-myocardial infarction to prevent or limit scarring and to promote myocardial repair.

Disclosed herein are chimeric receptors comprising an extracellular domain with affinity and specific for the Fc portion of an immunoglobulin molecule (Ig), an Fc-binding domain; a transmembrane domain; at least one co-stimulatory signaling domain; and a cytoplasmic signaling domain comprising an immunoreceptor tyrosine-based activation motif (ITAM). Also provided herein are nucleic acids encoding such chimeric receptors and immune cells expressing the chimeric receptors. Such immune cells can be used to enhance antibody-dependent cell-mediated cytotoxicity and/or to enhance antibody-based immunotherapy, such as cancer immunotherapy.

Several embodiments disclosed herein relate to methods and processes for the co-expansion of multiple types of immune cells, in order to generate a mixed cell population. Some embodiments relate to the use of various stimuli specific to the various subpopulations to achieve expansion of those subpopulations at a particular time in a culturing process in order to generate an expanded population of immune cells having a desired ratio of the various subpopulations. In several embodiments, such mixed cell populations exhibit desirable characteristics, such as cytotoxic effects against tumor cells that enhance the efficacy of cancer immunotherapy.

The present disclosure relates to the field of cell therapy, and more specifically, to improving CAR and/or TCR function through improvement of the tumor microenvironment via improvement in cytokine signaling.