Abstract: Recombinant proteins that stimulate an immune response in the presence of naturally inhibitory ligand binding are described. The recombinant proteins include an extracellular domain of an inhibitory immune cell protein and an intracellular domain of a stimulatory immune cell protein connected via a transmembrane domain. The recombinant proteins can be used to stimulate immune cell activation in the fight against cancers and infectious diseases, among other uses.

Abstract: Activity-inducible fusion proteins including a transcription factor and a heat-shock protein 90 (hsp90) binding domain are described. The activity of the transcription factor is regulated utilizing a drug molecule that binds the hsp90 binding domain. In the absence of the drug molecule, the transcription factor is in an inactive state but can be activated in the presence of the drug molecule. The activity-inducible transcription factors can be used to alter the activation state of immune cells, and optionally can be co-expressed with a chimeric antigen receptor (CAR).

Abstract: Various implementations described herein relate to oligonucleotides that specifically bind ?4?1. According to some implementations, oligonucleotides are conjugated to a support, a tag, a linker, or a drug. Compositions described herein can be used for diagnosis or treatment of various diseases, such as T cell-mediated autoimmune diseases. An example method includes exposing a solution of cells to the oligonucleotides and isolating cells that express ?4?1 from the solution of cells, wherein the cells that express ?4?1 are bound to the oligonucleotides. Example methods and compositions described herein can be used for cell selection, diagnostic, therapeutic, or research purposes.

Abstract: The invention is directed to a bispecific chimeric antigen receptor, comprising: (a) at least two antigen-specific targeting regions; (b) an extracellular spacer domain; (c) a transmembrane domain; (d) at least one co-stimulatory domain; and (e) an intracellular signaling domain, wherein each antigen-specific targeting region comprises an antigen-specific single chain Fv (scFv) fragment, and binds a different antigen, and wherein the bispecific chimeric antigen receptor is co-expressed with a therapeutic control. The invention also provides methods and uses of the bispecific chimeric antigen receptors.

Abstract: T cell manufacturing methods that co-culture T cells with autologous cell types to stimulate the T cells during manufacture are described. The T cells express a recombinant receptor. A binding domain expressed by the T cells binds an epitope on stimulating autologous cell types and/or an immune cell activating multi-specific binding molecule (e.g., a bi-specific antibody) during the co-culture. The methods can also allow for the expression of large transgenes by utilizing electroporation and transposons to deliver transgenes encoding the recombinant receptor. The disclosed methods create manufactured T cell populations with a high number of cells in comparison to starting cell numbers, a high percentage of recombinant receptor-expressing T cells within the cell number, and a beneficial naïve T cell marker profile.

Abstract: Methods, compositions, and systems for treating subject(s) in need of plasma Factor VIII, particularly a subject having preexisting anti-FVIII inhibitory antibodies, are provided. The methods involve administering to the subject a therapeutically effective amount of an inflammation suppressor, a therapeutically effective amount of a CD8+ T cell depleting agent, and a therapeutically effective amount of a composition comprising a lentiviral vector (LV) comprising an optimized FVIII expression cassette expressibly linked to a megakaryocyte-specific promoter. Such methods, compositions, and systems are useful to treat subjects with blood clotting disorder(s), such as hemophilia A.

Abstract: Some embodiments of the methods and compositions provided herein include methods and/or systems for increasing an activity of a cell comprising a chimeric antigen receptor (CAR), comprising use of a first nucleic acid encoding a transcription response element (TRE); and a second nucleic acid encoding a CAR, wherein the activity of the cell is increased compared to a cell lacking the first nucleic acid. In some embodiments, the increased activity of the cell is selected from: (i) survival of a subject administered the cell, wherein the subject comprises a target cell comprising an antigen, wherein the CAR is capable of specifically binding to the antigen; (ii) killing of a target cell comprising an antigen, wherein the CAR is capable of specifically binding to the antigen; and (iii) proliferation of the cell in the presence of a target cell comprising an antigen, wherein the CAR is capable of specifically binding to the antigen.

Abstract: Gene-editing to allow for expression of functional factor VIII for the treatment of hemophilia A is described. The disclosure further provides nanoparticles to deliver gene-editing components to liver sinusoidal endothelial cells (LSEC) to correct mutant factor VIII genes.

Abstract: Early detection of lysosomal storage diseases (LSDs) including Mucopolysaccharidosis Type I (MPS I) and Pompe Disease can greatly improve patient outcome as each disease can be fatal once symptoms emerge. Screening for MPS I and Pompe Disease using biological samples including dried blood spots (DBS), buccal swab, peripheral blood mononuclear cells (PBMCs), or white blood cells (WBCs) is described. The disclosed methods and assays provide a robust way to screen newborns for LSDs. The disclosed methods and assays can also allow rapid prediction of whether a patient with LSD will develop an immune response to enzyme replacement therapy (ERT), thus improving treatment for patients with LSDs. The disclosed methods and assays can also further reduce the number of false positives caused by pseudo deficiency cases of LSD, such as MPS I and Pompe Disease.

Abstract: Activity-inducible fusion proteins whose activity is post-translationally regulated utilizing a hsp90 binding domain and a drug molecule are described. In the absence of the drug molecule, the activity-inducible fusion proteins are inactivated but can be activated by a relevant physiological parameter in the presence of the drug molecule. Examples of the activity-inducible fusion proteins include chimeric antigen receptors (CAR) wherein the relevant physiological parameter is antigen binding.

Abstract: Activity-inducible fusion proteins whose activity is post-translationally regulated utilizing a hsp90 binding domain and a drug molecule are described. In the absence of the drug molecule, the activity-inducible fusion proteins are inactivated but can be activated by a relevant physiological parameter in the presence of the drug molecule. Examples of the activity-inducible fusion proteins include chimeric antigen receptors (CAR) wherein the relevant physiological parameter is antigen binding.

Abstract: The present disclosure provides improved compositions for the homology directed repair of the human globin locus for the prevention, treatment, or amelioration of at least one symptom of a hemoglobinopathy.

Abstract: Aspects of the invention described herein relate to methods of making and using inducible promoters for transgene expression. The inducible promoters are derived from the NFAT-RE inducible system and are used to improve or enhance T cell survival and proliferation.

Abstract: In Hybrid and truncated immune cell proteins are described. Hybrid proteins are stimulatory and include an extracellular domain of one stimulatory immune cell protein, an intracellular domain of a different stimulatory immune cell protein, and a transmembrane domain linking the extracellular domain to the intracellular domain. Truncated proteins include an immune cell receptor ligand and a transmembrane domain but lack a functional intracellular domain. The hybrid and truncated proteins can be used to modulate and/or diversify immune cell activation in the fight against cancers and infectious diseases, among other uses.

Abstract: Hematopoietic stem/progenitor cells (HSPC) and/or non-T effector cells are genetically modified to express (i) an extracellular component including a ligand binding domain that binds a cellular marker preferentially expressed on an unwanted cell; and (ii) an intracellular component comprising an effector domain. Among other uses, the modified cells can be administered to patients to target unwanted cancer cells without the need for immunological matching before administration.

Abstract: The present disclosure relates to biomarker profiles and their use to predict a subject's response to an immunomodulatory treatment. Biomarkers in these profiles include cytokines and other proteins associated with the interleukin 1 family and the type 1 interferon family. Particular biomarkers include interleukin (IL)-2, soluble IL-2 receptor alpha (sIL-2RA), IL-5, IL-6, IL-9, IL-10, IL-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), IL-22, C-type lectin-like receptor (CD161), CD56, interferon gamma (IFN?), granulocyte macrophage colony stimulating factor (GM-CSF), serum amyloid A (SAA), and C-reactive protein (CRP). Particular biomarkers also include populations of cells including CD161+ cells and CD56+dim cells. The biomarker profiles can be used to predict a subject's responsiveness to an immunomodulatory treatment (e.g.

Abstract: The disclosure provides immunogenic peptides comprising at least a portion of a Plasmodium HAP2 paralog (“HAP2p”) protein, immunogenic compositions comprising or encoding the immunogenic peptides, antibodies binding the immunogenic peptides, and methods of preventing Plasmodium transmission incorporating the peptides, compositions, and/or antibodies. In some embodiments, the immunogenic peptide has a sequence comprising a sequence with at least 80% identity to a sequence of at least 10 continuous amino acids of SEQ ID NO:2, a Plasmodium HAP2 paralog (“HAP2p”) protein.

Abstract: The current disclosure provides chimeric antigen receptors (CARs) that bind a natural killer (NK) cell surface marker, resulting in destruction of the bound NK cell. The NK cell surface markers include an activating NK cell receptor, and an inhibitory NK cell receptor. Cells that are genetically modified to express these CARs and uses of the CAR modified cells are also described.

Abstract: Single-domain antibodies that bind the severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) spike protein are disclosed. The single-domain antibodies include binding domains that bind epitopes of the Spike ectodomain inside and outside the receptor binding domain. The single-domain antibodies can be used for multiple purposes including in the research, diagnosis, and prophylactic or therapeutic treatment of COVID-19.

Abstract: The use of inhibitors upstream of mTOR in the CSF1 pathway of neuroinflammation, inhibitors of chemokine receptor CXCR3, functional derivatives thereof, and/or immunosuppressant drugs to reduce neuroinflammation are disclosed. The inhibitors and/or immunosuppressant drugs can treat genetic or environmental encephalopathies and/or reduce microglial activation. Treated encephalopathies include Leigh Syndrome and Wernicke encephalopathy.