A fusion protein comprising: a first component comprising an antibody, or a fragment or variant thereof; and a second component comprising a cytokine trap or an adenosine deaminase or a fragment or variant thereof. In certain embodiments, the antibody is an anti-PD-1 antibody. In certain embodiments, the antibody binds to a tumor antigen, for example a MUC16 or MUC1 antigen. In certain embodiments, the cytokine trap is a TGF- trap. A polynucleotide encoding such a fusion protein and a vector comprising such a polynucleotide. A composition comprising the fusion protein. A method of using the composition, including in the treatment of cancer.

A 3D semiconductor device including: a first level including a first single crystal layer and first transistors, which each include a single crystal channel; a first metal layer with an overlaying second metal layer; a second level including second transistors, overlaying the first level; a third level including third transistors, overlaying the second level; a fourth level including fourth transistors, overlaying the third level, where the second level includes first memory cells, where each of the first memory cells includes at least one of the second transistors, where the fourth level includes second memory cells, where each of the second memory cells includes at least one of the fourth transistors, where the first level includes memory control circuits, where second memory cells include at least four memory arrays, each of the four memory arrays are independently controlled, and at least one of the second transistors includes a metal gate.

Provided herein are methods of treating an aging-related disease or inflammatory disease in a subject that include (i) a therapeutically effective amount of an NK cell activating agent and/or an NK cell and/or monoclonal antibody; and (ii) a therapeutically effective amount of a Treg cell activating agent and/or a Treg cell and/or a monoclonal antibody and/or AGE inhibitor.

Provided herein are methods of treating an aging-related disease or inflammatory disease in a subject that include (i) a therapeutically effective amount of an NK cell activating agent and/or an NK cell and/or monoclonal antibody; and (ii) a therapeutically effective amount of a Treg cell activating agent and/or a Treg cell and/or a monoclonal antibody and/or AGE inhibitor.

There is provided according to the invention a method of treating a mammal suffering from or susceptible to an immune reaction to drug treatment comprising the raising of anti-drug antibodies which method comprises (a) ex-vivo treating antigen presenting cells obtained from the mammal with an agent which induces IDO in said antigen presenting cells in the presence of said drug or an epitope containing fragment thereof and (b) after IDO has been induced in said antigen presenting cells, transferring said cells back to the mammal thereby to establish immune tolerance to the drug.

The present invention encompasses genetically-modified immune cells (and populations thereof) expressing a microRNA-adapted shRNA (shRNAmiR) that reduces the expression of a target endogenous protein. Methods for reducing the expression of an endogenous protein in an immune cell are also provided wherein the method comprises introducing a shRNAmiR that targets the endogenous protein. Using shRNAmiRs for knocking down the expression of a target protein allows for stable knockdown of expression of endogenous proteins in immune cells.

Adoptive T-cell therapy has shown tantalizing promise as a cancer treatment strategy, with several clinical trials reporting that T cells expressing chimeric antigen receptors (CARs) can eradicate tumors in patients with relapsed disease. However, CAR-T cells rely on receptor-mediated recognition of surface-bound antigens that are seldom tumor-exclusive, resulting in severe on-target, off-tumor toxicities that have led to patient deaths in clinical trials. There is a growing consensus that the lack of suitable antigens poses a major obstacle to the broad application of engineered tumor-targeting T cells. The ability to overcome T cells' reliance on surface antigen presentation and interrogate intracellular disease signatures would significantly expand the pool of detectable tumor markers and improve tumor-targeting specificity. Here, we present a novel strategy to reprogram T-cell-mediated cytotoxicity to interrogate intracellular disease signatures. We have engineered a switchable form of the cytotoxic protein Granzyme B (GrB) that is produced and delivered by T cells into target cells, but becomes active if and only if a tumor-associated protease is present inside the target cell. As a proof of concept, we have developed a GrB switch that responds to Sentrin-specific protease 1 (SENP1), an oncoprotein known to be overexpressed in prostate, pancreatic, and thyroid oncocytic tumor cells. We demonstrate that this GrB switch, termed cytoplasmic oncoprotein verification evaluator and response trigger (COVERT), is efficiently expressed and packaged by human T cells and properly trafficked to the immunological synapse between T cells and target cells. Furthermore, we show that COVERT is produced as an enzymatically inert protein that is activated by SENP1 in a dose-dependent manner. Finally, we describe designs to adapt COVERT into a modular platform technology that will expand the repertoire of candidate target antigens. We envision that COVERT can be utilized in combination with existing CAR technology to improve the tumor-targeting precision of cell-based immunotherapy.

Copyright American Institute of Chemical Engineers. All rights reserved.

Disclosed herein are methods of producing a hypoimmune cell and methods of mediating localized immune tolerance.

The present disclosure is directed towards genetically engineered TCR-T cells to recognize tumor antigens and simultaneously secrete a binding protein that blocks an immune checkpoint molecule and TGF. These engineered T cells demonstrate stronger antitumor response and reduced T cell exhaustion. The present disclosure provides immunotherapy against HPV- or EBV-positive cancers, among others.

The present disclosure provides improved compositions for adoptive T cell therapies for treating, preventing, or ameliorating at least one symptom of a cancer, infectious disease, autoimmune disease, inflammatory disease, and immunodeficiency, or condition associated therewith.