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 present disclosure provides methods for genetically engineering T cells, such as CD4+ T cells, for use in cell therapy. In some aspects, the provided methods include one or more steps for incubating the cells under stimulating conditions, introducing a recombinant polypeptide to the cells through transduction or transfection, and cultivating the cells under conditions that promote proliferation and/or expansion. In some aspects, the incubation and/or the cultivation is performed in the presence of recombinant IL-2. In some aspects, the provided methods are an efficient, reliable means to produce genetically engineered T cells with a high degree of success.

This document relates to methods and materials involved in treating mammals having a cancer (e.g., a cancer having one or more CD19 positive extracellular vesicles (EVs) and/or one or more small EVs in the tumor microenvironment). For example, methods of treating a mammal having a blood cancer including one or more CD19 positive EVs and/or one or more small EVs in the blood by administering one or more cancer immunotherapies (e.g., one or more chimeric antigen receptor (CAR) T-cell therapies) to the mammal are provided.

Provided herein are T cells expressing a chimeric antigen receptor (CAR) targeted to B cell activating factor receptor (BAFF-R). The CAR targeted to BAFF-R (BAFF-R CAR) described herein includes a domain that binds BAFF-R. Methods of making and using the BAFF-R CAR are also provided.

The present invention discloses populations of T cells expressing a chimeric antigen receptor (CAR), wherein said T cells are placental T cells derived from cord blood, placental perfusate, or a mixture thereof. Such populations of cells are shown to be improved in a number of aspects over alternative populations of cells such as those derived from peripheral blood mononuclear cell T cells. It also discloses methods of treating cancer, such as a hematologic cancer, e.g., a B cell cancer, or a symptom thereof in a patient in need thereof. These methods comprise administering to the patient an amount of the population of T cells of any one of the invention effective to alleviate the cancer or symptom thereof in the patient.

Described herein is a cell comprising a feedback circuit. In some embodiment, the circuit may comprise: (a) a first polypeptide that is activated by an external stimulus and, downstream from the first polypeptide: (b) a target protein and (c) a fusion protein comprising: (i) a domain that binds to the target protein of (b) and (ii) a degron or E3 ligase-recruiting domain. In these embodiments, the first polypeptide of (a), in its activated form, independently activates the expression of (b) and (c); and the fusion protein of (c) binds to the first polypeptide of (a), thereby causing degradation of the first polypeptide in trans. Methods using the cell are also provided.

The invention comprises methods and compositions for treating autoimmune diseases with engineered immune cells including cytotoxic T cells and natural killer (NK) cells. The engineered immune cells comprise a chimeric antigen receptor (CAR). Methods of making the engineered cells, methods of administration and treatment regimens are also disclosed.

Provided herein are a recombinant chimeric antigen receptor (CAR) fusion protein, a method of modifying an immune cell into a CAR immune cell by treating the immune cell with the recombinant CAR fusion protein, and a method of treating cancer by administering the CAR immune cell to a subject in need thereof.

The disclosure provides synthetic immune receptors (SIRs), nucleic acids encoding the SIRs, methods of making and using the SIRs, in, for example, adoptive cell therapy.

A humanized antibody specific for CD22 and a chimeric antigen receptor using the same, and, in some aspects, a chimeric antigen receptor including the antibody or a CD19CD22 antibody, a CAR-T cell expressing the chimeric antigen receptor, and a pharmaceutical composition including the same for preventing or treating a disease mediated by B cells.