The present invention relates to improved compositions and methods for treating diseases, such as cancers that express aberrantly glycosylated MUC1 proteins, by providing a cell immunotherapy, wherein the cell immunotherapy is an immunomodulatory cell expressing a chimeric antigen receptor (CAR) that binds aberrantly glycosylate MUC1 proteins. The invention further relates to polynucleotides, expression vectors, and immunomodulatory cells comprising the immunotherapy, as well as related methods.

Chimeric antigen receptors having a chlorotoxin domain and an IL-13 are described. These dual targeted chimeric antigen receptors are useful for treating glioblastoma and other cancers of neuroectodermal origin.

Provided are genetically engineered induced pluripotent stem cells (iPSCs) and derivative cells thereof expressing a polyethylene glycol (PEG) receptors and methods of using the same. Also provided are compositions, polypeptides, vectors, and methods of manufacturing.

Provided herein are compositions and methods for manufacturing engineered lymphocytes. Also provided are the prepared engineered lymphocytes which have increased proportions of juvenile/naive lymphocytes leading to increased therapeutic efficacy. The methods in various embodiments are expedited as compared to the conventional technology, and produce lymphocytes with improved viability, transduction success rates, and in vivo antitumor efficacy.

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.

The present disclosure relates to treating a subject comprising administering to the subject a therapy (e.g., a cell therapy, e.g., an adoptive cell therapy, e.g., a CAR-T cell therapy), wherein, prior to the administration, the subject has been preconditioned with a personalized amount of a chemotherapeutic agent. The personalized amount provides an optimal exposure to the chemotherapeutic agent.

The present disclosure provides transposon-based systems for introducing cellular therapeutic products, such as CAR and TCR, into a target immune cell. The transposon-based systems can carry larger payloads than conventional viral vector-based technologies, simplifying multi-genetic editing and can reduce undesired recombination between homologous sequences in the payload. Also provided is a shortened autologous process that can be completed within a few days, within one day or even within a few hours. Even without immune cell activation, enrichment or expansion, the resulting cell populations achieve greatly higher in vivo therapeutic efficacy than the much lengthier autologous process that employs viral vectors.

The disclosure relates to immune cells comprising systems of two engineered receptors each having a ligand binding domain, collectively designed to target cells identified by loss of heterozygosity and used to treat a disease or disorder, for example, cancer. The disclosure provides immune cells expressing two engineered receptors, methods of making same, and polynucleotides and vectors encoding same.

Provided herein is a method of treating a subject who has multiple myeloma. A single infusion of chimeric antigen receptor (CAR)-T cells comprising an anti-BCMA CAR comprising a polypeptide is administered to the subject. In certain embodiments, the dose of CAR-T cells administered to the subject is from 1.010.sup.5 to 5.010.sup.6 of CAR-T cells per kilogram of the subject's mass. The method of treatment is effective in obtaining and maintaining minimal residual disease negativity status, as well as other beneficial clinical outcomes related to efficacy and safety.

The present application relates to functionally improved third generation BCMA-CARs comprising modified intracellular co-stimulatory domains, which can be used in adoptive cell therapy, e.g., in treatment of diseases and disorders such as cancer.