The present invention relates to the use of interleukin-15 (IL-15) as selectable marker for gene transfer, preferably of at least one gene of therapeutic interest, into a mammalian cell or cell line, in particular a human cell or cell line. The present invention furthermore relates to transgenic mammalian cells or cell lines expressing IL-15 as selectable marker and co-expressing at least one protein of interest encoded by at least one gene of interest, which is preferably a protein of therapeutic interest. The present invention is in particular suitable for chimeric antigen receptors (CARs) as the gene or protein of interest and their expression in lymphocytes. The transgenic mammalian cells and cell lines are furthermore suitable for use as a medicament, in particular in the treatment of cancer and in immunotherapy, such as adoptive, target-cell specific immunotherapy.

Described herein are immune cells (e.g., natural killer (NK), T cells) expressing a chimeric protein comprising IL2 and IL2R? (e.g., CIRB), a chimeric protein comprising IL2, IL2R? and IL21R (e.g., CIRB21), a chimera protein comprising IL2, IL2R?, and CD28 (e.g., CIRB28), or a combination thereof, and comprising a nucleic acid encoding a pore-forming protein, and methods of using such immune cells for treating a subject (e.g., a subject having cancer, graft-versus-host disease (GVHD), or an autoimmune disease. Expression of the pore-forming protein can be induced to promote destruction of immune cells expressing CIRB, CIRB21, CIRB28, or a combination thereof.

Provided are modified tumor-infiltrating lymphocyte and the use thereof, in particular provided is a method for culturing the tumor-infiltrating lymphocyte (TIL), which comprises increasing the expression and/or enhancing the activity of at least one cytokine of the TIL. Also provided is a method for preventing and/or treating tumors by using the tumor-infiltrating lymphocyte.

The presently disclosed subject matter provides for chimeric receptors that target MUC16 and cells comprising such chimeric receptors. The presently disclosed subject matter further provides uses of the chimeric receptors for treatment.

In one embodiment, the present disclosure provides an engineered cell having a first chimeric antigen receptor polypeptide including a first antigen recognition domain, a first signal peptide, a first hinge region, a first transmembrane domain, a first co-stimulatory domain, and a first signaling domain; and a second chimeric antigen receptor polypeptide including a second antigen recognition domain, a second signal peptide, a second hinge region, a second transmembrane domain, a second co-stimulatory domain, and a second signaling domain; wherein the first antigen recognition domain is different than the second antigen recognition domain.

Provided herein are constitutively active chimeric cytokine receptors (CACCRs). When present on chimeric antigen receptor (CAR)-bearing immune cells, such CACCRs allow for increased immune cell activation, proliferation, persistence, and/or potency. Also provided are methods of making and using the CACCRs described herein.

Provided herein are tumor-infiltrating lymphocytes (TILs) engineered to express a membrane-bound interleukin 15 (mbIL15). The mbIL15 TILs can be expanded in vitro using a rapid expansion protocol without the use of exogenous interleukin 2 (IL2) and can be used in adoptive cell therapy without concomitant use of an exogenous cytokine such as IL2. The TIL can be further engineered such that the mbIL15 is operably linked to one or more drug responsive domains (DRDs), polypeptides that can regulate the abundance and/or activity of the IL15 upon binding of the DRD with a ligand. Also provided herein are components for making the modified TILs and methods for making and using the modified TILs.

Provided herein are mutants of estrogen receptor alpha ligand binding domain (ER-LBD), and chimeric proteins including such mutant ER-LBD. Also provided are methods of modulating transcription and modulating localization of such chimeric proteins.

In certain aspects, provided herein are compositions and methods for treating cancer. The methods of the present disclosure comprise administering to a subject in need thereof a NK cell expressing a CAR in combination with an antigen-binding molecule that binds to a tumor antigen, wherein the CAR-NK cell targets tumor cells through binding to the antigen-binding molecule.

Described herein are immunoresponsive cells engineered to express cytokines, chimeric receptors, and synthetic transcription factor systems. Also described herein are nucleic acids, cells, and methods directed to the same.