This invention relates to the field of therapeutics. Most specifically invention provides methods of generating in vitro engineered immune cells conditionally expressing interleukin-12 (IL-12) and one or more immunomodulators under the control of a gene expression modulation system in the presence of activating ligand and uses for therapeutic purposes in animals.

Provided herein are de novo binding domain containing polypeptides (DBDpp) that specifically bind a target of interest. Nucleic acids encoding the DBDpp, and vectors and host cells containing the nucleic acids are also provided. Libraries of DBDpp, methods of producing and screening such libraries and the DBDpp identified from such libraries and screens are also encompassed. Methods of making and using the DBDpp are additionally provided. Such uses include, without limitation, affinity purification, and diagnostic and therapeutic applications.

A technique for enhancing functions such as proliferation ability and imparting an activity of capturing cytokines which may cause side effects in immune cells for use in the adoptive immunotherapy is disclosed. A chimeric cytokine receptor having a ligand-binding region with a cytokine-binding region of a cytokine receptor at the N-terminal side and a T-cell activating region having the transmembrane domain and the intracellular domain of an IL-7 receptor chain at the C-terminal side is provided. Amino acid sequence SEQ ID NO: 1 of the transmembrane domain has an insertion of one of: (a) amino acid sequence SEQ ID NO: 2 between positions 243 and 244, (b) amino acid sequence SEQ ID NO: 3 between positions 241 and 242, (c) amino acid sequence SEQ ID NO: 4 between positions 244 and 245, (d) amino acid sequence of SEQ ID NO: 5 between positions 244 and position 245, or (e) amino acid sequence of SEQ ID NO: 6 between positions 246 and 247.

The present invention relates to compositions and methods relating to chimeric antigen receptor (CAR) polypeptides and methods relating thereto. In one embodiment, the present invention relates to engineered cells having chimeric antigen receptor polypeptides directed to at least two targets. In another embodiment, the present invention relates to engineered cells having chimeric antigen receptor polypeptides and an enhancer moiety.

The present disclosure provides chimeric antigen receptors, compostions, and methods thereof. In one embodiment the present disclosure provides a method of treating autoimmune diseases, asthma, and preventing or mediating organ rejection in a subject.

The present invention relates to a new generation of chimeric antigen receptors (CAR) referred to as multi-chain CARs, which are made specific to the antigen CD123. Such CARs aim to redirect immune cell specificity and reactivity toward malignant cells expressing the tumor antigen CD123. The alpha, beta and gamma polypeptides composing these CARs are designed to assemble in juxtamembrane position, which forms flexible architecture closer to natural receptors, that confers optimal signal transduction. The invention encompasses the polynucleotides, vectors encoding said multi-chain CAR and the isolated cells expressing them at their surface, in particularly for their use in immunotherapy. The invention opens the way to efficient adoptive immunotherapy strategies for treating cancer, especially leukemia.

Provided are specific binding molecules, or fragments thereof, that bind to an epitope of IL13R?2, a receptor polypeptide preferentially found on the surface of cancer cells rather than healthy cells. Exemplary specific binding molecules are bispecific binding molecules that comprise a fragment of an IL13R?2 binding molecule and a peptide providing a second function providing a signaling function of the signaling domain of a T cell signaling protein, a peptide modulator of T cell activation, or an enzymatic component of a labeling system. Also provided are polynucleotides encoding such a specific binding molecule (e.g., bispecific binding molecule), vectors, host cells, pharmaceutical compositions and methods of preventing, treating or ameliorating a symptom associated with a cancer disease such as a solid tumor disease (e.g., glioblastoma multiforme).

Some embodiments of the methods and compositions provided herein relate to chimeric antigen receptors (CARs) that specifically bind to human extracellular domains of the IL-13 alpha 2 (IL13Ra2) receptor, cells containing such CARs, and methods of cell-based immunotherapy targeting cancer cells, such as cells of solid tumors.

Engineered orthogonal cytokine receptor/ligand pairs, and methods of use thereof, are provided.

The present disclosure provides modified immune cells or precursors thereof (e.g. T cells) comprising a first chimeric antigen receptor (CAR) capable of binding human IL13R2, a second CAR capable of binding EGFR or an isoform thereof, and a dominant negative TGF type II receptor (DN-TGFRII). Compositions and methods of treatment are also provided.