Chimeric antigen receptors containing CD123 antigen binding domains are disclosed. Nucleic acids, recombinant expression vectors, host cells, antigen binding fragments, and pharmaceutical compositions, relating to the chimeric antigen receptors are also disclosed. Methods of treating or preventing cancer in a subject, and methods of making chimeric antigen receptor T cells are also disclosed.

The present application relates to a chimeric antigen receptor (CAR) which comprises a target-dependent on-switch CAR. The CAR of the invention may reduce cytotoxicity towards normal cells and improve CAR-T safety. CAR molecules were designed using the transmembrane and juxtamembrane motifs of the IL2 receptor β chain (IL2Rβ or IL2Rb), the L ow-Density Lipoprotein Receptor (LDLR), the Seizure 6-like Protein 2 (SEZ6L2), and degradation sequence (PSKFFSQL) of IL2Rβ, which resulted in greatly reduced CAR expression at the cell surface in the absence of target antigen, while retaining downstream activation ability in response to antigen-expressing target cells. In the absence of target antigen, CAR surface expression is undetectable. The present application has shown that primary T cells expressing these surface-unstable CAR variants are able to elicit antigen-dependent target cell killing. By limiting CAR activity in this way, the present application can reduce therapeutic toxicity and T cell exhaustion. Due to its limited detectability in the absence of antigen, the present application refers to this system as a “Stealth CAR”. The present application further relates to compositions, preparation methods and uses of the Stealth CAR of the present application.

The present disclosure describes systems and methods for immunotherapies Immune cells can be engineered to exhibit enhanced half-life as compared to control cell (e.g., a non-engineered immune cell). Immune cells can be engineered to exhibit enhanced proliferation as compared to a control cell. Immune cells can be engineered to effectively and specifically target diseased cells (e.g., cancer cells) that a control cell otherwise is insufficient or unable to target. The engineered Immune cells disclosed herein can be engineered ex vivo, in vitro, and in some cases, in vivo. The engineered Immune cells that are prepared ex vivo or in vitro can be administered to a subject in need thereof to treat a disease (e.g., myeloma or solid tumors). The engineered Immune cells can be autologous to the subject. Alternatively, the engineered immune cells can be allogeneic to the subject.

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.

The present disclosure relates to an engineered immune cell and use thereof. The present disclosure provides an engineered immune cell comprising a CAR or engineered TCR, which CAR or engineered TCR can comprise a first antigen binding domain and a second antigen binding domain. The engineered immune cells of the present disclosure, when administered into a subject, can inhibit the host immune cells such as T cells and/or NK cells and enhance the survival and persistence of the engineered immune cells in vivo, thereby exhibiting more effective tumor killing activity.

The disclosure provides compositions and related methods for detecting, inhibiting, reducing or killing tumor-infiltrating regulatory T cells (Tregs) characterized by expression of inducible T cell costimulator (ICOS) and Interleukin-1 receptor type 1 (IL-1R1). The reagents can include a bi-specific affinity reagent with a first domain that specifically binds ICOS and a second domain that specifically binds IL-1R1 or, separately, a first affinity reagent that specifically binds ICOS and a second affinity reagent that specifically binds IL-1R1. In some embodiments, the reagent can comprise engineered immune cells expressing a first chimeric antigen receptor (CAR) specific for ICOS and a second CAR specific for IL-1R1, wherein the cell requires binding by the first CAR and second CAR to activate, such as a logic-gated CAR T cell.

The present disclosure provides modified immune cells or precursors thereof (e.g. T cells) comprising chimeric antigen receptors (CARs) capable of binding human IL13R2. Also provided are bispecific CARs, parallel CARs, tandem CARs, BiTEs, BiTE/CARs, and BiTE/BiTEs. Compositions and methods of treatment are also provided.

An engineered immune cell comprising a first functional exogenous receptor capable of binding and depleting natural killer (NK) cells, and a second functional exogenous receptor, wherein the engineered immune cell has reduced MHC I on cell surface.

Provided herein are chimeric transmembrane receptor polypeptides configured to oligomerize upon recognition of an extramembrane signal. The receptors include an extramembrane domain, a transmembrane domain, and an intramembrane domain configured to induce activation of one or more intramembrane signal pathways upon oligomerization of the receptor. The provided receptors are particularly useful for engineered cell therapies. Also provided are systems and host cells including the disclosed receptors, and methods for using the disclosed materials.

The present disclosure relates to the field of cell therapy, and more specifically, to improving CAR and/or TCR function through cytokine signaling or cytokine receptor signaling.