Low-density lipoprotein receptor cysteine-rich domains 2 and 3-based chimeric antigen receptor (CR2/3-CAR)

The Low-density lipoprotein receptor CR2/3 domain-based chimeric antigen receptor (CR2/3-CAR) is a specialized synthetic receptor designed to bridge CAR-T cell therapy and oncolytic virotherapy. It incorporates the cysteine-rich (CR) repeats 2 and 3 of the human low-density lipoprotein receptor (LDLR), which have been identified as the primary binding sites for the vesicular stomatitis virus glycoprotein (VSV-G) (Nikolic et al., 2018). By replacing the standard antibody-derived scFv with these LDLR domains, the CAR-T cell is engineered to recognize and bind VSV-G-expressing agents, such as the oncolytic virus VSVΔ51. This configuration enables a "two-in-one" therapeutic strategy where CAR-T cells serve as "Trojan horses" to deliver oncolytic viruses directly into the immunosuppressive microenvironment of solid tumors, such as glioblastoma (Chen et al., 2024). The interaction between the CR2/3-CAR and VSV-G not only facilitates viral hitchhiking but also triggers robust T-cell activation and tumor cell lysis upon contact with the virus or infected cells. This modular approach aims to overcome the limitations of traditional CAR-T therapies in solid tumors by combining direct viral oncolysis with potent, targeted immune effector functions.

Other names

LDLR-CR2/3 CARVSV-G-targeting CARCR2/3-engineered CARViro-CAR

The CR2/3-CAR is expressed on the surface of T cells and utilizes the cysteine-rich (CR) domains 2 and 3 of the human LDLR to specifically bind the glycoprotein G of the vesicular stomatitis virus (VSV-G). This interaction allows CAR-T cells to act as carriers for oncolytic viruses (e.g., VSVΔ51), facilitating their delivery to tumor sites. Upon binding VSV-G on the virus or on infected tumor cells, the CAR's intracellular signaling domains (such as CD3-zeta and 4-1BB) trigger T-cell activation, proliferation, and cytotoxic activity against the target cells.