Researchers in the Department of Medicine and the Department of Microbiology, Immunology and Molecular Genetics have created novel bi-specific chimeric antigen receptors.

BACKGROUND: Chimeric antigen receptors (CARs) are synthetic receptors engineered to redirect T cells towards specific targets on other cells, typically using a single chain antibody. These CAR-T cells have revolutionized treatment for B cell-based cancers by genetically modifying T cells to attack cancerous B cells. However, there are instances when having bi-specific CAR (BSCAR) CAR-T cells would be advantageous. For example, cancer cells can downregulate CAR target markers like CD19, and dual targeting would be harder to escape. Another example would be using the frequent reactivations of endogenous cytomegalovirus to stimulate CAR-T cells that target cancer and CMV.

INNOVATION: Current strategies to create BSCARs include using tandem antibody CARs, separate transduced T cell populations, single bi-cistronic vectors, or co-transducing with two vectors, each with drawbacks such as steric hindrance of tandem antibodies, complexity of production, unwieldy, vector size, and potential uneven transduction. UCLA researchers led by Dr. Otto Yang harnessed a cross-over dual variable (CODV) strategy for creating bi-specific antibody CARs. The CODV strategy arranges the variable regions in a crossed-over manner to avoid steric hindrance between the two binding specificities. With the use of CODV technology, one can produce BSCARs that recognize two independent antigens, circumventing the limitations described above by using delivering a single CAR to target T cells against both antigens.

POTENTIAL APPLICATIONS:

• Improve the versatility of CAR-T cell therapies by enabling simultaneous targeting of multiple antigens on cancer cells to reduce risk of escape.
• Using one antigen to drive CAR-T persistence against another antigen, e.g. CMV infection to enhance anti-cancer CAR-T cells.

ADVANTAGES:

• Feasibility of targeting multiple antigens with compact single CAR
• Avoiding the need to use bi-cistronic vectors or multiple vectors
• Application to reduce cancer cell escape or to enhance CAR-T cell persistence

DEVELOPMENT-TO-DATE: Proof of concept via in vitro proliferation and killing assays.     

Keywords: CAR, T-cells, cancer, bi-specific antibodies, immunotherapy, cytotoxic T cells, CAR-T cell persistence, antigenic escape