Developing Immunotherapy Approaches to Target Surface Proteins on Virally Infected Cancer Cells

Many EBV-associated cancers express virally-encoded transmembrane proteins. Two such proteins Latent Membrane Protein1 (LMP1) and Latent Membrane Protein 2 (LMP2) that play roles in oncogenesis. Both are multi-spanning transmembrane proteins, with a small extracellular region that is exposed on the surface of the infected cell.  Our hypothesis is that the exposed extracellular regions of LMP1 and LMP2 could be targeted by cytotoxic T cells expressing chimeric antigen receptors (CARs). However, the development of CAR based therapies to target LMP-expressing malignancies are currently hampered by a lack of antibodies that recognize the extracellular domains of these proteins. Using a humanized mouse model, we are working to isolate human antibodies that specifically recognize the extracellular domains of membrane-anchored LMP1 and LMP2, and to convert these antibodies into chimeric antigen receptors that can be used to direct potent T-cell-mediated killing to EBV+ cancer cells.