UCLA researchers from the Departments of Medicine and Infectious Diseases have developed novel chimeric antigen receptors against human cytomegalovirus.
BACKGROUND:
Human cytomegalovirus (CMV) is an infectious virus that is found in over half the world’s population. In most healthy people, the virus is suppressed by the body’s immune system. However, in immunocompromised individuals, such as those with an illness like AIDS or those undergoing therapeutic immunosuppression for an organ transplant, the viral infection can spread and lead to death. Infants infected in utero can also experience disease symptoms that can impede neurological development.
INNOVATION:
CMV enters cells by expressing glycoproteins, which are a group of proteins that can bind to receptors on the cell surface and allow the virus to infiltrate the cell. Viral entry into a cell can be prevented by neutralizing antibodies. These neutralizing antibodies bind to the glycoproteins on the virus, preventing CMV from being able to bind to a cell. Infected cells also express these glycoproteins on their surface. UCLA researchers have created eight chimeric antigen receptors (CARs) from neutralizing antibodies against viral glycoproteins and transformed them into CD8+ T cells. CAR T cells are genetically engineered immune cells that can target a specific protein on CMV-infected cells. Previously only one CMV-specific CAR has been reported in the literature and it has not advanced to clinical trials to our knowledge.
POTENTIAL APPLICATIONS:
• Treatment of CMV infections in immunosuppressed individuals
ADVANTAGES:
• Specific targeting of CMV-infected cells
• CAR-T modality is an alternative typical drug therapies that have many toxic side effects
DEVELOPMENT-TO-DATE:
Successful CAR protein expression in primary CD8+ T lymphocytes has been validated by Western blot and flow cytometry in eight CARs. T cells transduced with CARs were particularly potent in capacity to recognize infected cells in terms of specific cytokine release, cell killing, and suppression of CMV replication in culture.
RELATED PAPERS:
1. Wussow et. al., PLos Pathog. 2014 Nov; 20(10) (PMID 25412505).
2. Chiuppesi et. al., J Virol. 2015 Dec; 89(23):11884-98 (PMID 26378171).