Chimeric Antigen Receptor T Cell Bearing Herpes Virus Entry Mediator Co-stimulatory Signal Domain Exhibits High Functional Potency

Chimeric antigen receptor (CAR) is a hybrid molecule consisting of an antigen-binding domain and a signal transduction domain. The artificial T cells expressing CAR (CAR-T cells) are expected to be a useful tool for treatment of various diseases, such as cancer. The addition of a co-stimulatory signal domain (CSSD) to CAR is shown to be critical for modulating CAR-T cell activities. However, the interplay among types of CSSDs, effector functions, and characteristics of CAR-T cells is largely unknown. To elucidate the interplay, we analyzed effector functions, differentiation to memory T cell subsets, exhaustion, and energy metabolism of the CAR-T cells with different CSSDs. Comparing to the CAR-T cells bearing a CD28- or 4-1BB-derived CSSD, which are currently used for CAR-T cell development, we found that the CAR-T cells with a herpes virus entry mediator (HVEM)-derived CSSD exhibited enhanced effector functions and efficient and balanced differentiation to both central and effector memory subsets, associated with an elevated energy metabolism and a reduced level of exhaustion. Thus, we developed the CAR-T cells bearing the CSSD derived from HVEM with high functional potency. The HVEM-derived CSSD may be useful for developing effective CAR-T cells.