The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity

SIMPLE SUMMARY: Members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) provide crucial co-stimulatory signals to many if not all immune effector cells. With distinct and unique functional features on multiple types of immune effector cells, the co-stimulatory activity of TNFRSF members is being implemented in the tailoring of Chimeric Antigen Receptor (CAR) T cell activity for cancer therapy. This integration of intracellular TNFRSF stimulatory domains into a CAR provides a unique signaling output. Here, we highlight the rationale and summarize the current evidence for the application and the unique attributes of co-stimulatory signaling by TNFRSF members (4-1BB; OX40; CD40; CD27; GITR; HVEM) in CAR-T therapy. ABSTRACT: The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells.