Purpose: In previous research, we have found that LMP1-specific chimeric antigen (HELA/CAR) T cells can specifically recognize and kill LMP1-positive NPC cells. However, the tumor-inhibitory effectiveness of HELA/CART cells needs to be enhanced.
Methods: We created two CARs that contain the T cell receptor-ζ (TCR-ζ) signal transduction domain with the CD28 and CD137 (4-1BB) or CD134 (OX-40) intracellular domains in tandem (HELA/137CAR or HELA/134CAR). Then, the tumor-inhibitory functions of two new CAR-T cells were investigated, both in vitro and in vivo.
Results: The results showed that, after short-term expansion, primary human T cells were subjected to lentiviral gene transfer, resulting in large numbers of cells with >80% CAR expression. All CART cells were effective in killing SUNE1-LMP1 and C1R-neo cells, while HELA/137CART cells produced greater quantities of IFN-γ and IL-2 than HELA/CART cells. However, the level of IL-2 not INF-γ secreted by HELA/134CART cells was increased under the stimulation of LMP1 antigen. In an LMP1-positive NPC mouse xenograft model, HELA/137CART cells exhibited better antitumor activity and longer survival time in vivo compared with HELA/CAR T cells.
Conclusion: The findings suggest that CD137 and CD28 is a better costimulatory signaling domain than CD28 only for optimizing tumor-inhibitory roles.
Keywords: chimeric antigen receptors, LMP1, EBV, CD137