NARULA, M.; Englisch, J.; Ou, C.; Honda, T.; San Sebastian, I. d. l. I.; Arnett, A. B.; Mo, F.; Mamonkin, M.; Watanabe, N.

TCR based cell therapies offer broad targeting of tumor antigens with high sensitivity but often low durability due to insufficient costimulation (signal 2) and cytokine (signal 3) support. To address this, we developed a dual stimulatory receptor (DSR) consisting of the 4 1BBL ectodomain fused to the thrombopoietin receptor (cMPL) endodomain. DSR engages 4-1BB that is transiently upregulated upon TCR stimulation eliciting signal 2 and simultaneously activates cMPL driven STAT3/5 phosphorylation providing signal 3. DSR increases the expansion of T cells, preserving their effector function and an effector-associated transcriptional profile upon repeated antigen stimulation. DSR arming significantly improves in vivo antitumor activity of T cells redirected to cancer through engineered TCRs or soluble T-cell engagers in diverse xenograft tumor models by enhancing T cell expansion and persistence post-infusion. These results demonstrate broad utility and establish DSR as a modular receptor for the effective and synchronized delivery of signals 2 and 3 to support TCR based immunotherapies.