STING ablation in T cells is required for the efficacy of STING agonists in CAR-T cell immunotherapy of pancreatic cancer

BACKGROUND & AIMS: Chimeric antigen receptor (CAR) T cells have shown great potential in hematological cancers, but lack efficacy in solid tumors, highlighting the need for novel strategies. STING activation was shown to inflame the tumor microenvironment, but combination of STING agonists and CAR-T cells might be limited by detrimental outcomes of T cell-intrinsic STING activation. In this study, we evaluated the potential of combining STING agonists and CAR-T cells in the context of pancreatic cancer METHODS: We assessed the synergy of CRISPR-Cas9-edited CAR-T cells and the STING agonist diABZI within a T cell exhaustion model in vitro and both xenograft and syngeneic mouse models in vivo. RESULTS: Combination of STING-ablated CAR-T cells and diABZI resulted in enhanced cancer cell killing, increased CAR-T cell proliferation, reduced exhaustion and expansion of an effector-memory phenotype in vitro. Mechanistically, superior CAR-T cell functionality required genetic ablation of STING in CAR-T cells and was dependent on cancer cell-intrinsic STING signaling upon STING-agonistic treatment. Moreover, we identified a synergistic feedback loop comprising the T cell-secreted cytokines IFN-

• Piseddu, I.
• Endres, R.
• Lanzl, F.
• Hammann, L.
• Bérouti, M.
• Thaler, M.
• Fahr, L.
• Fischer, H.
• Varlamova, V.
• Gärtig, J.
• Nixdorf, D.
• Layritz, P.
• Marx, C.
• Hörth, C.
• Witte, C.
• Bulut, A.
• Illig, D.
• Senz, A. M.
• Holdt, L.
• Regel, I.
• Gottschlich, A.
• Subklewe, M.
• Mayerle, J.
• Anz, D.
• Kobold, S.
• Linder, A.
• Hornung, V.