A novel microbubble platform for cancer immunotherapy

The innate immune sensor cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) has recently emerged as a potential therapeutic target to boost antitumor immune responses. However, STING is a cytoplasmic protein, and its natural activator cGAMP is a negatively charged dinucleotide that is difficult to deliver intracellularly. We have developed a new platform called Microbubble-assisted UltraSound (US)-guided Immunotherapy of Cancer (MUSIC) to activate STING with spatio-temporal control to treat cancer. MUSIC showed greater STING activation compared to cGAMP alone in vitro. In murine models,MUSIC showed dramatic tumor growth inhibition and increased survival in both syngeneic breast cancer models. The absence of antitumor immune responses in STING-/- mice shows that MUSIC action is STING-dependent. Furthermore, 6/10 MUSIC-treated mice were tumor-free versus 2/10 cGAMP-treated mice. All the rechallenged MUSIC-treated mice remained tumor-free 30 days after rechallenge. MUSIC also resulted in a 7-fold decrease in metastatic burden when compared to cGAMP alone. In summary, MUSIC showed efficient STING activation invitro. In addition, local MUSIC treatment of primary tumors produced systemic antitumor immune responses in vivo as well as anticancer immune memory preventing tumor growth upon rechallenge. We are now exploring the use of nanobubbles for systemic administration. [Work supported by CPRIT Grants RR150010 and RP190233. R.F.M. is a CPRIT Established Investigator.]