The recent success of immune checkpoint inhibitors (ICIs) for the treatment of refractory metastatic melanoma, lung and renal cell carcinoma has provided optimism that similar approaches could be generalized to a broader range of cancers. However, a large subset of cancer patients do not respond to ICIs as they harbor immunologically silent (or “cold”) tumors . Recent studies have shown that the activation of the innate immune sensor cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS-STING) promotes antigen presentation and T-cell activation, thus transforming cold tumors to immunologically responsive (or “hot”) tumors  [1]. However, because STING is a cytosolic protein and a key mediator of inflammation, activation of STING needs to be specific to antigen-presenting cells (APCs) in tumor tissues.

To address this technical challenge and meet the clinical need, a technology termed MUSIC (Microbubble-assisted Ultrasound-guided Immunotherapy of Cancer) was developed. MUSIC is a novel, first-in-class non-immunogenic platform for delivery of diverse therapeutic payload that utilizes gas-filled microbubbles (MBs) conjugated with APC-targeting antibodies, and conjugated with cationic biopolymers. This platform was first used to provide spatiotemporal control to activate STING by delivering the STING activator cGAMP  to APCs in a desired location under image-guidance.

Preliminary results show that, upon exposure to ultrasound, MUSIC produces robust STING activation and type I IFN responses in APCs and more efficiently primes antigen-specific CD4+ and CD8+ T cells in vitro. These immune stimulatory effects of MUSIC directly translated into antitumor responses in vivo, as MUSIC generated antitumor effects against syngeneic orthotopic primary (EO771) and metastatic (4T1) murine breast cancer models. Both models showed dramatic antitumor responses following local treatment of the primary tumor. Specifically, 6 out of 10 EO771 tumor-bearing animals were tumor-free after 50 days while 4T1 tumor-bearing mice exhibited a significant decrease of the systemic disease burden including lung metastases [2]. Succesful establishment of systemic immune memory following MUSIC treatments was also confirmed as mice rejected tumor cells upon re-challenge. No obvious toxicity was observed in these studies.

The efficacy of MUSIC was further confirmed in two syngeneic murine melanoma models (B16-F10 and D4M) with 100% of D4M-tumor bearing animals and 50% of B16-tumor-bearing animals achieving complete remission when treated with a combination of MUSIC and immune checkpoints inhibitors [3].

The MUSIC technology is now expanding for multiplexed delivery of a wide range of therapeutics with high spatial and temporal precision under US control to dramatically improve therapeutic response, enhance therapeutic index, and minimize or eliminate treatment-related side effects.

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Image/Figure Caption:

Microbubbles conjugated with anti-CD11b antibodies and cGAMP nanocomplexes target CD11b receptors on APCs and, under US exposure, deliver cGAMP and tumor antigens into the cytosol via sonoporation to activate STING and promote MHC-I mediated antigen presentation to enhance cytotoxic T lymphocytes (CTL) priming against cancer antigens.

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