Researchers created ultrasound-guided microbubbles to enhance immunotherapy performance

The University of Texas MD Anderson Cancer Center scientists have created an ultrasound-guided cancer immunotherapy approach that promotes systemic antitumor immunity and increases immune checkpoint blockade therapeutic potential. Nature Nanotechnology published the results of the pioneering study.

The Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) methodology, which is a first-of-its-kind framework, uses nanocomplexes and microbubbles to give effective cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an immunotransmitter involved in anticancer immunity, into antigen-presenting cells (APCs).

The microbubbles produce cGAMP inside the APCs, which activates the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which induces type I interferon responses necessary for priming tumor-specific T cells.

When used as monotherapy in breast cancer models in a preclinical investigation, the MUSIC approach achieved a 60% full tumor elimination rate. MUSIC dramatically increased anticancer responses with low toxicity when coupled with an anti-PD-1 antibody, particularly improved primary tumor control and reduced systemic disease progression.

Furthermore, as contrasted to either therapy alone, the combined therapy showed a higher survival benefit, with a 76% improvement in median survival.

By investigating the mechanisms of action in producing a robust STING activation, we identified a new strategy to activate both the innate and adaptive antitumor immune responses. Our findings show that the MUSIC strategy is capable of paving the way toward novel image-guided strategies for targeted cancer immunotherapy.”

Wen Jiang, MD, PhD, Study Co-Senior Author and Assistant Professor, Radiation Oncology, University Of Texas MD Anderson Cancer Center

Immunotherapy has revolutionized cancer treatment, providing therapeutic improvements to patients with treatment-resistant metastatic tumors like melanoma, non-small cell lung cancer, and renal cell carcinoma.

Immune checkpoint blockade, however, does not work for many patients. As a result, creating a more powerful immunotherapy strategy that will help a larger percentage of cancer patients with both localized and metastatic disease remains an unmet medical requirement.

Although the majority of cancer immunotherapies have focused on boosting the adaptive branch of the body’s immune system, there has been a growing realization that both the innate and adaptive branches of the body’s immune system need to be engaged to generate optimal antitumoral immunity. This understanding has led to the development of new immunotherapies that target the regulators of innate immune systems, including the cGAS-STING pathway.”

Wen Jiang, MD, PhD, Study Co-Senior Author and Assistant Professor, Radiation Oncology, University Of Texas MD Anderson Cancer Center

Natural agonists, like cyclic dinucleotides, stimulate the cGAS-STING pathway, but clinical translation has been hampered by concerns about low cytosolic entry, serum stability, and systemic toxicity. To address these issues, Jiang and his colleagues created MUSIC, the first image-guided cancer immunotherapy method that employs antibody targeting to trigger STING in APCs via molecular drug delivery.

The scientists use ultrasound scanners to assess the tumor and precisely identify the site where the microbubbles have gathered since the microbubbles also act as contrast agents for ultrasonography.

After verifying that the microbubbles are linked to the tumors, the researchers employ ultrasonic frequencies to induce the microbubbles to oscillate and rupture, allowing nucleic acids to be transported straight into the cell cytoplasm.

The MUSIC platform is the first to attach nanocomplexes to microbubbles to transport cGAMP immunotransmitters directly into APCs. This technology, known as sonoporation, has already been utilized on tumor cells.

The beauty of our platform is that ultrasound machines are already clinically available in many outpatient settings and microbubbles are FDA-approved contrast agents for ultrasound imaging. Therefore, we expect there is a very real opportunity to translate MUSIC into a clinic application to benefit cancer patients.”

Wen Jiang, MD, PhD, Study Co-Senior Author and Assistant Professor, Radiation Oncology, University Of Texas MD Anderson Cancer Center

The microbubble technique of the MUSIC platform might be easily converted to nanoscale systems for targeted systemic administration and activation of innate immune sensors with image guidance for cancer immunotherapy purposes, according to Jiang.

“Our MUSIC platform is exciting because it provides a new framework for developing image-guided immunotherapy by using acoustically responsive biomaterials to enable efficiently, targeted, and robust immune activation to produce potent antitumor effects while minimizing systemic toxicity,” Jiang said.

Jiang also said, “The versatility of the MUSIC platform could potentially be applied to targeted delivery of other immune-stimulating agents, such as nucleotide-based vaccines, mRNAs, and other gene therapies for multiple human diseases.”