Scientists at the University of Texas MD Anderson Cancer Center report the development of an ultrasound-guided cancer immunotherapy platform that generates systemic antitumor immunity and improves the therapeutic efficacy of immune checkpoint blockade. The findings from the preclinical study “Cancer immunotherapy based on image-guided STING activation by nucleotide nanocomplex-decorated ultrasound microbubbles” appear in Nature Nanotechnology.

The Microbubble-assisted UltraSound-guided Immunotherapy of Cancer (MUSIC) approach employs nanocomplexes combined with microbubbles to deliver cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), an immunotransmitter involved in anticancer immunity, into antigen-presenting cells (APCs). Inside the APCs, the microbubbles release cGAMP to activate the GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which stimulates type I interferon responses that are essential for priming tumor-specific T cells.

“The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumor immunity through antigen-presenting cells (APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity, and rapid tissue clearance,” write the investigators.

Microbubbles are contrast agents for ultrasound. When the microbubbles are first injected, ultrasound scanners are used to image the tumor and localize where the microbubbles accumulate/distribute. Once the microbubbles are confirmed to be in the right place and within the tumors (aka no leakage etc.), the pulses are activated and the cargo from the bubbles are released. The platform provides an image-guided approach to activate the microbubbles and, hence, the immune system. [Wen Jiang, MD, PhD/University of Texas MD Anderson Cancer Center]

“Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2’3′-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumor growth in both localized and metastatic murine cancer models.

“Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumor immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.”

In the preclinical study, the MUSIC strategy demonstrated a complete tumor eradication rate of 60% when administered as monotherapy in breast cancer models. When combined with an anti-PD-1 antibody, MUSIC significantly improved antitumor responses with minimal toxicity effects, including enhanced primary tumor control and decreased systemic disease progression. In addition, the combination therapy demonstrated superior survival benefit, with a 76% increase in median survival compared to either therapy alone.

“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,” said Wen Jiang, MD, PhD, assistant professor of radiation oncology and the study’s co-senior author. “Our findings show that the MUSIC strategy is capable of paving the way toward novel image-guided strategies for targeted cancer immunotherapy.”

Immunotherapy has transformed cancer treatment, offering clinical benefits for patients with treatment-refractory metastatic cancers such as melanoma, non-small cell lung cancer, and renal cell cancer. However, not all patients respond to immune checkpoint blockade. Therefore, developing a more effective immunotherapy strategy to benefit larger numbers of cancer patients with localized and metastatic disease remains an unmet clinical need.

“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,” Jiang said. “This understanding has led to the development of new immunotherapies that target the regulators of innate immune systems, including the cGAS-STING pathway.”

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