Despite advances in the treatment of locally advanced cancers, patients with metastatic cancer often develop treatment resistance and succumb to the disease. Therefore, identifying new and effective treatment options for metastatic cancer is a major challenge and unmet clinical need. Cancer immunotherapy that targets the adaptive immune system such as immune checkpoint blockers has recently emerged as a revolutionary treatment for metastatic cancers. However, only a small subpopulation of patients benefits from immune checkpoint inhibitor treatment. There is now a realization that to improve the response rate of cancer patients to immunotherapy, stimulation of the innate immune system is al...

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Despite advances in the treatment of locally advanced cancers, patients with metastatic cancer often develop treatment resistance and succumb to the disease. Therefore, identifying new and effective treatment options for metastatic cancer is a major challenge and unmet clinical need. Cancer immunotherapy that targets the adaptive immune system such as immune checkpoint blockers has recently emerged as a revolutionary treatment for metastatic cancers. However, only a small subpopulation of patients benefits from immune checkpoint inhibitor treatment. There is now a realization that to improve the response rate of cancer patients to immunotherapy, stimulation of the innate immune system is also highly critical. As a result, agonists that target several innate immune regulators, including the STING pathway, are being investigated and already produced highly promising results. However, STING agonists such as cGAMP, cannot be easily administered into antigen presenting cells (APCs), which is needed to activate inflammatory response and generate antitumor immunity, thus severely limiting their clinical potential. We aim to address this major limitation by developing an innovative microbubble-assisted ultrasound-guided platform to efficiently deliver cGAMP into APCs to prime potent antitumor T cell responses. This technology platform, which we termed Microbubble-assisted Ultrasound-guided Immunotherapy of Cancer (MUSIC), comprises of a clinically approved microbubble ultrasound contrast agent that we engineered to carry cGAMP and specifically target immune cells. When applying ultrasound pulses with a clinical scanner, microbubbles will generate small transient pores on APC’s surface and release cGAMP directly into the cells to activate STING and down-stream pathways. If successful, our proposed research will overcome a major technical hurdle that is currently facing STING-targeted immunotherapy and greatly advance its progress towards clinical translation.

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