Ultrasound-Guided Targeted STING Activation for Breast Cancer Immunotherapy
Abstract
Breast cancer is the most common cancer among women with approximately 250,000 patients diagnosed each year in the US. Among all breast cancer diagnoses, 10% are classified as stage IV disease, where the cancer has metastasized to distant organs. Compared to early-stage breast cancer, the prognosis for metastatic breast cancer patient is dismal with a 5-year relative survival rate of only 20%. Metastatic breast cancer is also more likely to be resistant to therapy as almost all patients with metastatic breast cancer eventually develop treatment resistance and succumb to the disease. Therefore, identifying new and effective treatment options for metastatic breast 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 including melanoma, non-small cell lung and renal cell carcinoma. The efficacy of cancer immunotherapy against breast cancer, however, has been limited, with only a subpopulation of patients with triple-negative breast cancer appearing to benefit in the case of immune checkpoint inhibitor treatment. Increasingly, there is 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 cytosolic DNA sensor cyclic GMP-AMP Synthase-Stimulator of Interferon Genes pathway (cGAS-STING) are now being investigated and produced highly promising results. However, STING agonists such as cyclic GMP-AMP (cGAMP), cannot easily penetrate into antigen presenting cells (APCs) cytosol, which is needed to activate inflammatory response and generate antitumor immunity, thus severely limiting their clinical potential. Our present proposal aims to address this major limitation of STING-targeted cancer immunotherapy by proposing 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 MUSIC, comprises of a clinically approved microbubble contrast agent modified to load cGAMP and to specifically target immune cells. When applying ultrasound pulses with a clinical scanner, the microbubbles will generate small transient pores on APC’s surface and release cGAMP directly into the cytosol to activate STING and down-stream pathways. We hypothesize that MUSIC represents an revolutionary way to deliver STING agonists into immune cells and provide an effective immunotherapy strategy to treat metastatic breast cancer. Furthermore, it can be combined with T cell therapies such as anti-PD-1 antibody to produce improved therapeutic effect across multiple breast cancer subtypes. Our preliminary experiments showed that MUSIC treatment can drastically improve the activation of STING and downstream inflammatory cascade in APCs. This led to the generation of more potent priming of antigen-specific T cells needed to eradicate the tumors. Our current study will test our overall hypothesis by using the following specific aims. In Aim 1, we will evaluate MUSIC treatment’s ability to activate STING and inhibit breast tumor growth in vivo. In Aim 2, we will determine the antitumor effect of MUSIC against metastatic breast cancers, and study whether MUSIC can be combined with anti-PD-1 therapy to produce more potent antitumor immune response. We will also evaluate the toxicity profile of the combination treatment in preparation for clinical trials. Cancer immunotherapy has revolutionized the way we treat patients with many types of cancers and patients diagnosed with previously terminal cancers can now achieve long-term remission. Our proposed research will further advance the field and provide new ways to boost the efficacy of cancer immunotherapy in breast cancer. If successful, our proposed resea
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110332
Entities
People
- Wen Jiang
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army