Circular mRNA Vaccine Platform for Immunotherapy of Breast Cancer Dormancy
Abstract
Breast cancer mortality is mainly due to distant recurrence of the disease following successful treatment of early-stage breast cancer. The disease recurrences are usually because of the establishment of tumor dormancy following conventional cancer therapies. Since dormant tumor cells cannot be detected in cancer survivors, there is no treatment which can target and eliminate them in order to prevent their reawakening in the form of advanced stage disease. Because of the lack of any therapeutic or preventive intervention, cancer survivors have to go through stressful wait and watch for tumor recurrences. We propose to use a low-dose neoadjuvant chemotherapy (5-FU + Adriamycin + Cyclophosphamide), which is less toxic and more effective in inducing anti-tumor immune responses in patients with early-stage breast cancer. We will combine it with a first-in-class, potent, and orally bioavailable specific inhibitor of survival pathway in dormant tumor cells in order to eliminate them. We have discovered that dormant tumor cells that were established by chemotherapies, depend on a specific survival pathway named Bcl-xL. We will use an orally bioavailable inhibitor of Bcl-xL, A-1331852, to destroy dormant tumor cells in two animal models of spontaneous breast cancer (Aim 1). In addition, to achieve a long-lasting immunological memory for the prevention of secondary breast cancer as well as metastatic tumor recurrences in distant organs, we will design and test the efficacy of a personalized mRNA vaccine. We have developed a small circular mRNA (circRNA) platform for coding tumor neoantigens. The circRNA is highly stable and does not require the freezing temperature for storage and shipment. The vaccine will be given after the completion of neoadjuvant chemotherapy and surgical removal of primary breast cancer in two animal models of spontaneous breast cancer. The vaccine is expected to target both dormant tumor cells and otherwise actively dividing tumor cells or minimal residual disease (Aim 2). These two therapeutic strategies are less toxic than current conventional therapies and are expected to revolutionize treatment regimens by changing the current wait and watch approach in cancer survivors to active immunotherapy of breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210794
Entities
People
- Guizhi Zhu
Organizations
- United States Army
- Virginia Commonwealth University