A Novel Targeted Therapy for Metastases from Triple-Negative Breast Cancer
Abstract
This application addresses the Overarching Challenges Eliminate the mortality associated with metastatic breast cancer and Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival under the FY21 BCRP Breakthrough Award Level 1. The ultimate applicability of the research is to cure/help cure patients with triple negative breast cancer (TNBC) by preventing and eliminating the metastases. The goal of this research is to radically minimize the deaths (90%) of TNBC patients caused by metastasis to other organs. No current therapies effectively prevent or stop metastases from breast cancer, particularly for TNBC, which is the most aggressive subtype and does not have a targeted therapy. We desire to change that situation. This application will develop the first targeted therapy for metastatic TNBC, in which the engineered macrophages will directly target TNBC to locally deliver TNF-alpha (TNFa), which cooperates with a small molecule compound called IAP antagonist (IAPa), to kill metastatic cancer specifically and effectively. The potential clinical application: The combined approach of the engineered macrophages and an IAPa will act as a novel adjuvant therapy for TNBC. After the primary BC is surgically resected, we will draw some blood from the patient to expand and engineer the macrophages. After 7-10 days, the engineered macrophages will be given back to the patient who will also receive an IAPa treatment for 2-3 weeks in order to eliminate all the remaining BC cells. Thus, the cancer will not recur or metastasize. Similarly, this adoptive macrophage combined with an IAPa could be used to treat advanced metastasis from TNBC. Several IAP antagonists have been confirmed safe in patients. The engineered macrophages just serve as a vector to deliver targeted TNFa and will not result in cytokine release syndrome like CAR-T cells. The macrophages are terminal, differentiated cells and cannot further proliferate. The engineered macrophages will disappear soon after cancer treatment since their life span is only months. In case of mild symptoms related to the engineered macrophages, the macrophages can be depleted by clodronate or the symptom can be mitigated by anti-TNF therapy. The projected time it may take to achieve a patient-related outcome: Upon completion of the proposed studies in mice, and if it is successful, we will spend 2 more years completing the biosafety evaluation, using a GMP (good manufacturing practice) level of engineered macrophage. We anticipate that 5 to 6 years from now, we will propose clinical trials to test its efficacy in combination with an IAPa to prevent and treat the metastasis from TNBC. The likely impact of this study is to advance BCRP s mission of ending breast cancer by, at least, reducing the mortality rate associated with TNBC. We may also develop engineered macrophages to target other subtypes of BC, such as Her2, in order to take another step toward ending breast cancer by preventing and eliminating BC metastasis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210049
Entities
People
- Zhenqiang Yao
Organizations
- United States Army
- University of Rochester