Targeted Immunotherapy of Breast Cancer Brain Metastasis by Chimeric Antigen Receptor Macrophage
Abstract
Rationale, Objectives, and Aims Breast cancer is becoming a curative disease if it is diagnosed at an early stage; however, over 40,000 breast cancer patients still die every year in the U.S. More than 90% of breast cancer-related deaths are due to metastatic disease. According to an autopsy study, approximately 10%–15% of women with stage IV breast cancer develop brain metastases, although brain metastases are found in 30% of patients with advanced breast cancer. Brain metastasis profoundly affects cognitive and sensory functions as well as morbidity, with the 1-year survival rate being less than 20%; and the median survival time of such patients ranges from 3 to 6 months. Currently, there are only limited choices available to treat brain metastasis because most chemotherapeutic drugs cannot reach the tumor in the brain because blood vessels in the brain have special structures to prevent penetration of chemical drugs. Therefore, there is an urgent need to develop a better therapeutic approach to treat brain metastasis of breast cancer. Recent developments in immunotherapy have revolutionized cancer therapy; however, brain metastasis is mostly resistant to these treatments again because of the brain blood vessel structure. However, macrophages can readily penetrate into the brain tumor and eat up tumor cells. The objective of this study is to develop a novel therapeutic method by engineering macrophages to specifically target brain metastatic tumors. We hypothesize that chimeric antigen receptor macrophages (CARMA) specifically targeted mesothelin (MSLN) can block brain metastasis of breast cancer by exerting their functions of phagocytosis and the bystander effect. We also hypothesize that a combination of CARMA and stereotactic radiation significantly suppresses brain metastasis progression. To test this hypothesis, we will identify the optimum conditions for CARMA efficacy (Aim 1). In Aim 2, we will decipher the underlying mechanism of the CARMA-mediated bystander effect on cancer cells (Aim 2). In addition, we will test the efficacy of the combination of CARMA and radiation therapy for brain metastasis progression using our animal model (Aim 3). Which overarching challenge(s) does this research address? The ultimate goal of our study is to develop a novel immunotherapeutic approach for breast cancer brain metastasis using CARMA. Therefore, this project addresses the Overarching Challenges Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival, and Eliminate mortality associated with metastatic breast cancer. What types of patients will it help and how will it help them? We are developing a novel therapeutic approach for brain metastasis using macrophages. The target of this therapy is breast cancer patients with brain metastasis or risk of brain metastasis, such as triple-negative and Her2-positive patients. What are the potential clinical applications, benefits, and risks? We plan to bring our drug eventually to a clinical trial by targeting breast cancer patients who can benefit the most from this therapeutic approach. Engineered macrophages are very specific to tumors; therefore, the benefit/risk ratio will be very high. What is the projected time it may take to achieve a patient-related outcome? We plan to complete the proposed experiments over 3 years. We will then move to a clinical trial that may take as long as 5 years to obtain initial results. How will the proposed project lead to or make a breakthrough in breast cancer and accelerate progress toward the Breast Cancer Research Program’s (BCRP’s) mission of ending breast cancer? The goal of this project is to develop a novel therapeutic approach for treating patients with brain metastasis, for which there is no curative approach. Therefore, this project is in line with the BCRP’s mission to end breast cancer. If the research is too basic for clinical applicability, des
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210463
Entities
People
- Kounosuke Watabe
Organizations
- United States Army
- Wake Forest University