Focused Ultrasound-Mediated Mechanical Destruction to Enhance Therapeutic Responses in Metastatic Breast Cancer
Abstract
Breast cancer is the most common invasive cancer in females worldwide. It accounts for 16% of all female cancers and 22.9% of invasive cancers in women. In addition, 18.2% of all cancer deaths worldwide, including both males and females, are from breast cancer. The current standard therapies are inadequate to subvert the existing local and systemic immune suppression characteristic for patients with metastatic cancer. Current clinical evidence suggests that strategies aimed to elicit an anti-tumor immune response may be effective in advanced breast cancer, where tumor infiltration with T lymphocytes is associated with improved clinical outcome. However, until recently, such strategies have not demonstrated success despite tremendous efforts to harness the anti-tumor properties of the immune system. The redundancy within the multiple signaling pathways activated in breast cancer, along with the likelihood of drug resistance and immune tolerance, suggests that combination therapy strategies will be required for effective disease management. However, not all patients treated with immunotherapies demonstrate durable responses. Focused Ultrasound (FUS) is an emerging non-invasive therapeutic modality for localized treatment of cancers by using ultrasonic energy to target tissue without incisions or radiation. FUS can deliver high energies to cause coagulative necrosis (thermal-FUS) or it can deliver low energies to cause mechanical destruction. We hypothesize that low energy deposition into tumors by FUS will lead to mechanical damage to initiate an immune response through release of tumor antigens and enhancing immunogenic cell death (ICD). Further, we hypothesize that FUS combined with immune checkpoint (PD-1) inhibitors will enhance systemic therapeutic response to mediate rejection of both FUS-treated and untreated tumors (abscopal effect). However, just like other ablative techniques, the immune response induced by thermal FUS has been shown to be minimal. Mechanical FUS is thought to be more advantageous for inducing systemic immunity than thermal FUS or other ablative therapies because it could potentially release large amounts of non-ablated antigens, as well as immunogenic signals. Thus, this application addresses the following overarching challenge(s): “revolutionize treatment regimens by replacing them with ones that are more effective and less toxic” and “eliminate the mortality associated with metastatic breast cancer.” The above hypotheses will be tested in two specific aims: (1) Investigate the capacity of FUS to stimulate systemic and tumor infiltrating T cell responses in metastatic breast cancer. (2) Investigate effects of mechanical FUS in combination with PD-1 to control of metastatic breast cancer. The immune system does not mount an immune response against most breast cancers since cancer cells are not recognized as foreign cells. However, FUS treatment can unmask these cancer cells, making them recognizable by the host immune system. In this study, a single primary breast tumor site will receive mechanical FUS therapy to create stable and precisely controlled energy deposition to limit heating, along with administration of PD-1 inhibitors. We believe that this approach will increase the percentage of patients who will respond to immunotherapies by stimulating a breast cancer-specific systemic immune response. We envision a treatment that can immunize breast cancer patients against their own future metastases. The impact of the basic science advances of this project will be amplified through subsequent application in the development of clinically useful approaches for metastatic breast cancer therapy for all women around the world. Focused ultrasound ablation is already approved by the Food and Drug Administration for uterine fibroids, bone metastases, and prostate ablation; therefore, our study with promising results could be tried as a Phase I clinical trial within the next 2-3 y
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910595
Entities
People
- Kumari Andarawewa
Organizations
- United States Army
- University of Virginia