Intrapleural Conditioning to Reverse EMT in Metastatic Triple-Negative Breast Cancer Effusions
Abstract
Overarching Challenges: (1) Identify why some breast cancers become metastatic to the pleura; (2) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; (3) Eliminate the mortality associated with metastatic breast cancer Malignant pleural effusions (MPE) have a U.S. incidence of more than 150,000 cases per year and a life expectancy measured in months. Breast cancer constitutes approximately 26% of all malignant effusions, which in 2014 (a study published in 2020) accounted for more than $1.6 billion in hospitalization charges alone. In our institution, metastatic breast cancer accounts for approximately 37% of all MPE cases. We estimate a U.S. incidence of MPE in TNBC patients of 3,400 cases per year with an annual hospitalization cost of $84 million. Current standard of care treatment for breast cancer MPE is palliative, consisting of drainage, followed by systemic therapy (chemotherapy, endocrine, or immunotherapy). When TNBC metastasizes to the pleura, it is invariably accompanied by an influx of immune cells. Rather than combating the tumor, these immune cells are suppressed by the local pleural environment. We envision a new immunotherapy in which we drain immune cells from the pleura, activate them and re-instill them, while altering the immune environment of the pleural space to make it receptive and hospitable for these cells to survive and kill the tumor. The procedure that we envision has many advantages over engineered T-cell therapy, because pleural T cells recognize many varied and patient-specific tumor targets and the manufacturing is relatively fast and simple, therefore less expensive and potentially less risky than competing cellular therapeutics such as genetically engineered T cells. Although we plan on delivering these therapeutic T cells directly to the pleura, they can be expected to migrate to other metastatic sites. Administering therapeutic monoclonal antibody drugs such as tocilizumab, atezolizumab or nivolumab locally, to make the pleural environment receptive to antitumor responses, may mitigate adverse reactions that are common when these drugs are given intravenously. Lastly, the ability to repeatedly sample the metastatic environment of the pleura through catheters routinely used to drain the effusion will allow us to monitor pleural immune environment, measure whether we have changed it, and precisely determine how much drug should be administered and when. Providing a localized immunotherapeutic strategy based on the patient s own immune cells and repurposed FDA-approved drugs, we hope to generate effective antitumor responses that will target metastases throughout the body, ultimately eliminating the mortality associated with metastatic TNBC. What types of patients and how it will help them? This therapy will help patients with TNBC metastatic to the chest cavity. Immunotherapeutic monoclonal antibodies are effective in a proportion of metastatic TNBC patients, but not those with pleural effusions. We are working toward a new approach to immunotherapy that combines delivery of immunotherapy drugs into the pleural space with activating a patient s own cells and then reinfusing them. We hypothesize that the physical barriers that protect the metastatic tumor can be exploited to concentrate antibody-based drugs in the pleural space, aiding in re-educating the patient s immune cells. We envision that this approach has the potential to drive an effective immune response and break the cycle that promotes invasive tumor growth. What are the clinical applications, benefits, risks? The clinical application is to change the immune environment of the pleural space in TNBC patients with MPE in such a way that it supports and recruits an antitumor response. Although the approach that we are developing has not been tested in humans, there is good reason to believe that localized treatment will be well toler
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210009
Entities
People
- Vera Donnenberg
Organizations
- United States Army
- University of Pittsburgh