Exosomes from Mesenchymal Stem Cells for Treatment of Malignant Mesothelioma
Abstract
Military Relevance Focus Area: Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship that may affect the general population but have a particularly profound impact on the health and well-being of active duty Service members, Veterans, and their beneficiaries. The current application focuses on gaps in effective treatment for mesothelioma. Scientific Objective and Rationale: Malignant mesothelioma (MM) is an aggressive tumor that results from asbestos exposure and can present amongst military personnel and Veterans. MM is difficult to treat even with standard therapies like chemotherapy and surgery and the average survival after the onset of symptoms of the disease is unfortunately often less than 12 months. While surgery, radiotherapy, and chemotherapy have improved quality of life but have made little impact on survival with this tumor. Therefore, there is an immediate unmet need for more effective treatment approaches for this deadly disease. Exosomes are cell-derived natural manometric vesicles that are widely distributed in body fluids. Exosome-based nanometric vehicles have a number of advantages: they are non-toxic, non-immunogenic, and can be engineered to have robust delivery capacity and targeting specificity. Moreover, safety concerns for cell-free, exosome-based clinical trials will be milder than those relevant to live stem cell trials currently in progress, as mutagenicity and oncogenicity concerns will be null. We previously identified two subsets of mesenchymal stem cells (MSCs) which were characterized as anti-tumorigenic MSC1 and pro-tumorigenic MSC2. We hypothesize that exosomes from MSC1 and MSC2 contain distinct cargo materials and exercise anti-tumorigenic and pro-tumorigenic activities, respectively. Exosomes derived from antitumor MSCs are ingested by target cells and can transfer biological signals between local or distant cells and thus confer antitumor activities. This study is to generate a definitive preclinical dataset that support the advancement of exosome-based therapy into first-inhuman testing for malignant mesothelioma. Ultimate Applicability of Research: The ultimate applicability of this research is that an exosome-based therapy could be applied to the treatment of patients with MM. This new therapy could be applied to patients who undergo surgical disease reduction or their disease has recurred after standard chemotherapy or radiotherapy. The findings from this proposal in terms of exosome biology and the favorable effects on the tumor microenvironment will overcome the limitation of other current therapies in failure to target tumor mutagenicity and immune evasion and therefore will be potentially applicable to a myriad of solid tumors. The delivery of this work to the clinical setting is maximized by the fact that the active elements of this therapy can be accessed and approved for use in humans with this disease. Military Relevance: Approximately 1,000 Veterans per year are diagnosed with MM, and the long latency period of the disease makes it likely that MM will continue to be diagnosed in Veterans for many years to come. While Veterans represent 8% of the nation’s population, they comprise an astonishing 30% of all known mesothelioma deaths that have occurred in the U.S. This proposal is responsive to the FY19 PRCRP topic “mesothelioma” and addresses the Military Relevance Focus Area of “Gaps in cancer prevention, early detection/diagnosis, prognosis, treatment, and/or survivorship”. Our study, if successful, will increase the potential agents available to treat mesothelioma for Service personnel, Veterans and other military beneficiaries and to be applied to the disease to significantly prolong survival of the patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010545
Entities
People
- Huabiao Chen
Organizations
- Massachusetts General Hospital
- United States Army