Enhancing Natural Killer Cell Efficacy Against Mesothelioma with Nanodepot-Based Tumor Priming and Evasion of TGF Beta-Mediated Suppression
Abstract
The overarching goal of this project is to develop a natural killer (NK) cell-based therapeutic for mesothelioma, which poses a disproportionately increased disease burden to Veterans, active-duty members of the US military, and their families, compared to the general population. Our proposal focuses directly on the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of “Mesothelioma” and “Immunotherapy” as well the FY19 PRCRP Military Health Focus Area of “Gaps in cancer treatment that may affect the general population but have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries.” Mesothelioma is a rare cancer of the mesothelium, the thin cell lining of the body’s internal organs, caused by prolonged asbestos exposure. The microscopic asbestos fibers enter the body through the lung, causing inflammation and scarring of the mesothelium, which can lead to the development of mesothelioma. Not only can direct asbestos exposure cause mesothelioma, but the residual asbestos fibers in an exposed person’s clothing can indirectly expose others (e.g., spouse, children), increasing their risk for mesothelioma development as well. Although the United States military has been phasing out the use of asbestos-containing products, the risk of asbestos exposure for military personnel and their families is still present, especially when serving in the Navy or in countries where the use of asbestos is less regulated. Due to the long delay between asbestos exposure and evidence of the disease (about 30 to 50 years), military personnel and their families exposed to asbestos remain at risk for developing mesothelioma. Presently, surgery, radiation therapy, and chemotherapy are standard treatments for patients with mesothelioma. However, the survival of people with mesothelioma 5 years after being diagnosed is poor (10 %). Hence, there is an urgent need for the development of novel therapies for these patients. In response to this need, we are developing an NK cell-based therapeutic for treating mesothelioma. NK cells are attractive immune cells for treating cancer because they possess the ability to kill tumor cells. However, the efficacy of NK cells for treating mesothelioma is limited by two factors: (1) their inability to effectively infiltrate mesothelioma tumors to elicit optimal tumor killing and (2) the secretion of the inhibitory factors like TGF-beta from tumor cells that inhibits NK cell function. We propose to enhance the efficacy of NK cells for the treatment of mesothelioma in a two-step process: (1) “priming” the mesothelioma tumor microenvironment (TME) to facilitate NK cell infiltration and (2) engineering NK cells to resist inhibition from TGF-beta. For priming the mesothelioma TME, we propose to attach the enzyme heparanase onto nanoparticles (Hep-NPs). Heparanase on the Hep-NPs serves to digest components of the tumor stroma, thus priming it for NK-cell infiltration and NK-cell killing of the tumor cells. Additionally, we will engineer TGF-beta-resistant and IL-15-expressing NK cells to elicit potent antitumor activity in the Hep-NP-primed mesothelioma TME. To confer resistance to TGF-beta, we utilize a dominant negative receptor, which would block the negative effects of TGF-beta, while IL-15 serves as an important factor that would help NK cell survive and proliferate after encounter with the tumor cells. In the short-term, successful completion will advance scientific insight into the combination of nanoparticles with gene-modified NK cells for more effectively treating mesothelioma. This will provide the impetus for further testing and development of our novel therapy for mesothelioma, which will facilitate our long-term goal of clinical translation of the therapy. Given the higher risk and disease burden associated with mesothelioma for Veterans, active-duty members of the US military, and their families,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010502
Entities
People
- Rohan Fernandes
Organizations
- George Washington University
- United States Army