Maximizing CAR-T Cell Therapy for Lung Cancer via Metabolic Reprogramming
Abstract
The goal of this project is to develop an innovative and effective adoptive T cell therapy for the treatment of lung cancer. Lung cancer accounts for about one-fifth of all cancer-related deaths, with 80-85% classified as non-small cell lung cancer (NSCLC). For patients with metastatic NSCLC, only 6-10% live 5 years beyond diagnosis. The high mortality rate is largely due to the fact that most patients are diagnosed with advanced stage disease or are resistant to standard treatments including chemotherapy, targeted therapy, immunotherapy, and supporting care. Thus, there is a need for new therapies that could improve outcome for patients who fail current therapies, and which might ultimately reduce the incidence of long-term treatment-related complications in all patients. Adoptive T cell therapy would be an appealing addition to the current treatment armamentarium of lung cancer and other cancers because of its potential to selectively kill malignant cells effectively, thus reducing short and long-term side effects. Adoptive T cell therapy has represented an exciting breakthrough in the treatment of patients with hematologic malignancies leading to the FDA approval of three T cell therapies. In contrast, the antitumor activity of T cell therapy in solid tumors has been modest so far in clinical studies. This can be explained by limited T cell persistence and the immunosuppressive tumor microenvironment (TME). A key but largely overlooked problem of adoptive T cell therapy for solid tumors is nutrient competition between tumor cells and T cells in the nutrient-poor TME. The high nutrient demands of cancer cells can restrict the function of T cells through competition for nutrients and by producing immunosuppressive molecules. In this proposal, we will make the adoptive T cell therapy more powerful by providing T cells more energy. We have engineered the T cells to both produce a protein named CAR (chimeric antigen receptor) that recognizes a NSCLC specific antigen HER2 and secrete a protein named adenosine deaminase with the ability of converting immunosuppressive molecules (adenosine) to the nutrient (inosine), increasing the effectiveness of the T cells and their activation. We believe that this optimized adoptive T cell therapy will more effectively eradicate tumors than current adoptive T cell therapies. If this early translational study is successful, the adoptive T cell therapy will be further evaluated in a Phase 1 clinical trial in 3-4 years to treat patients with advanced HER2 positive NSCLC who fail current therapies. This study has direct relevance to military health since this early translation study will develop a lead therapeutic product for the treatment of military Service Members, Veterans, and their families with lung cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210701
Entities
People
- Xiaotong Song
Organizations
- Texas A&M Health Science Center
- United States Army