Expanding Lung Cancer Immunotherapy by Using TCR-T cells
Abstract
Background: Lung cancer is a leading cause of cancer-related deaths in the United States and worldwide. Immune checkpoint drugs have been approved by U.S. Food Drug Administration (FDA) for the treatment of lung cancer. However, despite the impressive clinical response to immune checkpoint therapy, the majority of lung cancer patients do not respond to these drugs. To broaden the coverage of immune checkpoint immunotherapy, various combinations of immune checkpoint therapy with chemotherapies have been tested, but with unpredicted outcomes. Thus, novel immunotherapy approaches are urgently needed for metastatic lung cancer patients who do not respond to immune checkpoint therapy. We previously identified a protein called NY-ESO-1 as one of the most immunogenic antigens recognized by immune cells. Recent studies show that immunotherapy by engineering T cells for their specific recognition by the surface protein (called T cell receptor, TCR) led to a 55% clinical response rate in metastatic synovial sarcoma and melanoma and to 80% in myeloma without toxicity. However, NY-ESO-1 is expressed in only a fraction (10-15 %) of lung cancer samples, limiting its broad application in lung cancer. Our recent studies show that a new protein CT83 is highly expressed in approximately 50-70% of human lung cancer, but not in normal tissues with exception of testis. Thus, it is likely that CT83 can serve as an attractive immune target for immune cell-based immunotherapy for lung cancer. Areas of Emphasis: The proposal is designed to identify innovative strategies for the treatment of lung cancer. Hypothesis and Specific Aims: Despite the rapid progress in the field of immunotherapy, the majority of lung cancer patients still do not respond to immune checkpoint therapy. We therefore hypothesized that CT83 could serve as a specific cancer antigen marker for immune cells such as T cells for recognition and destruction of cancer cells. Furthermore, the maximal therapeutic immunity could be achieved by TCR-directed T cells alone or in combination with the immune checkpoint therapy. To test our hypotheses, we have recently generated CT83-specific TCRs and thus are well positioned to test our hypothesis in preclinical settings and translate our findings into early clinical application: Aim 1. To generate and improve MHC I- and II-restricted CT83 TCRs. Aim 2. To determine the potency and safety of CT83 TCR-T cell immunotherapy in animal models. Aim 3. To enhance CT83 TCR-T cell mediated therapeutic immunity by blockade of immune suppression. Upon the completion of the proposed studies, we are well prepared to produce GMP grade TCR master cell banks and viral particles products for IND application of a future phase I clinical trial in lung cancer. Dr. Nieva (Co-investigator) will facilitate the translation of preclinical studies into clinical trials for further development. Impact: This novel immunotherapy will help lung cancer patients who do not respond to immune checkpoint and/or chemotherapy through adoptive transfer of T cells with the ability to recognize cancer cells, but spare the normal cells. We will plan to initiate a phase I clinical trial for lung cancer patients. Due to strong specificity of engineered immune cell therapy, we expect that lung cancer patients will have great clinical benefits after receiving T cell therapy. To overcome the potential sides that may rise due to unexpected cross-reactivity of engineered T cells, we will investigate these possibilities in preclinical studies, thus providing solid foundation for us to continue our translational and clinical development of T cell immunotherapy against lung cancer. The short-term impact of this project is to identify innovative strategies for the treatment of lung cancer. The long-term impact of this project would likely open new opportunities for the treatment of lung cancer with TCR-T cell immunotherapy, leading to the development
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110335
Entities
People
- Rongfu Wang
Organizations
- United States Army
- University of Southern California