Discovery of Immune Biomarkers That Predict Response to a Novel Chimeric Immuno-Oncolytic Virus Encoding Anti-PD-L1 in Gastric Cancer Peritoneal Carcinomatosis
Abstract
This proposal addresses the FY18 PRCRP Topic Area of stomach cancer, which (1) disproportionately affects our military personnel (active duty and Veterans alike); (2) is associated with military-relevant increased risk factors and exposures such as bacterial infection with H. pylori, Epstein-Barr Virus (EBV) infection, as well as tobacco consumption and excess radiation exposure; and (3) lacks effective therapies, especially for patients with the final stage of the disease that has spread to the peritoneal cavity. We have developed a novel anti-cancer agent for treating stomach cancer by creating a novel cancer-killing virus that selectively infects and directly kills cancer cells while leaving normal cells unharmed, which also promotes anti-cancer immune responses by producing a protein that disarms a mechanism of cancer protective immunity. More specifically, our novel virus CF33 is armed with an antibody against the immune-suppressive protein PD-L1 (anti-PD-L1). PD-L1 is expressed by cancers to suppress the body s own anti-cancer immunity s ability to fight off the tumor. Thus, anti-PD-L1 binds to and blocks PD-L1 and unleashes the body s own immune system s anti-tumor activity. We have learned that when cancer cell lines in the laboratory are exposed to this new virus, the cells respond with an increase in PD-L1 protein expression, which is the actual target of the anti-PD-L1 protein produced by our virus, CF33-anti-PD-L1. We then expect that our new virus expressing anti-PD-L1 will have an additional, stronger anti-cancer activity and therefore, be an effective therapeutic candidate against stomach cancer. However, what molecules and cells of the patient s stomach cancer are involved in CF33-anti-PD-L1 response has yet to be tested. We believe that there is a specific cellular composition or combination of molecules present in the patient s tumor and its surrounding immune cells that make them respond better to this virus. This is something we want to discover, as this knowledge will facilitate the development of new tests to find the patients who will have the greatest benefit from therapy with CF33-anti-PD-L1. To achieve this knowledge, we will study samples of stomach cancer cells from the peritoneum of stomach cancer patients and examine the composition of cells and molecules mediating immune cell communication and inflammation in the peritoneal tumor environment. We will also incubate patient samples with CF33-anti-PD-L1 and measure the virus s activity in killing cancer cells from gastric cancer patients in a test tube. Finally, the virus s tumor-killing activity index will be correlated with the molecules and cells that compose the patients samples to screen for the factors that indicate positive responses to the CF33-anti-PD-L1 virus. This study will also answer if stomach cancer that spreads to the peritoneal cavity can be treated by CF33-anti-PD-L1, and whether we can identify the cell types on a patient s sample that may indicate propensity to respond to CF33-anti-PD-L1 treatment, as well as other molecules that may be present in the tumor or immune cells from the peritoneal samples to impact the treatment response. The information we learn with this study will be critical for the design of subsequent clinical trials to bring CF33-anti-PD-L1 from the bench to the bedside of patients suffering from a currently incurable stage of stomach cancer. Importantly, a significant portion of our military personnel is at a greater risk of being affected by stomach cancer due to their increased exposure to the risk factors for stomach cancer highlighted above, especially those of Hispanic or Asian ethnicity, which are known to be disproportionately affected by stomach cancer. In particular, stomach cancer incidence in young Hispanic men (who make up about 15% of our military personnel) has been on the rise. Thus, our new therapeutic approach will be beneficial to the men and women who serve in our military a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910225
Entities
People
- Yanghee Woo
Organizations
- Beckman Research Institute of City of Hope
- United States Army