Immunotherapeutic Treatment for EBV-Associated Lymphomas
Abstract
To address the Fiscal Year 2019 (FY19) Peer Reviewed Cancer Research Program (PRCRP) Military Topic Areas immunotherapy and lymphoma, we will develop and test two new antibody treatment strategies as a combination treatment against lymphomas caused by infection with Epstein-Barr virus (EBV). In 2019, more than 82,500 new cases of lymphoma will be diagnosed in the United States alone. Great numbers of lymphomas have been reported among military personnel, due to exposures to chemicals, such as the herbicide Agent Orange used during the Vietnam War. Lymphomas associated with chemical exposures are often also associated with EBV, a cancer-causing virus that infects more than 90% of the population. Although the currently available treatments for lymphoma have led to improved survival, none of these treatments are specific for lymphomas that arise from EBV-infected cells. Non-specific treatments can result in numerous life-altering and life-threatening side effects, such as infertility, secondary cancers, and heart disease. Therefore, there is a dire need for treatments that will target EBV+ lymphomas specifically. Our objective is to develop a treatment that targets only EBV-infected cells, ensuring that only infected cells are killed and that the treatment does not cause side-effects from targeting healthy cells. To accomplish this objective, our first approach will take advantage of the unique properties of EBV-infected cells. Such cells have unique viral proteins exposed on the cell surface as well as inside the cell nucleus, which are not present in healthy cells. We will use an antibody that targets and binds to LMP2, a viral protein exposed on the surface of infected cells, as a means to target only infected cells. This antibody will be used as a drug delivery vehicle to carry a drug called P4 peptide. The P4 peptide targets EBNA1, a viral protein present in the nucleus of all EBV-infected cells. We will make an antibody-peptide conjugate by joining the LMP2 antibody to the P4 peptide. The LMP2 antibody will send the drug to EBV-infected cells, and once the P4 peptide enters the infected cells, it will bind to EBNA1, which will cause the infected cells to die. Our second approach is a treatment to target EBV directly to prevent further infection. When an EBV-infected cell dies, it releases new viruses into the blood, which can infect other healthy cells within the body. When this happens, the newly infected cells have the potential to become cancerous, causing a relapse of the lymphoma. To mop up any released viruses before they infect new cells, we will make antibodies that target three proteins expressed on the surface of EBV, called gp350, gH, and gL. These proteins are crucial for viral infection of different cell types in the body. We have developed a potent neutralizing antibody that targets gp350 to block EBV from infecting B cells and plan to develop a neutralizing antibody that targets gH and gL to block EBV from infecting epithelial and B cells. We will combine both antibodies to make a single, bi-specific neutralizing antibody (bi-nAb). Treatment with the bi-nAb will bind and kill any released EBV, clearing the virus from the body and preventing it from causing any new infections. By combining these two treatments, we expect that we will be able to treat EBV+ lymphomas in two ways. The antibody-peptide conjugate will target and kill EBV-infected cells and the bi-nAbs will prevent any new virus from infecting healthy cells. Over the next 2 years, we will develop and test these treatments in cells grown in the laboratory, as well as in mouse models. In the next 5 years, results from these laboratory studies will support early clinical trials in healthy adults. In the long term, to address the FY19 PRCRP Military Health Focus Areas Exposure risk factors associated with cancer and gaps in cancer treatment that have a profound impact on the health and well-being of military personnel, we expect our project to intro
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010613
Entities
People
- Javier Ogembo
Organizations
- Beckman Research Institute of City of Hope
- United States Army